Cytarabine amino-acid ester composition and application thereof

Abstract

The invention provides an oral administration composition combining a cytarabine amino-acid ester medicine and chidaridine, and belongs to the field of medicines. The invention provides a cytarabine amino-acid ester composition. The cytarabine amino-acid ester composition comprises cytarabine amino-acid ester or salt of the cytarabine amino-acid ester and chidaridine. In one aspect, the pharmaceutical composition of the present invention relates to a method for increasing the oral bioavailability of cytarabine by increasing the permeability of the small intestine. The compound has a more excellent effect of inhibiting the activity of cytidine deaminase, and the metabolism of cytarabine is reduced. The specific proportion effect of the pharmaceutical composition disclosed by the invention is superior to the effect of the combination of the non-cytarabine amino-acid ester prodrug and the chidaridine.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and in particular relates to a composition containing cytarabine amino acid ester prodrug and cytidine deaminase inhibitor and application thereof. Background Art

[0002] In humans and other organisms, cytidine deaminase deaminates natural aminopyrimidines, which can convert nucleoside analog drugs into inactive metabolites that inactivate them. Cytidine deaminase converts cytidine and deoxycytidine into uridine and deoxyuridine, respectively, by hydrolytic deamination. The conversion of cytosine compounds into uridine derivatives results in loss of therapeutic activity or increased side effects. Cytidine deaminase is highly expressed in the intestine and liver, and can therefore affect the bioavailability of therapeutic cytidine analogs.

[0003] Cytarabine (cas: 147-94-4), also known as Cytarabine in English, is a purine metabolic drug. It is converted into active cytarabine triphosphate in the body. Cytarabine triphosphate competitively inhibits DNA polymerase (including DNA polymerase-α and DNA polymerase-β. The inhibitory effect of the former affects DNA synthesis, while the latter affects DNA repair). In addition, cytarabine triphosphate can also be embedded in RNA and DNA, interfering with the elongation of long chains and the connection of newly synthesized DNA, thereby inhibiting tumor cell proliferation and promoting tumor cell apoptosis. However, the polarity of cytarabine molecules is very high, resulting in poor membrane permeability in the small intestine, making the oral bioavailability of cytarabine very low (about 20%). Therefore, the free hydroxyl group of cytarabine is modified to improve its oral bioavailability. However, cytarabine is rapidly deaminated in the human body to form ineffective uracil derivatives, resulting in cytarabine not being readily bioavailable.

[0004] Cedazuridine (CAS: 1141397-80-9), also known in English as Cedazuridine, has a chemical name of (4R)-2-deoxy-2,2-difluoro-3,4,5,6-tetrahydrouridine. It is a recently developed cytidine deaminase inhibitor and is used in combination with decitabine in clinical practice.

[0005] Current treatments using cytarabine require continuous parenteral injections over 120 hours due to its poor bioavailability when administered orally. Cytarabine amino acid esters with high oral bioavailability could reduce the burden of monthly, multi-day intravenous infusions or subcutaneous injections. Summary of the invention

[0006] In order to overcome the deficiencies of the prior art, the purpose of the present invention is to provide an oral administration composition of cytarabine amino acid ester drugs and cedaruridine, which reduces the metabolism of cytarabine and increases the oral bioavailability of cytarabine.

[0007] To solve the above problems, the technical solution adopted by the present invention is as follows: a cytarabine amino acid ester composition, the composition comprising cytarabine amino acid ester or a salt thereof, and cedaruridine; the cytarabine amino acid ester or a salt thereof is 5'-OL-cytarabine valine ester or a pharmaceutically acceptable salt thereof, 5'-OD-cytarabine valine ester or a pharmaceutically acceptable salt thereof, 5'-OL-cytarabine isoleucine ester or a pharmaceutically acceptable salt thereof, 5'-OL-cytarabine phenylalanine ester or a pharmaceutically acceptable salt thereof, 5'-OD-cytarabine phenylalanine ester or a pharmaceutically acceptable salt thereof, 5'-OL-cytarabine proline ester or a pharmaceutically acceptable salt thereof, 5'-OL-cytarabine tryptophan ester or a pharmaceutically acceptable salt thereof.

[0008] In the pharmaceutical composition of the present invention, cytarabine amino acid ester or its salt can be used in combination with cedaridine in any ratio calculated as cytarabine, especially in a mass ratio of 1:1-10, including but not limited to: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

[0009] In the pharmaceutical composition of the present invention, cytarabine amino acid ester or its salt can be used in combination with cedaridine in any ratio calculated as cytarabine, especially in a mass ratio of 1:0.0625-1, including but not limited to: 1:0.0625, 1:0.125, 1:0.25, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.

[0010] Alternatively, the mass ratio of 5'-OL-arabinoside valine ester or its salt to cedaridine is 1:1-10 based on arabinoside.

[0011] Alternatively, the mass ratio of 5'-OD-arabinoside valine ester or its salt to cedaridine is 1:1-10 based on arabinoside.

[0012] Alternatively, the mass ratio of 5'-OL-arabinoside isoleucine ester or its salt to cedaridine is 1:1-10 based on arabinoside.

[0013] Alternatively, the mass ratio of 5'-OL-arabinoside phenylalanine ester or its salt to cedaridine is 1:1-10 based on arabinoside.

[0014] Alternatively, the mass ratio of 5'-OD-arabinoside phenylalanine ester or its salt to cedaridine is 1:1-10 based on arabinoside.

[0015] Alternatively, the mass ratio of 5'-OL-arabinoside proline ester or its salt to cedaridine is 1:1-10 based on arabinoside.

[0016] Alternatively, the mass ratio of 5'-OL-arabinoside tryptophan ester or its salt to cedaridine is 1:1-10 based on arabinoside.

[0017] Preferably, in the pharmaceutical composition, the mass ratio of cytarabine amino acid ester or its salt to cedaridine is 1:0.0625-10, calculated as cytarabine; further, in the pharmaceutical composition, the mass ratio of cytarabine amino acid ester or its salt to cedaridine is 1:0.0625-5, calculated as cytarabine.

[0018] As a preferred technical solution of the present invention, in the pharmaceutical composition, the mass ratio of cytarabine amino acid ester or its salt to cedaridine is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1:4.75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0019] or 5'-OL-arabinoside valine ester or its salt, calculated as arabinoside and cedaridine, the mass ratio of the two is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1:4 .75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0020] or 5'-OD-arabinoside valine ester or its salt, calculated as arabinoside and cedaridine, the mass ratio of the two is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1:4 .75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0022] Or 5'-OL-arabinoside isoleucine ester or its salt is calculated as arabinoside and cedaridine, and the mass ratio of the two is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1: 4.75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0023] Or 5'-OL-arabinoside phenylalanine ester or its salt is calculated as arabinoside and cedaridine, and the mass ratio of the two is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1: 4.75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0024] Or 5'-OD-arabinoside phenylalanine ester or its salt is calculated as arabinoside and cedaridine, and the mass ratio of the two is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1: 4.75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0025] Or 5'-OL-arabinoside proline ester or its salt is calculated as arabinoside and cedaridine, and the mass ratio of the two is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1:4 .75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0026] or 5'-OL-arabinoside tryptophan ester or its salt, calculated as arabinoside and cedaridine, the mass ratio of the two is 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75, 1:4, 1:4.25, 1:4.5, 1:4 .75, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1:9.75, 1:10.

[0027] Alternatively, the mass ratio of 5'-OL-arabinoside valine ester or its salt to cedaridine is 1:0.1-1 based on arabinoside.

[0028] Alternatively, the mass ratio of 5'-OD-arabinoside valine ester or its salt to cedaridine is 1:0.1-1 based on arabinoside.

[0029] Alternatively, the mass ratio of 5'-OL-arabinoside isoleucine ester or its salt to cedaridine is 1:0.1-1 based on arabinoside.

[0030] Alternatively, the mass ratio of 5'-OL-arabinoside phenylalanine ester or its salt to cedaridine is 1:0.1-1 based on arabinoside.

[0031] Alternatively, the mass ratio of 5'-OD-arabinoside phenylalanine ester or its salt to cedaridine is 1:0.1-1 based on arabinoside.

[0032] Alternatively, the mass ratio of 5'-OL-arabinoside proline ester or its salt to cedaridine is 1:0.1-1 based on arabinoside.

[0033] Alternatively, the mass ratio of 5'-OL-arabinoside tryptophan ester or its salt to cedaridine is 1:0.1-1 based on arabinoside.

[0034] As a preferred technical solution of the present invention, in the pharmaceutical composition: the mass ratio of cytarabine amino acid ester or its salt to cedaruridine is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, or 1:1.

[0035] Or 5'-OL-arabinoside valine ester or its salt is calculated as arabinoside and cedaridine, and the mass ratio between the two is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0036] Or 5'-OD-arabinoside valine ester or its salt is calculated as arabinoside and cedaridine, and the mass ratio between the two is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0037] Or 5'-OL-arabinoside isoleucine ester or its salt, calculated as arabinoside and cedaridine, the mass ratio between the two is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0038] Or 5'-OL-arabinoside phenylalanine ester or its salt, calculated as arabinoside and cedaridine, the mass ratio between the two is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0039] Or 5'-OD-arabinoside phenylalanine ester or its salt, calculated as arabinoside and cedaridine, the mass ratio between the two is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0040] Or 5'-OL-arabinoside proline ester or its salt, calculated as arabinoside and cedaridine, the mass ratio between the two is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0041] Or 5'-OL-arabinoside tryptophan ester or its salt, calculated as arabinoside and cedaridine, the mass ratio between the two is 1:0.0625, 1:0.125, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.

[0042] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogenbisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid; and related inorganic and organic acids.

[0043] Preferably, in the cytarabine amino acid ester composition, the salt is: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromate, iodate, acetate, propionate, octanoate, acrylate, formate, isobutyrate, decanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0044] Pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

[0045] As a preferred technical solution of the present invention, in the pharmaceutical composition, the structure of 5'-OL-arabinoside valine ester hydrochloride is as follows:

[0046]

[0047] As a preferred technical solution of the present invention, in the pharmaceutical composition, the structure of 5'-OD-arabinocytosine valine ester hydrochloride is as follows:

[0048]

[0049] As a preferred technical solution of the present invention, in the pharmaceutical composition, the structure of 5'-OL-arabinoside isoleucine ester hydrochloride is as follows:

[0050]

[0051] As a preferred technical solution of the present invention, in the pharmaceutical composition, the structure of 5'-OL-arabinoside phenylalanine ester hydrochloride is as follows:

[0052]

[0053] As a preferred technical solution of the present invention, in the pharmaceutical composition, the structure of 5'-OD-cytarabine phenylalanine ester hydrochloride is as follows:

[0054]

[0055] As a preferred technical solution of the present invention, in the pharmaceutical composition, the structure of 5'-OL-arabinoside proline ester hydrochloride is as follows:

[0056]

[0057] As a preferred technical solution of the present invention, in the pharmaceutical composition, the structure of 5'-OL-arabinoside tryptophan ester hydrochloride is as follows:

[0058]

[0059] The present invention further provides the use of the aforementioned composition in preparing a drug for treating cancer. The present invention further provides the use of the aforementioned pharmaceutical composition in preparing a drug for treating hematological cancers and solid tumors.

[0060] Preferably, the cancer includes hematological tumors and solid tumors.

[0061] Preferably, the blood tumor includes myelodysplastic syndrome, leukemia and lymphoma.

[0062] Preferably, the leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, myeloproliferative neoplasms or chronic myelomonocytic leukemia.

[0063] Preferably, the solid tumors include pancreatic cancer, ovarian cancer, peritoneal cancer, lung cancer, breast cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast cancer, ovarian cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, head and neck malignancies, urinary system malignancies, endometrial cancer, cervical cancer, thyroid cancer, hepatoblastoma, Wilms' tumor and sarcoma.

[0064] In an embodiment of the present invention, the cancer is selected from hematological cancer and solid tumors. In some embodiments, the hematological cancer is selected from acute myeloid leukemia and chronic myeloid leukemia. In some embodiments, the solid tumor is selected from pancreatic cancer, ovarian cancer, non-small cell lung cancer and breast cancer.

[0065] The beneficial effects of the technical solution of the present invention are as follows: the pharmaceutical composition of the present invention is used to increase the oral bioavailability of cytarabine by increasing the permeability of the small intestine. It has a more excellent effect of inhibiting the activity of cytidine deaminase and reducing the metabolism of cytarabine. The specific ratio effect of the pharmaceutical composition of the present invention is better than the effect of the combination of non-cytarabine amino acid ester prodrug and cedaruridine. DETAILED DESCRIPTION

[0066] The present invention is further described in detail below with reference to the examples, but is not limited thereto. The raw materials used in the examples of the present invention are cytarabine, cytarabine amino acid ester, and cidaridine, and the mass of each substance used in the experiment is calculated based on the free concentration, that is, the free salt of cytarabine amino acid ester is calculated based on cytarabine.

[0067] Example 1: Pharmacokinetic Experiment

[0068] In the oral pharmaceutical composition of the present invention, when cytarabine is 5'-OL-cytarabine valine ester, in the form of a pharmaceutically acceptable salt 5'-OL-cytarabine valine ester hydrochloride, it is orally administered with cedaruridine in a ratio of 1:0.0625 / 1:0.125 / 1:0.25 / 1:0.5 / 1:1 / 1:4 / 1:10, and an ICR male mouse model is selected to demonstrate the ability of the compound combination of the present invention to enhance oral bioavailability.

[0069] 1.1 Trial drugs: cytarabine, 5'-OL-cytarabine valine ester hydrochloride, cedaruridine

[0070] 1.2 Trial Grouping

[0071] They are cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine valine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), cytarabine: cedaridine (po) = 1:1 group (5 mg / kg + 5 mg / kg), 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride / Cedaridine=1:0.25 group (5mg / kg+1.25mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine).

[0072] 1.3 Preparation:

[0073] Calculated as free base, a certain amount of drugs were weighed and dissolved in normal saline to prepare cytarabine (iv) group (1 mg / mL), cytarabine (po) group (0.25 mg / mL), 5'-OL-cytarabine valine ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), cytarabine: cedar uridine (po) = 1:1 group (0.25 mg / mL: 0.25 mg / mL), 5'-OL-cytarabine valine ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), Cytidine valine ester hydrochloride: cedar uridine = 1:0.0625 group (0.25mg / mL: 0.3125mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride: cedar uridine = 1:0.0625 group (0.25mg / mL: 0.015625mg / mL, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride: cedar uridine = 1:0.125 group (0.2 5mg / mL: 0.03125mg / mL, calculated as arabinoside), 5'-OL-arabinoside valine ester hydrochloride: cedaridine = 1:0.25 (0.25mg / mL: 0.0625mg / mL, calculated as arabinoside), 5'-OL-arabinoside valine ester hydrochloride: cedaridine = 1:0.5 (0.25mg / mL: 0.125mg / mL, calculated as arabinoside), 5'-OL-arabinoside valine ester hydrochloride: cedaridine = 1:0.5 (0.25mg / mL: 0.125mg / mL, calculated as arabinoside), Cytidine valine ester hydrochloride: cedaridine = 1:1 group (0.25 mg / mL: 0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride: cedaridine = 1:4 (0.25 mg / mL: 1 mg / mL, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride: cedaridine = 1:10 (0.25 mg / mL: 2.5 mg / mL, calculated as cytarabine).

[0074] 1.4 Dosage regimen

[0075] Male ICR mice (20 g ± 2 g) were randomly divided into 11 groups according to their body weight, with 5 mice in each group, including cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine valine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), cytarabine: cedaridine (po) = 1:1 group (5 mg / kg + 5 mg / kg), 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-Ara-Cytosine valine ester hydrochloride / cedaridine=1:0.25 group (5mg / kg+1.25mg / kg, calculated as ara-Cytosine), 5'-OL-Ara-Cytosine valine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as ara-Cytosine), 5'-OL-Ara-Cytosine valine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as ara-Cytosine), 5'-OL-Ara-Cytosine valine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as ara-Cytosine), 5'-OL-Ara-Cytosine valine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as ara-Cytosine). After administration, 100 μL of whole blood was collected from the retro-orbital venous plexus and placed in a heparinized EP tube with tetrahydrouridine (0.322 mM) added, centrifuged at 13,000 rpm for 5 min, and the upper plasma was collected to determine the concentrations of cytarabine and uridine arabinoside by HPLC-MS / MS.

[0076] 1.5 Experimental Results

[0077] 1.5.1 Pharmacokinetic parameters of cytarabine

[0078] Table 1 Example 1 Pharmacokinetic parameters of cytarabine

[0079]

[0080] Table 2 Pharmacokinetic parameters of uridine arabinoside in Example 1

[0081]

[0082]

[0083] 1.6 Conclusions of mouse pharmacokinetic experiments

[0084] As shown in Table 1, when the dosage was 5 mg / kg, the C max The results showed that the bioavailability of cytarabine was significantly improved after combined with cytarabine, and its AUC was increased by about 1.5 times compared with the cytarabine injection group, reflecting a good synergistic effect. The pharmacokinetic parameters of cytarabine in the in vivo mouse pharmacokinetic experiment showed that the combination of 5'-OL-cytarabine valine ester hydrochloride / cytarabine = 1:0.25 was superior to other ratio combinations.

[0085] As shown in Table 2, the C of the inactive metabolite arabinuridine in the group of 5'-OL-arabinoside valine ester hydrochloride / sidauridine = 1:0.25 is max The AUC was 4847±798nmol / L and the AUC was 10469±1431nmol·h / L, which was significantly lower than that of the Ara-C (iv) group and the 5'-OL-Ara-C valine ester hydrochloride (po) group. The pharmacokinetic parameters of uridine arabinoside showed that the 5'-OL-Ara-C valine ester hydrochloride / Cidarudin = 1:1 group had a good effect in inhibiting the metabolism of uridine arabinoside.

[0086] Embodiment 2:

[0087] In the oral pharmaceutical composition of the present invention, when cytarabine is 5'-OD-cytarabine valine ester, in the form of a pharmaceutically acceptable salt 5'-OD-cytarabine valine ester hydrochloride, it is orally administered with cedaruridine in a ratio of 1:0.0625 / 1:0.125 / 1:0.25 / 1:0.5 / 1:1 / 1:4 / 1:10, and an ICR male mouse model is selected to demonstrate the ability of the compound combination of the present invention to enhance oral bioavailability.

[0088] 2.1 Experimental drugs: cytarabine, 5'-OD-cytarabine valine ester hydrochloride, cedaridine

[0089] 2.2 Trial Grouping

[0090] The cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OD-cytarabine valine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine = 1:0.25 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine). / kg+1.25mg / kg, calculated as cytarabine), 5'-OD-arabinocytosine valine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OD-arabinocytosine valine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OD-arabinocytosine valine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OD-arabinocytosine valine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine).

[0091] 2.3 Preparation:

[0092] Calculated as free base, a certain amount of drugs were weighed and dissolved in normal saline to prepare cytarabine (iv) group (1 mg / mL), cytarabine (po) group (0.25 mg / mL), 5'-OD-cytarabine valine ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride: cedar uridine = 1:0.0625 group (0.25 mg / mL, calculated as cytarabine). g / mL: 0.3125mg / kg, calculated as cytarabine), 5'-OD-arabinoside valine ester hydrochloride: cedaridine = 1:0.0625 group (0.25mg / mL: 0.015625mg / mL, calculated as cytarabine), 5'-OD-arabinoside valine ester hydrochloride: cedaridine = 1:0.125 group (0.25mg / mL: 0.03125mg / mL, 5'-OD-arabinocytosine valine ester hydrochloride: cedaridine = 1:0.25 (0.25 mg / mL: 0.0625 mg / mL, calculated as arabinocytosine), 5'-OD-arabinocytosine valine ester hydrochloride: cedaridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, calculated as arabinocytosine), 5'-OD-arabinocytosine valine ester hydrochloride: cedaridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, calculated as arabinocytosine), 5'-OD-arabinocytosine valine ester hydrochloride: Cedaridine = 1:1 group (0.25 mg / mL: 0.25 mg / mL, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride: cedaridine = 1:4 (0.25 mg / mL: 1 mg / mL, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride: cedaridine = 1:10 (0.25 mg / mL: 2.5 mg / mL, calculated as cytarabine).

[0093] 2.4 Dosage regimen

[0094] Male ICR mice (20 g ± 2 g) were randomly divided into 10 groups according to their body weight, with 5 mice in each group, namely, cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OD-cytarabine valine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / Cedaridine=1:0.25 group (5mg / kg+1.25mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OD-cytarabine valine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine). After administration, 100 μL of whole blood was collected from the retro-orbital venous plexus and placed in a heparinized EP tube with tetrahydrouridine (0.322 mM) added, centrifuged at 13,000 rpm for 5 min, and the upper plasma was collected to determine the concentrations of cytarabine and uridine arabinoside by HPLC-MS / MS.

[0095] 2.5 Experimental Results

[0096] Table 3 Example 2 Cytarabine Pharmacokinetic Parameters

[0097]

[0098]

[0099] Table 4 Pharmacokinetic parameters of uridine arabinoside in Example 2

[0100]

[0101] 2.6 Pharmacokinetic results

[0102] As shown in Table 3, when the dosage was 5 mg / kg, the C maxThe C of the group with 5'-OD-arabinoside valine ester hydrochloride / Ciduridine = 1:0.25 was 2242 ± 324 nmol / L, Fab% (absolute bioavailability) and Frel% (relative bioavailability) were 31.12% and 133.3%, but significantly lower than that of the group with oral 5'-OL-arabinoside valine ester hydrochloride. max It was 7420±884nmol / L, Fab% and Frel% were 106.9% and 457.9%, indicating that the oral bioavailability of cytarabine increased after combined use with cedaridine, reflecting a good synergistic effect, but it was lower than the group of 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.25.

[0103] As shown in Table 4, the C of the inactive metabolite arabinuridine in the group of 5'-OL-arabinoside valine ester hydrochloride / sidauridine = 1:0.25 is max The results showed that the ratio of 5'-OL-arabinoside valine ester hydrochloride to sedacidine was 3036±1563nmol / L, and the AUC was 8878±1534nmol·h / L, which was significantly lower than that of the group taking 5'-OD-arabinoside valine ester hydrochloride alone. In summary, the in vivo mouse pharmacokinetic experiment showed that the combination of 5'-OL-arabinoside valine ester hydrochloride / sedacidine = 1:0.25 was superior to other ratio combinations in the same group, but lower than that of 5'-OL-arabinoside valine ester hydrochloride / sedacidine = 1:0.25.

[0104] Embodiment 3:

[0105] In the oral pharmaceutical composition of the present invention, when cytarabine is 5'-OL-cytarabine isoleucine ester, in the form of a pharmaceutically acceptable salt 5'-OL-cytarabine isoleucine ester hydrochloride, it is orally administered with cedaruridine in a ratio of 1:0.0625 / 1:0.125 / 1:0.25 / 1:0.5 / 1:1 / 1:4 / 1:10, and an ICR male mouse model is selected to demonstrate the ability of the compound combination of the present invention to enhance oral bioavailability.

[0106] 3.1 Trial drugs: cytarabine, 5'-OL-cytarabine isoleucine ester hydrochloride, cedaruridine

[0107] 3.2 Trial Grouping

[0108] The cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OD-cytarabine valine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:0.25 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine). / kg+1.25mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine).

[0109] 3.3 Preparation:

[0110] Calculated as free base, a certain amount of drugs were weighed and dissolved in normal saline to prepare cytarabine (iv) group (1 mg / mL), cytarabine (po) group (0.25 mg / mL), 5'-OL-cytarabine isoleucine ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride: cedar uridine = 1:0.0625 group (0.25 mg / mL, calculated as cytarabine). g / mL: 0.3125mg / kg, calculated as cytarabine), 5'-OL-arabinoside isoleucine ester hydrochloride: cedaridine = 1:0.0625 group (0.25mg / mL: 0.015625mg / mL, calculated as cytarabine), 5'-OL-arabinoside isoleucine ester hydrochloride: cedaridine = 1:0.125 group (0.25mg / mL: 0.03125mg / mL, 5'-OL-arabinocytidine isoleucine ester hydrochloride: cedaridine = 1:0.25 (0.25 mg / mL: 0.0625 mg / mL, calculated as arabinocytidine) 5'-OL-arabinocytidine isoleucine ester hydrochloride: cedaridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, calculated as arabinocytidine), 5'-OL-arabinocytidine isoleucine ester hydrochloride: cedaridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, calculated as arabinocytidine) Ciduridine = 1:1 group (0.25 mg / mL: 0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride: ciduridine = 1:4 (0.25 mg / mL: 1 mg / mL, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride: ciduridine = 1:10 (0.25 mg / mL: 2.5 mg / mL, calculated as cytarabine).

[0111] 3.4 Dosage regimen

[0112] Male ICR mice (20 g ± 2 g) were randomly divided into 10 groups according to their body weight, with 5 mice in each group, namely, cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine isoleucine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:0.25 group (5mg / kg + 1.25mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:0.5 group (5mg / kg + 2.5mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:1 group (5mg / kg + 5mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:4 group (5mg / kg + 20mg / kg, calculated as cytarabine), 5'-OL-cytarabine isoleucine ester hydrochloride / cedaridine = 1:10 group (5mg / kg + 50mg / kg, calculated as cytarabine). After administration, 100 μL of whole blood was collected from the retro-orbital venous plexus and placed in a heparinized EP tube with tetrahydrouridine (0.322 mM) added, centrifuged at 13,000 rpm for 5 min, and the upper plasma was collected to determine the concentrations of cytarabine and uridine arabinoside by HPLC-MS / MS.

[0113] 3.5 Experimental Results

[0114] Table 5 Example 3 Cytarabine Pharmacokinetic Parameters

[0115]

[0116]

[0117] Table 6 Pharmacokinetic parameters of uridine arabinoside in Example 3

[0118]

[0119] 3.6 Conclusions of mouse pharmacokinetic experiments

[0120] As shown in Table 5, when the dosage was 5 mg / kg, the C maxThe Fab% (absolute bioavailability) and Frel% (relative bioavailability) were 32.13% and 138.1%, respectively. However, the oral bioavailability of cytarabine was not improved compared with that of the 5'-OL-cytarabine valine ester hydrochloride (po) group. The C max It was 8919±1469nmol / L, Fab% and Frel% were 110.3% and 474.2%, indicating that the oral bioavailability of cytarabine increased after combined use with cedaridine, reflecting a good synergistic effect, but it was still lower than the 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.25 group.

[0121] As shown in Table 6, the C of the inactive metabolite arabinuridine in the oral 5'-OL-arabinoside isoleucine ester / sidauridine = 1:0.25 group was max The ratio of 5'-OL-arabinoside isoleucine ester hydrochloride / sidauridine = 1:0.25 was superior to other ratio combinations in the same group, but lower than the group of 5'-OL-arabinoside valine ester hydrochloride / sidauridine = 1:0.25.

[0122] Example 4: Pharmacokinetic Experiment

[0123] In the oral pharmaceutical composition of the present invention, when cytarabine is 5'-OL-cytarabine phenylalanine ester, in the form of a pharmaceutically acceptable salt 5'-OL-cytarabine phenylalanine ester hydrochloride, it is orally administered with cedaruridine in a ratio of 1:0.0625 / 1:0.125 / 1:0.25 / 1:0.5 / 1:1 / 1:4 / 1:10, and an ICR male mouse model is selected to demonstrate the ability of the compound combination of the present invention to enhance oral bioavailability.

[0124] 4.1 Trial drugs: cytarabine, 5'-OL-cytarabine phenylalanine ester hydrochloride, cedaruridine

[0125] 4.2 Experimental Grouping

[0126] The cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine phenylalanine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.25 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine). / kg+1.25mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine).

[0127] 4.3 Preparation:

[0128] Calculated as free base, a certain amount of drugs were weighed and dissolved in normal saline to prepare cytarabine (iv) group (1 mg / mL), cytarabine (po) group (0.25 mg / mL), 5'-OL-cytarabine phenylalanine ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride: cedar uridine = 1:0.0625 group (0.25 mg / mL, calculated as cytarabine). g / mL: 0.3125mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride: cedaridine = 1:0.0625 group (0.25mg / mL: 0.015625mg / mL, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride: cedaridine = 1:0.125 group (0.25mg / mL: 0.03125mg / mL, 5'-OL-Ara-Cytosine Phenylalanine Ester Hydrochloride: Ciduridine = 1:0.25 (0.25 mg / mL: 0.0625 mg / mL, based on cytosine) 5'-OL-Ara-Cytosine Phenylalanine Ester Hydrochloride: Ciduridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, based on cytosine) 5'-OL-Ara-Cytosine Phenylalanine Ester Hydrochloride: Ciduridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, based on cytosine) Ciduridine = 1:1 group (0.25 mg / mL: 0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride: ciduridine = 1:4 (0.25 mg / mL: 1 mg / mL, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride: ciduridine = 1:10 (0.25 mg / mL: 2.5 mg / mL, calculated as cytarabine).

[0129] 4.4 Dosage regimen

[0130] Male ICR mice (20 g ± 2 g) were randomly divided into 10 groups according to their body weight, with 5 mice in each group, namely, cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine phenylalanine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / Cedaridine=1:0.25 group (5mg / kg+1.25mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OL-cytarabine phenylalanine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine). After administration, 100 μL of whole blood was collected from the retro-orbital venous plexus and placed in a heparinized EP tube with tetrahydrouridine (0.322 mM) added, centrifuged at 13,000 rpm for 5 min, and the upper plasma was collected to determine the concentrations of cytarabine and uridine arabinoside by HPLC-MS / MS.

[0131] 4.5 Experimental Results

[0132] Table 7 Example 4 Cytarabine Pharmacokinetic Parameters

[0133]

[0134] Table 8 Pharmacokinetic parameters of uridine arabinoside in Example 4

[0135]

[0136]

[0137] 4.6 Conclusions of mouse pharmacokinetic experiments

[0138] As shown in Table 7, when the dosage was 5 mg / kg, the C maxThe bioavailability of 5'-OL-arabinoside valine ester hydrochloride (po) group was 2091±776 nmol / L, Fab% (absolute bioavailability, %) and Frel% (relative bioavailability, %) were 27.62% and 114.7%, respectively. However, the bioavailability of 5'-OL-arabinoside valine ester hydrochloride (po) group was not improved. The C max It was 7535±1034nmol / L, Fab% and Frel% were 104.3% and 433.1%, indicating that the oral bioavailability of cytarabine increased after combined use with sidauridine, reflecting a good synergistic effect, but it was lower than the group of 5'-OL-cytarabine valine ester hydrochloride / sidauridine = 1:0.25.

[0139] As shown in Table 8, the C of the inactive metabolite arabinuridine in the oral 5'-OL-arabinoside phenylalanine ester / sidauridine = 1:1 group max The AUC was 2973±699nmol / L and 7978±1137nmol·h / L, which were lower than those in the cytarabine (iv) group and the 5'-OL-cytarabine phenylalanine ester (po) group. In summary, the in vivo mouse pharmacokinetic experiment showed that the combination of 5'-OL-cytarabine phenylalanine ester hydrochloride / sidauridine = 1:0.25 was superior to other ratio combinations in the same group, but lower than the 5'-OL-cytarabine valine ester hydrochloride / sidauridine = 1:0.25 group.

[0140] Example 5: Pharmacokinetic Experiment

[0141] In the oral pharmaceutical composition of the present invention, when cytarabine is 5'-OD-cytarabine phenylalanine ester, in the form of a pharmaceutically acceptable salt 5'-OD-cytarabine phenylalanine ester hydrochloride, it is orally administered with cedaruridine in a ratio of 1:0.0625 / 1:0.125 / 1:0.25 / 1:0.5 / 1:1 / 1:4 / 1:10, and an ICR male mouse model is selected to demonstrate the ability of the compound combination of the present invention to enhance oral bioavailability.

[0142] 5.1 Experimental drugs: cytarabine, 5'-OD-cytarabine phenylalanine ester hydrochloride, cedaruridine

[0143] 5.2 Trial Grouping

[0144] The results were as follows: cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OD-cytarabine phenylalanine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.25 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine). g / kg+1.25mg / kg, calculated as cytarabine) 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine).

[0145] 5.3 Preparation:

[0146] Calculated as free base, a certain amount of drugs were weighed and dissolved in normal saline to prepare cytarabine (iv) group (1 mg / mL), cytarabine (po) group (0.25 mg / mL), 5'-OD-cytarabine phenylalanine ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride: cedar uridine = 1:0.0625 group (0.25 mg / mL, calculated as cytarabine). g / mL: 0.3125mg / kg, calculated as cytarabine), 5'-OD-arabinoside phenylalanine ester hydrochloride: cedaridine = 1:0.0625 group (0.25mg / mL: 0.015625mg / mL, calculated as cytarabine), 5'-OD-arabinoside phenylalanine ester hydrochloride: cedaridine = 1:0.125 group (0.25mg / mL: 0.03125mg / mL, 5'-OD-Ara-Cytosine Phenylalanine Ester Hydrochloride: Ciduridine = 1:0.25 (0.25 mg / mL: 0.0625 mg / mL, based on cytosine) 5'-OD-Ara-Cytosine Phenylalanine Ester Hydrochloride: Ciduridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, based on cytosine) 5'-OD-Ara-Cytosine Phenylalanine Ester Hydrochloride: Ciduridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, based on cytosine) Ciduridine = 1:1 group (0.25 mg / mL: 0.25 mg / mL, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride: ciduridine = 1:4 (0.25 mg / mL: 1 mg / mL, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride: ciduridine = 1:10 (0.25 mg / mL: 2.5 mg / mL, calculated as cytarabine).

[0147] 5.4 Dosage regimen

[0148] Male ICR mice (20 g ± 2 g) were randomly divided into 10 groups according to their body weight, with 5 mice in each group, namely, cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OD-cytarabine phenylalanine ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / Cedaridine=1:0.25 group (5mg / kg+1.25mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OD-cytarabine phenylalanine ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine). After administration, 100 μL of whole blood was collected from the retro-orbital venous plexus and placed in a heparinized EP tube with tetrahydrouridine (0.322 mM) added, centrifuged at 13,000 rpm for 5 min, and the upper plasma was collected to determine the concentrations of cytarabine and uridine arabinoside by HPLC-MS / MS.

[0149] 5.5 Experimental Results

[0150] Table 9 Example 5 Cytarabine Pharmacokinetic Parameters

[0151]

[0152] Table 10 Pharmacokinetic parameters of uridine arabinoside in Example 5

[0153]

[0154] 5.6 Conclusions of mouse pharmacokinetic experiments

[0155] As shown in Table 9, when the dosage was 5 mg / kg, the C maxThe bioavailability of the drug was 2021±425 nmol / L, and the Fab% (absolute bioavailability) and Frel% (relative bioavailability) were 25.38% and 103.1%, respectively. However, the bioavailability of the drug was not improved compared with that of the 5'-OL-arabinoside valine ester hydrochloride (po) group. The C max It was 7853±1208nmol / L, Fab% and Frel% were 98.00% and 368.7%, indicating that the oral bioavailability of cytarabine increased after combined use with cedaridine, reflecting a good synergistic effect, but it was lower than the group of 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.25.

[0156] As shown in Table 10, the C of the inactive metabolite arabinuridine in the oral administration group of 5'-OD-arabinoside phenylalanine ester / sidauridine = 1:0.25 was max The AUC was 2643±841nmol / L and 6868±1351nmol·h / L, which were lower than those in the cytarabine (iv) group and the 5'-OL-cytarabine phenylalanine ester (po) group. In summary, the in vivo mouse pharmacokinetic experiment showed that the combination of 5'-OL-cytarabine phenylalanine ester hydrochloride / sidauridine = 1:0.25 was superior to other ratio combinations in the same group, but lower than the 5'-OL-cytarabine valine ester hydrochloride / sidauridine = 1:0.25 group.

[0157] Embodiment 6:

[0158] In the oral pharmaceutical composition of the present invention, when cytarabine is 5'-OL-cytarabine proline ester, in the form of a pharmaceutically acceptable salt 5'-OL-cytarabine proline ester hydrochloride, it is orally administered with cedaruridine in a ratio of 1:0.0625 / 1:0.125 / 1:0.25 / 1:0.5 / 1:1 / 1:4 / 1:10, and an ICR male mouse model is selected to demonstrate the ability of the compound combination of the present invention to enhance oral bioavailability.

[0159] 6.1 Trial drugs: cytarabine, 5'-OL-cytarabine proline ester hydrochloride, cedaridine

[0160] 6.2 Trial Grouping

[0161] The cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine proline ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine = 1:0.25 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine). g / kg+1.25mg / kg, calculated as cytarabine) 5'-OL-arabinoside proline ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OL-arabinoside proline ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OL-arabinoside proline ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OL-arabinoside proline ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine).

[0162] 6.3 Preparation

[0163] Calculated as free base, a certain amount of drugs were weighed and dissolved in normal saline to prepare cytarabine (iv) group (1 mg / mL), cytarabine (po) group (0.25 mg / mL), 5'-OL-cytarabine proline ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride: cedar uridine = 1:0.0625 group (0.25 mg / mL, calculated as cytarabine). g / mL: 0.3125mg / kg, calculated as cytarabine), 5'-OL-arabinoside proline ester hydrochloride: cedaridine = 1:0.0625 group (0.25mg / mL: 0.015625mg / mL, calculated as cytarabine), 5'-OL-arabinoside proline ester hydrochloride: cedaridine = 1:0.125 group (0.25mg / mL: 0.03125mg / mL , calculated as cytarabine), 5'-OL-arabinoside proline ester hydrochloride: cedaridine = 1:0.25 (0.25 mg / mL: 0.0625 mg / mL, calculated as cytarabine) 5'-OL-arabinoside proline ester hydrochloride: cedaridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, calculated as cytarabine), 5'-OL-arabinoside proline ester hydrochloride: Ciduridine = 1:1 group (0.25 mg / mL: 0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride: ciduridine = 1:4 (0.25 mg / mL: 1 mg / mL, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride: ciduridine = 1:10 (0.25 mg / mL: 2.5 mg / mL, calculated as cytarabine).

[0164] 6.4 Dosage Regimen

[0165] Male ICR mice (20 g ± 2 g) were randomly divided into 10 groups according to their body weight, with 5 mice in each group, namely, cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine proline ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / Cedaridine=1:0.25 group (5mg / kg+1.25mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OL-cytarabine proline ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine). After administration, 100 μL of whole blood was collected from the retro-orbital venous plexus and placed in a heparinized EP tube with tetrahydrouridine (0.322 mM) added, centrifuged at 13,000 rpm for 5 min, and the upper plasma was collected to determine the concentrations of cytarabine and uridine arabinoside by HPLC-MS / MS.

[0166] 6.5 Test results

[0167] Table 11 Example 6 Cytarabine Pharmacokinetic Parameters

[0168]

[0169]

[0170] Table 12 Pharmacokinetic parameters of uridine arabinoside in Example 6

[0171]

[0172] 6.6 Conclusions of mouse pharmacokinetic experiments

[0173] As shown in Table 11, when the dosage was 5 mg / kg, the C maxThe bioavailability of the drug was 2140±742 nmol / L, and the Fab% (absolute bioavailability) and Frel% (relative bioavailability) were 28.07% and 108.3%, respectively. However, the bioavailability of the drug was not improved compared with the oral administration of 5'-OL-arabinoside valine ester hydrochloride. The C max It was 7485±1457nmol / L, Fab% and Frel% were 97.04% and 374.4%, indicating that the oral bioavailability of cytarabine increased after combined use with cedaridine, reflecting a good synergistic effect, but was lower than the group of 5'-OL-cytarabine valine ester hydrochloride / cedaridine = 1:0.25.

[0174] As shown in Table 12, the C of the inactive metabolite arabinuridine in the oral administration group of 5'-OL-arabinoside proline ester / sidauridine = 1:0.25 was max The results showed that the ratio of 5'-OL-arabinoside proline ester hydrochloride / sidauridine = 1:0.25 was better than that of the other ratios in the same group, but lower than that of 5'-OL-arabinoside valine ester hydrochloride / sidauridine = 1:0.25.

[0175] Embodiment 7:

[0176] In the oral pharmaceutical composition of the present invention, when cytarabine is 5'-OL-cytarabine tryptophan ester, in the form of a pharmaceutically acceptable salt 5'-OL-cytarabine tryptophan ester hydrochloride, it is orally administered with cedaruridine in a ratio of 1:0.0625 / 1:0.125 / 1:0.25 / 1:0.5 / 1:1 / 1:4 / 1:10, and an ICR male mouse model is selected to demonstrate the ability of the compound combination of the present invention to enhance oral bioavailability.

[0177] 7.1 Trial drugs: cytarabine, 5'-OL-cytarabine tryptophan ester hydrochloride, cedaridine

[0178] 7.2 Trial Grouping

[0179] The cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine tryptophan ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride / cedaridine = 1:0.25 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine). g / kg+1.25mg / kg, calculated as cytarabine) 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine=1:0.5 group (5mg / kg+2.5mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine=1:1 group (5mg / kg+5mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine=1:4 group (5mg / kg+20mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine=1:10 group (5mg / kg+50mg / kg, calculated as cytarabine).

[0180] 7.3 Preparation:

[0181] Calculated as free base, a certain amount of drugs were weighed and dissolved in normal saline to prepare cytarabine (iv) group (1 mg / mL), cytarabine (po) group (0.25 mg / mL), 5'-OL-cytarabine tryptophan ester hydrochloride (po) group (0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride: cedar uridine = 1:0.0625 group (0.25 mg / mL, calculated as cytarabine). g / mL: 0.3125mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride: cedaridine = 1:0.0625 group (0.25mg / mL: 0.015625mg / mL, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride: cedaridine = 1:0.125 group (0.25mg / mL: 0.03125mg / mL , calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride: cedaridine = 1:0.25 (0.25 mg / mL: 0.0625 mg / mL, calculated as cytarabine) 5'-OL-arabinoside tryptophan ester hydrochloride: cedaridine = 1:0.5 (0.25 mg / mL: 0.125 mg / mL, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride: Ciduridine = 1:1 group (0.25 mg / mL: 0.25 mg / mL, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride: ciduridine = 1:4 (0.25 mg / mL: 1 mg / mL, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride: ciduridine = 1:10 (0.25 mg / mL: 2.5 mg / mL, calculated as cytarabine).

[0182] 7.4 Dosage Regimen

[0183] Male ICR mice (20 g ± 2 g) were randomly divided into 10 groups according to their body weight, with 5 mice in each group, namely, cytarabine (iv) group (5 mg / kg), cytarabine (po) group (5 mg / kg), 5'-OL-cytarabine tryptophan ester hydrochloride (po) group (5 mg / kg, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride / cedaridine = 1:0.0625 group (5 mg / kg + 0.3125 mg / kg, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride / cedaridine = 1:0.125 group (5 mg / kg + 0.625 mg / kg, calculated as cytarabine), 5'-OL-cytarabine tryptophan ester hydrochloride / cedaridine = 1:0.25 group (5mg / kg + 1.25mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine = 1:0.5 group (5mg / kg + 2.5mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine = 1:1 group (5mg / kg + 5mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine = 1:4 group (5mg / kg + 20mg / kg, calculated as cytarabine), 5'-OL-arabinoside tryptophan ester hydrochloride / cedaridine = 1:10 group (5mg / kg + 50mg / kg, calculated as cytarabine). After administration, 100 μL of whole blood was collected from the retro-orbital venous plexus and placed in a heparinized EP tube with tetrahydrouridine (0.322 mM) added, centrifuged at 13,000 rpm for 5 min, and the upper plasma was collected to determine the concentrations of cytarabine and uridine arabinoside by HPLC-MS / MS.

[0184] 7.5 Experimental Results

[0185] Table 13 Example 7 Pharmacokinetic parameters of cytarabine

[0186]

[0187] Table 14 Pharmacokinetic parameters of uridine arabinoside in Example 7

[0188]

[0189] 7.6 Conclusions of mouse pharmacokinetic experiments

[0190] As shown in Table 13, when the dosage was 5 mg / kg, the C maxThe Fab% (absolute bioavailability) and Frel% (relative bioavailability) were 2369±752nmol / L, 26.14% and 102.5% respectively, but the oral bioavailability of cytarabine was not improved compared with the 5'-OL-cytarabine valine ester hydrochloride (po) group. The C max It was 6869±1035nmol / L, Fab% and Frel% were 88.63% and 347.3%, indicating that the oral bioavailability of cytarabine increased after combined use with cedaruridine, reflecting a good synergistic effect, but it was lower than the group of 5'-OL-cytarabine valine ester hydrochloride / cedaruridine = 1:0.25.

[0191] As shown in Table 14, the C of the inactive metabolite arabinuridine in the group of 5'-OL-arabinoside tryptophan ester / sidauridine = 1:0.25 is max The ratio of 5'-OL-arabinoside tryptophan ester hydrochloride / sidauridine = 1:0.25 was better than that of other ratio combinations, but lower than that of 5'-OL-arabinoside valine ester hydrochloride / sidauridine = 1:0.25.

[0192] In addition to the hydrochloride of cytarabine amino acid ester, the inventors also prepared a variety of other salt forms and found that except for cytarabine amino acid ester, various salts have good solubility and similar medicinal effects.

[0193] All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference.

Claims

1. A cytarabine amino acid ester composition, characterized in that: The composition comprises cytarabine amino acid ester or a salt thereof, and cedaridine; the cytarabine amino acid ester or a salt thereof is 5'-OL-cytarabine valine ester or a pharmaceutically acceptable salt thereof, 5'-OD-cytarabine valine ester or a pharmaceutically acceptable salt thereof, 5'-OL-cytarabine isoleucine ester or a pharmaceutically acceptable salt thereof, 5'-OL-cytarabine phenylalanine ester or a pharmaceutically acceptable salt thereof, 5'-OD-cytarabine phenylalanine ester or a pharmaceutically acceptable salt thereof, 5'-OL-cytarabine proline ester or a pharmaceutically acceptable salt thereof, and 5'-OL-cytarabine tryptophan ester or a pharmaceutically acceptable salt thereof.

2. The cytarabine amino acid ester composition according to claim 1, characterized in that The salts are: sulfate, pyrosulfate, hydrogensulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, bromate, iodide, acetate, propionate, octanoate, acrylate, formate, isobutyrate, decanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

3. The cytarabine amino acid ester composition according to claim 1, characterized in that In the pharmaceutical composition, the mass ratio of cytarabine amino acid ester or its salt to cedaruridine is 1:0.0625-10, calculated as cytarabine.

4. The cytarabine amino acid ester composition according to claim 3, characterized in that In the pharmaceutical composition, the mass ratio of cytarabine amino acid ester or its salt to cedaruridine is 1:0.25-5, calculated as cytarabine.

5. The cytarabine amino acid ester composition according to claim 3, characterized in that In the pharmaceutical composition, the mass ratio of cytarabine amino acid ester or its salt to cedaruridine is 1:0625; 1:0.125; 1:0.2; 1:0.25; 1:0.3; 1:0.35; 1:0.4; 1:0.45; 1:0.5; 1:0.55; 1:0.6; 1:0.65; 1:0.7; 1:0.75; 1:0.8; 1:0.85; 1:0.9; 1:0.95; 1:1; 1:1.5; 1:2; 1:2.5; 1:3; 1:3.5; 1:4; 1:4.5; 1:5; 1:5.5; 1:6; 1:6.5; 1:7; 1:7.5; 1:8; 1:8.5; 1:9; 1:9.5 or 1:

10.

6. Use of the composition according to any one of claims 1 to 5 in the preparation of drugs for treating cancer.

7. The use according to claim 6, characterized in that The cancers include hematological tumors and solid tumors.

8. The use according to claim 7, characterized in that The blood tumors include myelodysplastic syndrome, leukemia and lymphoma.

9. The use according to claim 8, characterized in that The leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, myeloproliferative neoplasms or chronic myelomonocytic leukemia.

10. The use according to claim 7, characterized in that The solid tumors include pancreatic cancer, ovarian cancer, peritoneal cancer, lung cancer, breast cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast cancer, ovarian cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, head and neck malignancies, urological malignancies, endometrial cancer, cervical cancer, thyroid cancer, hepatoblastoma, Wilms' tumor and sarcoma.

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