Irinotecan hydrochloride liposome and preparation method therefor

Abstract

Provided in the present invention is an irinotecan hydrochloride liposome composition, comprising the following components in a specific weight ratio: irinotecan hydrochloride, hydrogenated soybean phospholipid, cholesterol and mPEG2000-DSPE. The present invention also provides a preparation method for said liposome composition. The liposome of the present invention can significantly reduce the severe blood toxicity of irinotecan hydrochloride, and especially significantly reduce the incidence of neutropenia.

Description

Irinotecan hydrochloride liposome and preparation method thereof Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and more particularly to an irinotecan hydrochloride liposome composition and a preparation method thereof. Background Art

[0002] Irinotecan hydrochloride is a camptothecin derivative with proven efficacy and broad anti-tumor activity. Currently, irinotecan hydrochloride is available in two commercial formulations: a standard injection and a liposomal formulation. The standard injection, composed of lactic acid, sorbitol, and water for injection, is light-sensitive and packaged in brown glass bottles. It is primarily used as a monotherapy or in combination with other medications for the treatment of advanced colorectal cancer. The liposomal formulation, encapsulating irinotecan with the polyanion sucrose octasulfate, is indicated for second-line treatment of advanced metastatic pancreatic cancer in combination with 5-fluorouracil and folinic acid.

[0003] After administration, ordinary irinotecan hydrochloride injection produces toxic side effects such as bone marrow suppression and diarrhea, which are seriously life-threatening. The drug toxicity limits its clinical therapeutic application. Liposomes use closed capsules to encapsulate irinotecan to prevent its hydrolysis and ring opening. At the same time, they have a certain long-circulation effect, which can prolong the half-life of irinotecan, improve its tissue distribution, increase its accumulation in tumor sites, and enhance its anti-tumor effect. However, irinotecan liposomes prepared by existing technologies still face serious lethal and life-threatening neutropenia blood toxicity. For example, ONIVYDE, which was approved for marketing in 2015, still has a serious and lethal neutropenia listed in the FDA safety black box warning. New irinotecan liposome formulations with lower toxicity are still urgently needed in current clinical practice.

[0004] Irinotecan's hematologic toxicity primarily stems from the distribution and accumulation of its active metabolite, SN-38, in the bone marrow. SN-38 in the bone marrow is primarily derived from the metabolism of SN-38 in plasma and irinotecan distributed therein. Minimizing the distribution and accumulation of SN-38 in the bone marrow can effectively reduce drug-induced hematologic toxicity.

[0005] Summary of the Invention

[0006] The present invention aims to provide a liposome composition and formulation of irinotecan hydrochloride with reduced toxicity, as well as a method for preparing the same. Unexpectedly, it was discovered that by strictly controlling the ratio of irinotecan hydrochloride to phospholipids, the formulation composition of the liposomes, the composition and concentration of the internal aqueous phase, and the preparation method (particularly the mass ratio of phospholipids to ethanol, the ratio of the aqueous phase to the ethanol phase, and the insertion method of the long-circulating material), the bone marrow distribution and release characteristics of the irinotecan liposomes in the human body can be significantly optimized, significantly reducing hematotoxicity.

[0007] The irinotecan hydrochloride liposomes provided by the present invention can significantly reduce the severe blood toxicity of irinotecan hydrochloride, especially the incidence of neutropenia, and significantly improve the survival status of patients after being administered to patients with advanced or metastatic solid tumors.

[0008] To achieve the above object, the present invention provides an irinotecan hydrochloride liposome composition, characterized in that the liposome composition contains the following ingredients in a weight ratio: 1 part of irinotecan hydrochloride, 3.67-5.62 parts of hydrogenated soybean lecithin, 1.23-2.25 parts of cholesterol, and 0.055-0.200 parts (preferably 0.060-0.200 parts, preferably 0.070-0.200 parts, and more preferably 0.0801-0.200 parts) of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE); the weight ratio of the hydrogenated soybean lecithin to cholesterol is 2-4.5:1.

[0009] In some embodiments of the present invention, the liposome composition contains the following ingredients in the following weight ratio: 1 part of irinotecan hydrochloride, 4.13-5.05 parts of hydrogenated soybean lecithin, 1.23-1.86 parts of cholesterol, and 0.0801-0.150 parts of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE); the weight ratio of hydrogenated soybean lecithin to cholesterol is 2-3.5:1.

[0010] In some embodiments of the present invention, the liposome composition contains the following ingredients in the following weight ratio: 1 part of irinotecan hydrochloride, 4.13-5.05 parts of hydrogenated soybean lecithin, 1.39-1.71 parts of cholesterol, and 0.0810-0.110 parts of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE); the weight ratio of hydrogenated soybean lecithin to cholesterol is 2-3.5:1.

[0011] In some embodiments of the present invention, the liposome composition contains the following ingredients in the following weight ratio: 1 part of irinotecan hydrochloride, 4.59 parts of hydrogenated soybean lecithin, 1.5468 parts of cholesterol, and 0.0840 parts of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE).

[0012] In some embodiments of the present invention, the liposome composition contains ammonium sulfate in the internal aqueous phase, and the concentration of ammonium sulfate in the internal aqueous phase is 0.16-0.28M, preferably 0.20-0.24M, and more preferably 0.22M.

[0013] In some embodiments of the present invention, the irinotecan hydrochloride liposome composition is prepared by an ethanol injection method and an ammonium sulfate gradient method, wherein the mass ratio of hydrogenated soybean lecithin to ethanol in the ethanol phase is 0.1:1-0.5:1 (preferably 0.1:1-0.35:1, more preferably 0.1:1-0.2:1), the ammonium sulfate concentration in the aqueous phase is 0.16-0.28 M (preferably 0.20-0.24 M, more preferably 0.22 M), and the volume ratio of the ethanol phase to the aqueous phase is 1:3-1:6.

[0014] In some embodiments of the present invention, the irinotecan hydrochloride liposome composition is prepared by an ethanol injection method and an ammonium sulfate gradient method, wherein the mass ratio of hydrogenated soybean lecithin to ethanol in the ethanol phase is 0.1:1-0.35:1, the concentration of ammonium sulfate in the aqueous phase is 0.20-0.24 M, and the volume ratio of the ethanol phase to the aqueous phase is 1:3-1:6.

[0015] In some embodiments of the present invention, the irinotecan hydrochloride liposome composition is prepared by an ethanol injection method and an ammonium sulfate gradient method, wherein the mass ratio of hydrogenated soybean lecithin to ethanol in the ethanol phase is 0.1:1-0.2:1, the ammonium sulfate concentration in the aqueous phase is 0.22M, and the volume ratio of the ethanol phase to the aqueous phase is 1:3-1:6.

[0016] In some embodiments of the present invention, the particle size of the liposome composition is 90-110 nm, and the particle size D90 corresponding to 90% of the cumulative particle size distribution is <300 nm, for example, D90 <200 nm, D90 <150 nm.

[0017] In some embodiments of the present invention, the concentration of irinotecan hydrochloride in the liposome composition is 4.25-5.75 mg / ml.

[0018] In some embodiments of the present invention, the concentration of irinotecan hydrochloride in the liposome composition is 4.5-5.5 mg / ml.

[0019] In some embodiments of the present invention, the concentration of irinotecan hydrochloride in the liposome composition is 5 mg / ml.

[0020] The present invention also provides the use of ammonium sulfate as an internal aqueous phase in the irinotecan hydrochloride liposome composition of the present invention, wherein the concentration of ammonium sulfate in the internal aqueous phase is controlled at 0.16-0.28M.

[0021] The present invention provides a method for preparing an irinotecan liposome composition, comprising the following steps:

[0022] a. Preparation of ethanol phase: Dissolve hydrogenated soybean lecithin and cholesterol in anhydrous ethanol at 50-70°C and keep warm for later use;

[0023] b. Preparation of aqueous phase: dissolve ammonium sulfate in purified water at 50-70°C to obtain an ammonium sulfate solution with an ammonium sulfate concentration of 0.16-0.28M (preferably 0.20-0.24M, more preferably 0.22M), and keep warm for later use;

[0024] c. Inject the ethanol phase into the aqueous phase at a volume ratio of 1:3-1:6, and use an extruder to process the liposomes to 85-150 nm;

[0025] d. Removal of ammonium sulfate in the external aqueous phase: prepare a phosphate buffer solution with pH 5.0 to 7.0 as the replacement medium, and use a tangential flow ultrafiltration device to replace the external aqueous phase of the liposomes, so that the internal and external aqueous phases of the liposomes form a volume greater than 10 3 times the ammonium ion gradient difference;

[0026] e. Drug loading: Add the mixed solution of irinotecan hydrochloride and mPEG2000-DSPE to the blank liposomes with the above-mentioned ammonium ion gradient, incubate at 55-60° C. for 5-30 minutes, and obtain the irinotecan hydrochloride liposome composition.

[0027] In some embodiments of the present invention, the method further comprises the steps of incubating, quenching, and sterilizing the obtained irinotecan hydrochloride liposome solution by filtering it through a 0.2 μm filter membrane.

[0028] In some embodiments of the present invention, in step e, after the incubation is completed, the mixture is quenched in an ice bath, the obtained irinotecan hydrochloride liposome solution is sterilized by filtering through a 0.2 μm filter membrane, and the solution is filled with nitrogen and sealed in a vial.

[0029] In some embodiments of the present invention, the dissolution temperature in steps a and b is 60° C.; and / or the volume ratio of the ethanol phase to the aqueous phase in step c is 1:5; and / or the phosphate buffer in step d is 9% sucrose (w / v)-0.1 mol / L phosphate buffer at pH 6.5; and / or the drug loading time in step e is 10 min.

[0030] The present invention uses functional materials to modify liposomes while loading drugs, so that they have a long circulation effect, which neither affects the liposome encapsulation rate nor increases the high-temperature treatment time of mPEG2000-DSPE during liposome preparation, thereby facilitating the production of high-quality products.

[0031] In some embodiments of the present invention, the irinotecan hydrochloride liposome composition prepared by the preparation method has a liposome particle size of 90-110 nm, and the particle size D corresponding to the cumulative particle size distribution number reaching 90% is 90 <300nm, preferably D 90 <200nm, more preferably D 90 <150nm.

[0032] In some embodiments of the present invention, the irinotecan hydrochloride liposome composition prepared by the preparation method has an irinotecan hydrochloride concentration of 4.25-5.75 mg / ml, preferably 4.5-5.5 mg / ml, and more preferably 5 mg / ml.

[0033] The present invention also provides a preparation comprising the irinotecan hydrochloride liposome composition or the irinotecan hydrochloride liposome composition prepared by the preparation method, and pharmaceutically acceptable carriers and excipients. Preferably, the preparation is an intravenous injection preparation.

[0034] The irinotecan hydrochloride liposome composition or preparation provided by the present invention can be used to treat tumors or cancers.

[0035] The irinotecan hydrochloride liposome composition or preparation provided by the present invention has significantly reduced blood toxicity effects on the treated subject (for example, a significantly reduced incidence of neutropenia or leukopenia, etc., especially a significantly reduced incidence of life-threatening neutropenia).

[0036] The irinotecan hydrochloride liposome composition or preparation provided by the present invention can reduce the distribution and aggregation of SN-38 in the bone marrow.

[0037] The present invention provides a method for treating tumors or cancers, comprising administering the irinotecan hydrochloride liposome composition or formulation of the present invention to an individual in need thereof.

[0038] The present invention provides use of the irinotecan hydrochloride liposome composition or preparation in preparing a medicament for treating tumors or cancers.

[0039] The present invention provides use of the irinotecan hydrochloride liposome composition or preparation in preparing a drug for significantly reducing the blood toxicity of irinotecan on a subject.

[0040] The present invention provides use of the irinotecan hydrochloride liposome composition or preparation in preparing a drug that significantly reduces the distribution and aggregation of SN-38 in the bone marrow.

[0041] In some embodiments of the present invention, the tumor or cancer preferably includes gastric cancer, pancreatic cancer, lung cancer (e.g., non-small cell lung cancer), colorectal cancer, esophageal cancer, liver cancer, breast cancer, colorectal cancer, ovarian cancer, and cervical cancer, etc. More preferably, the tumor or cancer is selected from advanced solid tumors, including gastric cancer, pancreatic cancer, small cell lung cancer, colorectal cancer, esophageal cancer, liver cancer, and breast cancer, etc.

[0042] In some embodiments of the present invention, the composition or preparation has significantly reduced hematotoxic effects when used to treat tumors or cancers (e.g., a significantly reduced incidence of neutropenia or leukopenia, etc., especially a significantly reduced incidence of life-threatening neutropenia).

[0043] In some embodiments of the present invention, the incidence of grade ≥3 (e.g., grade 3 / 4) neutropenia in subjects is ≤50%, preferably ≤40%, preferably ≤30%, more preferably ≤20%, more preferably ≤10%, more preferably ≤5%, and most preferably 0%.

[0044] In some embodiments of the present invention, the incidence of grade ≥3 (eg, grade 3 / 4) leukopenia in subjects is ≤30%, preferably ≤20%, more preferably ≤10%, more preferably ≤5%, and most preferably 0%.

[0045] In some embodiments of the present invention, the subject is a patient with locally advanced or metastatic solid tumors who has failed standard treatment, is intolerant to standard treatment, or has no standard treatment options.

[0046] In some embodiments of the present invention, the irinotecan hydrochloride liposome composition or preparation is administered in combination with other drugs, such as 5-fluorouracil (5-FU), folinic acid (LV), and the like.

[0047] In some embodiments of the present invention, the irinotecan hydrochloride liposome composition or preparation is administered by injection, such as intravenous infusion.

[0048] In some embodiments of the present invention, the dosage of the irinotecan hydrochloride liposome composition or preparation is 40-100 mg / m 2 , preferably 60-90 mg / m 2 , preferably 70 or 80 mg / m 2 .

[0049] In some embodiments of the present invention, the irinotecan hydrochloride liposomal composition or formulation is administered once every two weeks.

[0050] The present invention provides a method for reducing the blood toxicity of a drug, comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition described above, the irinotecan hydrochloride liposome composition prepared by any of the preparation methods described above, or the preparation described above.

[0051] The present invention provides a method for reducing the incidence of neutropenia and / or leukopenia, comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition described in any one of the above, the irinotecan hydrochloride liposome composition prepared by any one of the above preparation methods, or the preparation described in any one of the above.

[0052] The present invention provides a method for reducing the incidence of neutropenia and / or leukopenia to ≤50%, comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition described in any one of the above, the irinotecan hydrochloride liposome composition prepared by any one of the above preparation methods, or the preparation described in any one of the above.

[0053] In some embodiments of the present invention, the neutropenia and / or leukopenia is neutropenia and / or leukopenia of grade 3 or higher.

[0054] The present invention provides a method for reducing the distribution and accumulation of SN-38 in the bone marrow, comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition described in any one of the above, the irinotecan hydrochloride liposome composition prepared by any one of the above preparation methods, or the preparation described in any one of the above.

[0055] The present invention provides a use of an irinotecan pharmaceutical composition for reducing blood toxicity, the use comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition described in any one of the above items, the irinotecan hydrochloride liposome composition prepared by any one of the above methods, or the preparation described in any one of the above items.

[0056] The present invention provides a use of an irinotecan pharmaceutical composition for reducing the incidence of neutropenia and / or leukopenia, wherein the use comprises administering to an individual in need thereof the irinotecan hydrochloride liposome composition described in any one of the above items, the irinotecan hydrochloride liposome composition prepared by any one of the above methods, or the preparation described in any one of the above items.

[0057] The present invention provides an irinotecan pharmaceutical composition for use in reducing the incidence of neutropenia and / or leukopenia to ≤50%, the use comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition described in any one of the above items, the irinotecan hydrochloride liposome composition prepared by any one of the above methods, or the preparation described in any one of the above items.

[0058] In some embodiments of the present invention, the neutropenia and / or leukopenia is neutropenia and / or leukopenia of grade 3 or higher.

[0059] The present invention provides a use of an irinotecan pharmaceutical composition for reducing the distribution and aggregation of SN-38 in the bone marrow, comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition described above, the irinotecan hydrochloride liposome composition prepared by any of the preparation methods described above, or the preparation described above.

[0060] Compared with the prior art, the present invention has the following beneficial effects:

[0061] 1) The obtained irinotecan hydrochloride liposome preparation has a simple formulation process, a high encapsulation efficiency, good stability, and a uniform particle size distribution, which is conducive to the control of its in vivo distribution process.

[0062] 2) By systematically controlling the composition and proportion of the liposomes, the ratio of the drug to phospholipids, the composition and concentration of the internal aqueous phase, the mass ratio of the phospholipids to ethanol, and the aqueous and organic phases in the liposome preparation method, the resulting liposome preparation has significantly reduced toxicity, especially significantly reduced hemotoxicity, and in particular significantly reduced the incidence of neutropenia and leukopenia (especially neutropenia).

[0063] 3) After being administered to patients with advanced solid tumors, the irinotecan hydrochloride liposomes of the present invention can significantly reduce the severe blood toxicity of irinotecan hydrochloride (especially the incidence of neutropenia) and significantly improve the survival status of patients. DETAILED DESCRIPTION

[0064] The following examples and test examples are used to further illustrate the present invention, but the present invention is not limited to these examples and test examples.

[0065] In the examples and test examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents and instruments used, if no manufacturer is specified, are commercially available conventional products.

[0066] Irinotecan hydrochloride was produced by Fermion. Hydrogenated soybean lecithin and MPEG2000-DSPE were produced by Lipoid GmbH. Cholesterol was produced by Nippon Seika Co., Ltd. Ammonium sulfate, disodium hydrogen phosphate, and sodium dihydrogen phosphate were produced by Hunan Jiudian. Sucrose was produced by Merck KGaA.

[0067] Example 1 Preparation of Irinotecan Hydrochloride Liposomes

[0068] Table 1

[0069] Preparation process

[0070] 1.1 Preparation of ethanol phase: Weigh the amount of hydrogenated soybean lecithin and cholesterol in Table 1 and dissolve them in the anhydrous ethanol in Table 1 at 60°C. Keep warm for later use.

[0071] 1.2 Preparation of aqueous phase: Weigh the amount of ammonium sulfate prescribed in Table 1 and dissolve it in 60°C purified water to obtain an ammonium sulfate concentration of 0.22M. Keep warm for later use;

[0072] 1.3 Inject the ethanol phase into the aqueous phase and use an extrusion device to process the liposomes to 95 nm through two 0.1 μm filter membranes;

[0073] 1.4 Removal of ammonium sulfate from the external aqueous phase: Prepare 9% sucrose (w / v)-0.1 M phosphate buffer (pH = 6.5) as the replacement medium, and use a tangential flow ultrafiltration device to replace the external aqueous phase of the liposomes. When the ammonium ion concentration at the permeate end is detected to be no greater than 0.11 mM, stop ultrafiltration to obtain blank liposomes;

[0074] 1.5 Drug Loading: A mixed solution of irinotecan hydrochloride and mPEG2000-DSPE in the prescribed amount was added to the blank liposomes with the above-mentioned ammonium ion gradient. The mixture was incubated at 55-60°C for 10 min and quenched in an ice bath to obtain an irinotecan hydrochloride liposome solution. The liposome solution was sterilized by filtering through a 0.2 μm filter and sealed in a vial filled with nitrogen. The liposome particle size was 99 nm, the encapsulation efficiency was 97.1%, and the irinotecan hydrochloride concentration was 5 mg / ml.

[0075] Experimental Example 1 Safety Study of Liposomal Irinotecan Hydrochloride in Patients with Advanced Solid Tumors

[0076] Test drug: irinotecan liposome hydrochloride; Specification: 10ml: 50mg; Administration: intravenous drip; Dose: 80mg / m 2 The study period was 2 cycles, each cycle was 14 days, and the drug was administered once every two weeks (q2w), with intravenous infusion for 1.5 hours (±10 minutes) on the first day of each cycle.

[0077] Comparative drug: Irinotecan hydrochloride injection (trade name: Campto); Specification: 5ml: 0.1g; Administration: intravenous drip; Dose: 180mg / m 2 The study period was 2 cycles, each cycle was 14 days, and the drug was administered once every two weeks (q2w), with intravenous infusion for 1.5 hours (±10 minutes) on the first day of each cycle.

[0078] The basis for the selection of the dose of the control drug and the test drug: The previous human pharmacokinetic study found that the irinotecan hydrochloride liposome group 80mg / m 2 Irinotecan hydrochloride injection 180 mg / m 2 Exposure in humans is similar.

[0079] Patient inclusion criteria: patients with histologically confirmed locally advanced or metastatic solid tumors (mainly colorectal cancer, pancreatic cancer, gastric cancer, lung cancer, and breast cancer), who have failed or cannot tolerate standard treatment or have no standard treatment, and who have at least one solid tumor efficacy evaluation criteria.

[0080] Twelve patients were enrolled, including 6 in the irinotecan hydrochloride liposome group and 6 in the irinotecan hydrochloride conventional injection group.

[0081] Results: Irinotecan liposome group 80 mg / m 2 Compared with the common injection 180mg / m 2 The efficacy is comparable, but the duration of disease remission (DOR) is significantly prolonged compared to that of ordinary injections. The safety test results are shown in Table 2 below. The incidence of grade 3 / 4 diarrhea is comparable to that of ordinary injections (16.7% vs 16.7%), while the incidence of grade 3 / 4 neutrophil and white blood cell count decreases is significantly less than that of ordinary injections (neutrophil count decreases 0% vs 50%, white blood cell count decreases 0% vs 33.3%). This shows that the irinotecan hydrochloride liposomes of the present invention can significantly reduce the blood toxicity of irinotecan after administration to patients with advanced solid tumors, especially significantly reduce the incidence of neutropenia, and significantly improve the survival status of patients.

[0082] Table 2 Safety results of irinotecan hydrochloride liposome group in humans

Claims

1. An irinotecan hydrochloride liposome composition, characterized in that: The liposome composition contains the following ingredients in a mass ratio: 1 part of irinotecan hydrochloride, 3.67-5.62 parts of hydrogenated soybean lecithin, 1.23-2.25 parts of cholesterol, and 0.055-0.200 parts of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE); the weight ratio of the hydrogenated soybean lecithin to cholesterol is 2-4.5:1; the liposome composition also contains ammonium sulfate in an inner aqueous phase, and the concentration of ammonium sulfate in the inner aqueous phase is 0.16-0.28M.

2. The irinotecan hydrochloride liposome composition according to claim 1, wherein the concentration of ammonium sulfate in the internal aqueous phase is 0.20-0.24M.

3. The irinotecan hydrochloride liposome composition according to claim 2, wherein the concentration of ammonium sulfate in the internal aqueous phase is 0.22M.

4. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 3, wherein the liposome composition contains the following ingredients in a weight ratio: 1 part of irinotecan hydrochloride, 4.13-5.05 parts of hydrogenated soybean lecithin, 1.23-1.86 parts of cholesterol, and 0.0801-0.150 parts of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE); the weight ratio of hydrogenated soybean lecithin to cholesterol is 2-3.5:

1.

5. The irinotecan hydrochloride liposome composition according to claim 4, wherein the liposome composition contains the following ingredients in a weight ratio: 1 part of irinotecan hydrochloride, 4.13-5.05 parts of hydrogenated soybean lecithin, 1.39-1.71 parts of cholesterol, and 0.081-0.110 parts of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE); the weight ratio of hydrogenated soybean lecithin to cholesterol is 2-3.5:

1.

6. The irinotecan hydrochloride liposome composition according to claim 5, comprising the following ingredients in a mass ratio: 1 part of irinotecan hydrochloride, 4.59 parts of hydrogenated soybean lecithin, 1.5468 parts of cholesterol, and 0.0840 parts of methoxy-terminated polyethylene glycol 2000 distearoylphosphatidylethanolamine (mPEG2000-DSPE).

7. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 6, wherein the irinotecan hydrochloride liposome composition is prepared by an ethanol injection method and an ammonium sulfate gradient method, wherein the mass ratio of hydrogenated soybean lecithin to ethanol in the ethanol phase is 0.1:1-0.5:1, the concentration of ammonium sulfate in the aqueous phase is 0.16-0.28 M, and the volume ratio of the ethanol phase to the aqueous phase is 1:3-1:

6.

8. The irinotecan hydrochloride liposome composition according to claim 7, wherein the mass ratio of hydrogenated soybean lecithin to ethanol in the ethanol phase is 0.1:1-0.35:1, and the concentration of ammonium sulfate in the aqueous phase is 0.20-0.24M.

9. The irinotecan hydrochloride liposome composition according to claim 8, wherein the mass ratio of hydrogenated soybean lecithin to ethanol in the ethanol phase is 0.1:1-0.2:1, and the concentration of ammonium sulfate in the aqueous phase is 0.22M.

10. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 9, wherein the particle size of the liposome composition is 90-110 nm, and the particle size D90 corresponding to 90% of the cumulative particle size distribution is less than 300 nm.

11. The irinotecan hydrochloride liposome composition according to claim 10, wherein the particle size D90 corresponding to the cumulative particle size distribution number reaching 90% is less than 200 nm.

12. The irinotecan hydrochloride liposome composition according to claim 11, wherein the particle size D90 corresponding to the cumulative particle size distribution number reaching 90% is less than 150 nm.

13. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 12, wherein the concentration of irinotecan hydrochloride in the liposome composition is 4.25-5.75 mg / ml.

14. The irinotecan hydrochloride liposome composition of claim 13, wherein the concentration of irinotecan hydrochloride in the liposome composition is 4.5-5.5 mg / ml.

15. The irinotecan hydrochloride liposome composition of claim 14, wherein the concentration of irinotecan hydrochloride in the liposome composition is 5 mg / ml.

16. The method for preparing the irinotecan liposome composition according to any one of claims 1 to 15, characterized in that: The steps include: a. Preparation of ethanol phase: dissolve hydrogenated soybean lecithin and cholesterol in anhydrous ethanol at 50-70°C; b. Preparation of aqueous phase: dissolve ammonium sulfate in 50-70°C purified water to obtain an ammonium sulfate solution with an ammonium sulfate concentration of 0.16-0.28 M; c. Inject the ethanol phase into the aqueous phase at a volume ratio of 1:3-1:6, and process the liposomes to 85-150 nm using an extruder; d. Removal of ammonium sulfate from the external aqueous phase: Prepare a phosphate buffer solution with a pH of 5.0 to 7.0 as the replacement medium to replace the external aqueous phase of the liposomes so that the internal and external aqueous phases form a larger than 10 3 times the ammonium ion gradient difference; e. Drug loading: Add the mixed solution of irinotecan hydrochloride and mPEG2000-DSPE to the blank liposomes with the above-mentioned ammonium ion gradient difference, incubate at 55-60° C. for 5-30 min, and obtain the irinotecan hydrochloride liposome composition.

17. The method for preparing the irinotecan liposome composition according to claim 16, further comprising the steps of incubating, quenching, and sterilizing the obtained irinotecan hydrochloride liposome solution by filtering it through a 0.2 μm filter membrane.

18. The preparation method according to any one of claims 16 to 17, characterized in that The dissolving temperature in steps a and b is 60° C.; and / or The volume ratio of the ethanol phase to the aqueous phase in step c is 1:5; and / or The phosphate buffer in step d is 9% sucrose (w / v)-0.1 mol / L phosphate buffer at pH 6.5; and / or The drug loading time in step e is 10 minutes.

19. A preparation comprising the irinotecan hydrochloride liposome composition according to any one of claims 1 to 15 or the irinotecan hydrochloride liposome composition prepared by the preparation method according to any one of claims 16 to 18 and a pharmaceutically acceptable carrier and / or excipient.

20. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 15, the irinotecan hydrochloride liposome composition prepared by the preparation method according to any one of claims 16 to 18, or the preparation according to claim 19 is used for treating tumors or cancers. Preferably, the tumors or cancers include gastric cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, esophageal cancer, liver cancer, breast cancer, colon cancer, ovarian cancer and cervical cancer.

21. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 15, the irinotecan hydrochloride liposome composition prepared by the preparation method according to any one of claims 16 to 18, or the preparation according to claim 19 is used for treating tumors or cancers, wherein the tumors or cancers are selected from advanced or metastatic solid tumors, preferably, the advanced or metastatic solid tumors include gastric cancer, pancreatic cancer, small cell lung cancer, colorectal cancer, esophageal cancer, liver cancer and breast cancer.

22. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 15, the irinotecan hydrochloride liposome composition prepared by the preparation method according to any one of claims 16 to 18, or the preparation according to claim 19 has significantly reduced blood toxicity when used to treat tumors or cancers, for example, significantly reducing the blood toxicity of irinotecan on the subject.

23. When the irinotecan hydrochloride liposome composition according to any one of claims 1 to 15, the irinotecan hydrochloride liposome composition prepared by the preparation method according to any one of claims 16 to 18, or the preparation according to claim 19 is used to treat tumors or cancer, the incidence of neutropenia of grade ≥ 3 in the treated subject is ≤ 50%.

24. The irinotecan hydrochloride liposome composition according to any one of claims 1 to 15, the irinotecan hydrochloride liposome composition prepared by the preparation method according to any one of claims 16 to 18, or the preparation according to claim 19 can reduce the distribution and aggregation of SN-38 in the bone marrow.

25. Use of the irinotecan hydrochloride liposome composition according to any one of claims 1 to 15, the irinotecan hydrochloride liposome composition prepared by the preparation method according to any one of claims 16 to 18, or the preparation according to claim 19 in medicine for treating tumors or cancers.

26. The use of claim 25, wherein the tumor or cancer comprises gastric cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, esophageal cancer, liver cancer, breast cancer, colon cancer, ovarian cancer and cervical cancer.

27. The use of claim 26, wherein the tumor or cancer is selected from advanced or metastatic solid tumors, preferably, the advanced or metastatic solid tumors include gastric cancer, pancreatic cancer, small cell lung cancer, colorectal cancer, esophageal cancer, liver cancer and breast cancer.

28. The use according to any one of claims 25 to 27, wherein the incidence of grade ≥ 3 neutropenia in the subjects is ≤ 50%.

29. A method for treating tumors or cancers, the method comprising administering to an individual in need thereof the irinotecan hydrochloride liposome composition according to any one of claims 1 to 15, the irinotecan hydrochloride liposome composition prepared by the preparation method of any one of claims 16 to 18, or the preparation according to claim 19.

30. The method of claim 29, wherein the tumor or cancer comprises gastric cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, esophageal cancer, liver cancer, breast cancer, colon cancer, ovarian cancer and cervical cancer.

31. The method of treatment according to claim 30, wherein the tumor or cancer is selected from advanced or metastatic solid tumors, preferably, the advanced or metastatic solid tumors include gastric cancer, pancreatic cancer, small cell lung cancer, colorectal cancer, esophageal cancer, liver cancer and breast cancer.

32. The method of any one of claims 29 to 31, wherein the dosage of the irinotecan hydrochloride liposome composition or preparation is 40-100 mg / m 2 , preferably 60-90 mg / m 2 , preferably 70 or 80 mg / m 2 .

33. The method of treatment according to any one of claims 29 to 32, having significantly reduced hematotoxic effects.

34. The treatment method according to any one of claims 29 to 33, which can significantly reduce the blood toxicity of irinotecan, including a significant reduction in the incidence of neutropenia or leukopenia, and especially a significant reduction in the incidence of life-threatening neutropenia.

35. The method of treatment of any one of claims 29-34, wherein the incidence of grade ≥ 3 (eg, grade 3 / 4) neutropenia in the treated subjects is ≤ 50%.

36. The treatment method of any one of claims 29-35, which can significantly reduce the distribution and aggregation of SN-38 in the bone marrow.

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