A lyophilized composition of a polymeric targeted anticancer conjugate and methods of making and using the same

Abstract

The application belongs to the field of medicine, and particularly relates to a freeze-dried composition of a polymerization targeted anticancer conjugate and a preparation method and use thereof. Specifically, the pharmaceutical composition of the application comprises a compound represented by formula (I) or a salt thereof, a supporting agent and a pH regulator. The active ingredient of the pharmaceutical composition provided by the application can be completely dissolved, the pH value of the pharmaceutical composition during storage can be ensured to be stable, the quality and stability of the active ingredient of the pharmaceutical are not affected, the impurity content is low, the pharmaceutical composition can be stored for a long time, and the pharmaceutical composition shows an important application prospect in the treatment of cancer and other related diseases. The preparation method of the pharmaceutical composition provided by the application is simple in operation, low in production cost, beneficial to large-scale production, and helpful for the wide application of pharmaceutical preparations.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a freeze-dried composition of a polymeric targeted anticancer conjugate, its preparation method, and its uses. Background Technology

[0002] Irinotecan is a derivative of camptothecin. Since its development and launch, it has been widely used worldwide and approved by the US FDA as a first-line chemotherapy drug for advanced metastatic colorectal cancer. For patients who have failed fluorouracil-containing chemotherapy, it can be used as a second-line treatment. It has also been included in the treatment guidelines for gastric cancer, esophageal cancer, cervical cancer, ovarian cancer, small cell lung cancer, and non-small cell lung cancer.

[0003] Nektar Therapeutics has developed an anti-tumor drug, NKTR-102, with the structure shown below. This drug connects irinotecan to a water-soluble multi-branched polyethylene glycol carrier via a biodegradable linker to improve water solubility, increase drug loading, prolong in vivo circulation time, reduce toxicity, and significantly improve the pharmacokinetic characteristics of irinotecan.

[0004]

[0005] However, NKTR-102 still has drawbacks, such as lack of active targeting, inability to act on specific cancer cells, and while killing cancer cells, it also affects the function of normal cells, leading to a high incidence of adverse reactions.

[0006] To develop novel antitumor molecules that can target tumor cells and have low toxicity, patent CN108727583A discloses a multi-arm targeted antitumor molecule with the structure shown in formula (I). Its water-soluble polymer modification enhances the compound's water solubility, thereby increasing drug loading. The targeting molecule increases targeting, resulting in higher concentrations of the compound in the target tissue, improving its clinical therapeutic effect and reducing toxicity. However, as a macromolecular drug, its oral absorption is poor, and it cannot achieve ideal efficacy as an oral formulation. Injection can solve the problem of poor oral absorption, but currently, there is no suitable and stable injectable formulation that can be stored for a long time.

[0007]

[0008] The compound represented by formula (I) is a complex molecule containing three structural modules: a targeting linker, a linker, and a toxin. The molecule has a large molecular weight, and the materials used to synthesize it are complex. The compound represented by formula (I) has poor stability. Therefore, how to prepare the compound represented by formula (I) into a stable pharmaceutical formulation is a technical challenge faced by those skilled in the art. Summary of the Invention

[0009] The problem the invention aims to solve

[0010] The purpose of this invention is to provide a lyophilized composition of a polymeric targeted anticancer conjugate, which, by adding excipients such as a support agent and a pH adjuster, yields a drug-grade formulation that is stable and suitable for long-term storage.

[0011] A second object of the present invention is to provide a method for preparing a freeze-dried composition;

[0012] A third object of the present invention is to provide the use of the lyophilized composition in the preparation of antitumor drugs.

[0013] To achieve the above objectives, the technical solution of the present invention is as follows:

[0014] The first aspect of this invention provides a lyophilized composition of a polymeric targeted anticancer conjugate, comprising a polymeric targeted anticancer conjugate molecule, a support agent, and a pH adjuster; wherein the polymeric targeted anticancer conjugate molecule is a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug thereof:

[0015]

[0016] The proppant is any one or more of sorbitol, mannitol, trehalose, and lactose.

[0017] Furthermore, the pH value of the lyophilized composition after reconstitution is 2.5 to 5.0; preferably, the pH value is 3.0 to 5.0; preferably, the pH value is 4.0.

[0018] Reconstitution refers to diluting the lyophilized sample with 0.9% sodium chloride solution to a concentration of irinotecan of compound (I) of 2 mg / ml.

[0019] Furthermore, the proppant and the compound of formula (I) are in an irinotecan mass ratio of 1 to 80:1;

[0020] Preferably, the mass ratio is 12.5 to 62.5:1, and more preferably, the mass ratio is 37.5:1.

[0021] The mass of the compound of formula (I) described in this invention is based on irinotecan, that is, the mass of irinotecan contained in the compound of formula (I). Unless otherwise specified, the mass or concentration of the compound of formula (I) in this invention is based on irinotecan.

[0022] Furthermore, the pH adjuster is an acid and / or a base; wherein the base is any one or more of sodium hydroxide, potassium hydroxide, and sodium bicarbonate, and the acid is any one or more of hydrochloric acid and phosphoric acid.

[0023] Preferably, the pH adjuster is hydrochloric acid and / or sodium hydroxide.

[0024] This invention utilizes a pH adjuster to control the pH value of the pharmaceutical composition within a specific range, ensuring that the compound of formula (I) can be completely dissolved during the preparation of the pharmaceutical composition, and guaranteeing the stability of the compound of formula (I) as the active pharmaceutical ingredient during storage, thus preventing its degradation.

[0025] Furthermore, the support agent is mannitol, sorbitol, or trehalose; preferably, the support agent is mannitol.

[0026] The support agent, as a carrier, makes the formulation easy to freeze-dry and maintains a good appearance. In this invention, mannitol, sorbitol or trehalose are preferred as support agents. They are chemically stable and do not affect the quality and efficacy of the main drug. After freeze-drying, the sample has good formability, which ensures that the composition has good appearance and stable storage after being made into freeze-dried powder injection with few impurities.

[0027] Furthermore, the lyophilized composition is contained in a vial containing 10 to 50 mg of the compound of formula (I) as irinotecan; that is, the mass of irinotecan contained in the compound of formula (I) contained in the pharmaceutical composition.

[0028] Furthermore, the compound of formula (I) has a mass of 50 mg based on irinotecan, and the proppant has a mass of 1875 mg.

[0029] Furthermore, the lyophilized composition is in a vial, wherein the mass of the compound of formula (I) is 10 mg based on irinotecan, and the mass of the support is 375 mg.

[0030] Furthermore, the present invention provides a lyophilized composition of a polymeric targeted anticancer conjugate, characterized in that it comprises 50 mg of the compound of formula (I) based on irinotecan and 1875 mg of mannitol; the pH value of the lyophilized composition after reconstitution is 3.0 to 5.0.

[0031] Furthermore, the present invention provides a lyophilized composition of a polymeric targeted anticancer conjugate, characterized in that it comprises 10 mg of the compound of formula (I) based on irinotecan and 375 mg of mannitol; the pH value of the lyophilized composition after reconstitution is 3.0 to 5.0.

[0032] A second aspect of the present invention provides a method for preparing a lyophilized composition containing the compound shown in formula (I), comprising the following steps: mixing a support agent, water for injection and the compound shown in formula (I) according to the prescribed amount, adjusting the pH value, adding water for injection to the full volume, and lyophilizing to obtain the final product.

[0033] Furthermore, the preparation method includes the following steps:

[0034] ① Mix the water for injection with the proppant.

[0035] ② Add the prescribed amount of the compound shown in formula (Ⅰ) and mix well;

[0036] ③ Adjust the pH value to around 4, add water for injection to the total volume, mix well, and obtain an intermediate solution. The pH value of the intermediate solution is between 3.0 and 4.5.

[0037] ④ Freeze-dry the intermediate solution to obtain the final product;

[0038] Furthermore, the freeze-drying process comprises three stages: pre-freezing, primary drying, and secondary drying; wherein, the pre-freezing temperature is -45℃ to 0℃, and the duration is 4 to 9 hours; the primary drying temperature is -35℃ to -5℃, the vacuum degree is 0.15 to 0.30 mbar, and the duration is 39.5 to 95 hours; the secondary drying temperature is 15℃ to 30℃, the vacuum degree is 0 to 0.30 mbarr, and the duration is 12 to 23 hours.

[0039] A third aspect of the present invention provides the use of the above-described lyophilized composition in the preparation of a medicament for antitumor purposes.

[0040] Furthermore, the tumor is selected from gastric cancer, pancreatic cancer, small cell lung cancer, colon cancer, breast cancer, lung adenocarcinoma, liver cancer, nasopharyngeal carcinoma, malignant glioma, lymphoma, kidney cancer, ovarian cancer, head and neck cancer, and squamous cell carcinoma.

[0041] The effects of the invention

[0042] The freeze-dried composition provided by this invention uses a support agent that allows the formulation to be easily freeze-dried and maintain a good appearance. The active ingredients can be completely dissolved, and the pH value of the drug composition can be kept stable during storage without affecting the quality and stability of the active ingredients. It has low impurity content and can be stored for a long time, showing important application prospects in the treatment of cancer and related diseases.

[0043] The method for preparing the freeze-dried composition of the present invention is simple to operate, has low production cost, is conducive to large-scale production, and the final product has low water content, can retain the original physicochemical properties and physiological activities of the drug, reduces the loss of the drug's effective ingredients, and meets the requirements of treatment standards.

[0044] The pharmaceutical composition provided by this invention shows significant application potential in the treatment of cancer and related diseases. Detailed Implementation

[0045] The following describes embodiments of the present invention, but the present invention is not limited thereto. The present invention is not limited to the various configurations described below, and various modifications can be made within the scope of the claims. Embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present invention.

[0046] Unless otherwise defined, the technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0047] In this specification, the range of values ​​referred to as “value A ~ value B” or “value A - value B” refers to the range including the endpoint values ​​A and B.

[0048] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0049] Unless otherwise stated, for conditions not specifically specified in this instruction manual, follow standard conditions or the manufacturer's recommended conditions. Reagents or instruments whose manufacturers are not listed are all commercially available standard products.

[0050] All units used in this specification are international standard units, and the numerical values ​​and ranges appearing in this invention should be understood to include unavoidable systematic errors in industrial production.

[0051] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "implementation," etc., refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to that embodiment, which are included in at least one of the embodiments described herein and may or may not be present in other embodiments. Furthermore, it should be understood that these elements may be combined in any suitable manner in various embodiments.

[0052] As a macromolecular drug, compound I has poor oral absorption, so injection is the preferred dosage form for this product. According to the inventors' in-depth research, under different pH values, the related substances in the aqueous solution of compound I will increase significantly after being placed at 40°C for 24 hours, indicating that the product has poor stability in solution. The inventors also found that preparing compound (I) into a lyophilized powder injection can solve the problem of poor solution stability.

[0053] The excipients of this product include sorbitol, mannitol, trehalose, lactose, hydrochloric acid, sodium hydroxide, and water for injection. Sorbitol, mannitol, trehalose, and lactose are the main excipients used as lyophilization support agents. Hydrochloric acid and sodium hydroxide are pH adjusters, and water for injection is the solvent, which is almost entirely removed during the lyophilization process. All excipients used are legally sourced pharmaceutical excipients in China.

[0054] The excipients selected for this product meet the requirements for injection grade use and the standards of the 2015 edition of the Chinese Pharmacopoeia.

[0055] Understandably, water for injection is the most commonly used aqueous solvent for injectable drugs. During the experimental phase of injectable drug development, purified water is generally used instead of water for injection, but in the final marketed formulation, water for injection is usually used.

[0056] The storage conditions for the pharmaceutical composition of the present invention are 2-8℃.

[0057] The mannitol used in this invention conforms to the standards of the 2020 edition of the Chinese Pharmacopoeia, and its bacterial endotoxin and microbial limits have been controlled. The relevant quality control limits are shown in Table 1.

[0058] Table 1. Bacterial endotoxins and microbial limit controls for mannitol.

[0059]

[0060] The preferred specifications of this invention are 10mg and 50mg (calculated as irinotecan), which can meet the dosing requirements of the high-dose group and dose expansion phase in clinical studies, reduce the amount of medication to be prepared, facilitate clinical operation, and improve the medication compliance of subjects.

[0061] Example 1

[0062] The inventors of this invention conducted a forced degradation experiment on the active pharmaceutical ingredient. After careful study and detailed statistical analysis, the experimental results are shown in Tables 2 and 3:

[0063] Table 2. Statistics of impurity profiles in forced degradation tests (related substances 1)

[0064]

[0065]

[0066] Note: 1. Solution degradation refers to preparing the raw material into a solution (concentration: 2mg / ml) using a diluent or appropriate solution (acid, alkali, oxidizing solution) and then conducting a degradation experiment. Alkali degradation is detected immediately after preparation.

[0067] 2. "-" indicates not detected.

[0068] Table 3. Statistics of impurity profiles in forced degradation tests (related substances 2)

[0069]

[0070]

[0071] Note: 1. Solution degradation refers to preparing the active pharmaceutical ingredient into a solution (concentration: 2mg / ml) using a diluent or appropriate solution (acid, alkali, oxidizing solution) and then conducting a degradation experiment; 2. "-" indicates not detected.

[0072] Through solid degradation experiments, the inventors found that this product is sensitive to light, heat, and humidity: light exposure (4500 lx ± 500 lx) leads to an increase in impurities RT0.91, RRT0.96, RRT0.97, and RRT0.98 in related substances 1 and irinotecan, RRT0.63, RRT0.89, and RRT0.93 in related substances 2; high humidity (75% RH) and high temperature (25°C) lead to an increase in impurities RT0.91 in related substances 1.

[0073] Through liquid degradation experiments, the inventors unexpectedly discovered that, in addition to light, heat, and humidity, alkaline conditions are also one of the main causes of degradation of this product, but the product is relatively stable in acidic conditions: acidic conditions lead to an increase in impurities with RRT 0.97 in related substances 1; alkaline conditions mainly lead to an increase in impurities with RRT 0.11, RRT 0.80, RT 0.91, and RRT 0.96 in related substances 1 and irinotecan in related substances 2. In comparison, the active pharmaceutical ingredient degrades the most under alkaline conditions and the least under acidic conditions.

[0074] Example 2

[0075] Take 40 mg of compound (I) as irinotecan and add 20 mL of purified water to prepare an aqueous solution of the active pharmaceutical ingredient with a concentration of 2 mg / mL (calculated as irinotecan). Using the prescription information in Table 4, add appropriate amounts of hydrochloric acid and sodium hydroxide to the obtained solutions to adjust the pH to 2.5, 3.0, 4.0, and 5.0. Place the different solutions at 40℃ for 24 hours, and take samples at 0, 4, 8, and 24 hours to detect relevant indicators. The results are shown in Table 5.

[0076] Table 4 Prescription Information

[0077]

[0078] Note: The amount of active pharmaceutical ingredient (API) needs to be converted to irinotecan for calculation of the dosage, and the same applies below.

[0079] Table 5. Stability of the drug substance aqueous solution at different pH values

[0080]

[0081]

[0082] The inventors discovered that the aqueous solution of the active pharmaceutical ingredient (API) is relatively stable at a pH of 2.5–5.0, preferably 3.0–5.0, and the contents of related substances and free irinotecan meet quality requirements. More preferably, the aqueous solution of the API has a lower content of free irinotecan at a pH of 4.0, which also avoids the problem of excessive irritation to the human body when the pH of the injection is too low, thus improving patient compliance while maintaining formulation stability.

[0083] Example 3

[0084] The prior art CN200910055100.3 (Irinotecan Hydrochloride Injection Patent) discloses that the stability of the injection solution remains good even without the addition of the stabilizer sorbitol, provided that a suitable buffer salt is selected. The inventors considered improving the stability of the formulation by adding a buffer solution to the solution: Based on the optimized results of Example 2, citrate buffer solution with a pH of approximately 4.0, acetate buffer solution, and purified water were used as the dissolving medium to prepare the drug solution. The solution was then placed at 40°C for 24 hours, and samples were taken before and after the placement to detect relevant indicators. The formulation information is shown in Table 6, and the results are shown in Table 7.

[0085] Table 6 Prescription Information

[0086]

[0087] Table 7

[0088]

[0089] A surprising finding was that the drug solution exhibited the best stability when using purified water as the dissolving medium and without adding buffer salts, with the smallest increase in free irinotecan content after 24 hours. In contrast, the drug solution with added buffer salts showed an increase in free irinotecan content nearly twice that of the solution without buffer salts after 24 hours. This contradicts the technical teachings of CN200910055100.3 (Irinotecan Hydrochloride Injection Patent), which states that buffer salts can increase the stability of liquid formulations.

[0090] Example 4

[0091] The inventors selected sorbitol, mannitol, sucrose, trehalose, lactose, maltose, glycine, and arginine as support agents, and prepared the drug solution according to the prescription information in Table 8 and then freeze-dried it.

[0092] Table 8 Prescription Information

[0093]

[0094]

[0095] Table 9. Product characteristics after freeze-drying

[0096] proppant Properties NA Many samples showed collapse and shrinkage. Sorbitol Uniform color, dense pores, and full shape Mannitol Uniform color, dense pores, and full shape sucrose Many samples showed collapse and shrinkage. Trehalose Uniform color, dense pores, and some samples showed bottom collapse. lactose Uniform color, dense pores, and full shape maltose Many samples showed collapse and shrinkage. glycine Many samples showed collapse and shrinkage. Arginine Many samples showed collapse and shrinkage.

[0097] The results were unexpected. Not all commonly known support agents, as known to those skilled in the art, could maintain the good appearance of the lyophilized formulation. For example, when using sucrose, maltose, glycine, or arginine as support agents, the appearance of the samples was similar to that without support agents, and neither could meet the requirements for lyophilized formulations. However, the inventors were also surprised to find that samples prepared using sorbitol, mannitol, or lactose as support agents had good appearance, while samples prepared using trehalose as support agents had slightly worse appearance but still met the usage requirements and could satisfy the drug stability requirements to support the market launch of the formulation. Therefore, further testing and stability studies were conducted on samples in the sorbitol, mannitol, trehalose, and lactose groups. The results are shown in Table 10: lactose, mannitol, trehalose, and sorbitol can all be used as support agents in the compositions of this invention, and can meet the drug stability requirements to support the market launch of the formulation. Preferably, mannitol as a support agent provides the best drug stability.

[0098] Table 10 Stability Study of Different Types of Supports

[0099]

[0100]

[0101] Example 5

[0102] Based on the results of Example 4, the inventors used mannitol as a proppant and prepared drug solutions with different proppant dosages (25 mg / ml, 75 mg / ml, and 125 mg / ml) according to the prescription information in Table 11. These solutions were then placed at 40°C for 24 hours. The inventors found that as the proppant dosage increased, the content of free irinotecan in the drug solution tended to decrease, further demonstrating that mannitol has a certain stabilizing effect on the drug solution. Furthermore, the content of related substances and free irinotecan in mannitol within the tested concentration range met the requirements; therefore, proppant concentrations of 25–125 mg / ml all met the drug preparation conditions. Considering minimizing the amount of excipients without affecting the quality and efficacy of the drug, and considering that lyophilized preparations generally have the best formability when the solid content is between 10% and 15%, the preferred proppant concentration is 75 mg / ml to ensure the appearance and quality of the lyophilized product. This means the mass ratio of proppant to compound (I) (calculated as irinotecan) is 37.5:1.

[0103] Table 11 Prescription Information

[0104]

[0105] Table 12 Stability study of different proppant dosages

[0106]

[0107]

[0108] Example 6

[0109] The inventors prepared solutions containing mannitol support at pH values ​​of 2.5, 3.0, 3.5, 4.0, and 4.5, respectively, and placed them at 40°C for 24 hours to further confirm the stability of the intermediate solutions under different pH conditions. The formulation information is shown in Table 13, and the results are shown in Table 14.

[0110] Table 13 Prescription Information

[0111]

[0112]

[0113] The inventors discovered that when the pH of the drug solution is 2.5, after standing at 40°C for 24 hours, the increase in unknown monoimides in related substances 1 is significant, failing to meet quality standards. This indicates that the intermediate drug solution is not suitable for preparation at pH 2.5. However, when the pH of the intermediate drug solution is between 3.0 and 4.5, with a preferred pH of 4.0, the increase in related substances after standing at 40°C for 24 hours is relatively small, meeting both quality standards and practical application needs in actual production.

[0114] Example 7

[0115] Taking Formula 23 as an example, the inventors used different freeze-drying procedures to prepare samples and test relevant indicators. The specific freeze-drying process parameters are shown in Table 15.

[0116] Table 15 Freeze-drying process parameters

[0117]

[0118] Note: / indicates not detected;

[0119] Table 16 Freeze-drying effect

[0120]

[0121] Note: / indicates not detected; reconstitution means diluting the lyophilized sample with 0.9% sodium chloride solution to a concentration of irinotecan of compound (I) of 2 mg / ml.

[0122] The inventors discovered through research that freeze-drying processes 1-3 can produce finished products with good appearance, good reconstitution effect, and satisfactory moisture content, active pharmaceutical ingredient content, and free irinotecan content. Choosing a slow-freezing pre-freezing procedure can solve the problem that, as a large molecule, the active pharmaceutical ingredient tends to form a denser structure after freeze-drying, resulting in a lower sublimation rate. Furthermore, during the primary drying process, gradient heating facilitates the slow and stable release of moisture.

[0123] According to further careful and detailed comparisons by the inventors, freeze-drying process 2 can reduce freeze-drying time and energy consumption while ensuring product quality. Therefore, freeze-drying process 2 is preferred as the freeze-drying process for this product.

[0124] Example 8: Other formulations and processes of the present invention

[0125] 1) Prescription composition:

[0126]

[0127] 2) Preparation steps: Prepare the product by following these steps according to the prescribed amounts of formulas 25-27:

[0128] a) Mix water for injection with mannitol;

[0129] b) Add the prescribed amount of the compound shown in formula (Ⅰ) and mix well;

[0130] c) Adjust the pH value to around 4, add water for injection to the total volume, mix well, and the pH value of the solution should be between 3.5 and 4.5;

[0131] d) Filtration: 0.2μm microporous filter membrane, made of PES;

[0132] e) Filling and partial stoppering: Select a suitable size of neutral borosilicate glass vial for filling;

[0133] f) Freeze-drying, the freeze-drying process is as follows:

[0134]

[0135]

[0136] Example 9: Other formulations and processes of the present invention

[0137] 1) Prescription composition:

[0138]

[0139] 2) Preparation steps: Prepare the product by following these steps according to the prescribed dosage of formula 28-30:

[0140] a) Mix water for injection with trehalose and the prescribed amount of the compound shown in formula (Ⅰ);

[0141] b) Adjust the pH value to around 5, add water for injection to the total volume, mix well, and the pH value of the solution should be between 3.0 and 4.0;

[0142] c) Filtration: 0.2μm microporous filter membrane, material PES;

[0143] d) Filling and partial stoppering: Select appropriately sized neutral borosilicate glass vials for filling;

[0144] e) Freeze-drying, the freeze-drying process is as follows:

[0145]

[0146] Example 10: Other formulations and processes of the present invention

[0147] 1) Prescription composition:

[0148]

[0149] 2) Preparation steps: Prepare the product by following these steps according to the prescribed amounts of formulas 31-33:

[0150] a) Mix water for injection with the prescribed amount of the compound represented by formula (Ⅰ);

[0151] b) Add sorbitol and mix well;

[0152] c) Adjust the pH value to around 4, add water for injection to the total volume, mix well, and the pH value of the solution should be between 3.5 and 4.5;

[0153] d) Filtration: 0.2μm microporous filter membrane, made of PES;

[0154] e) Filling and partial stoppering: Select a suitable size of neutral borosilicate glass vial for filling;

[0155] f) Freeze-drying, the freeze-drying process is as follows:

[0156]

[0157] Example 11 Other formulations and processes of the present invention

[0158] 1) Prescription composition:

[0159]

[0160]

[0161] 2) Preparation steps: Prepare the product by following these steps according to the prescribed amounts of formulas 34-36:

[0162] a) Mix the water for injection with the lactose;

[0163] b) Add the prescribed amount of the compound shown in formula (Ⅰ) and mix well;

[0164] c) Adjust the pH value to around 4, add water for injection to the total volume, mix well, and the pH value of the solution should be between 3.0 and 4.0;

[0165] d) Filtration: 0.2μm microporous filter membrane, made of PES;

[0166] e) Filling and partial stoppering: Select a suitable size of neutral borosilicate glass vial for filling;

[0167] f) Freeze-drying, the freeze-drying process is as follows:

[0168]

[0169] The inventors discovered that the freeze-dried compositions prepared using other formulations and processes as provided in Examples 8-11 have good properties, low moisture content, and meet quality standards. They also ensure pH stability during storage without affecting the quality and stability of the active pharmaceutical ingredient. The content of impurities (related substances 1, 2, free irinotecan, etc.) is low, allowing for long-term preservation. Furthermore, the active ingredient dissolves completely, and the solution becomes clear after reconstitution.

[0170] For those skilled in the art, various other corresponding changes and modifications can be made based on the technical solutions and concepts described above, and all such changes and modifications should fall within the protection scope of the claims of this invention.

Claims

1. A lyophilized composition of a polymeric targeted anticancer conjugate, characterized in that, The product comprises a polymeric targeted anticancer conjugate molecule, a proppant, and a pH adjuster; the polymeric targeted anticancer conjugate molecule is a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope label, or prodrug thereof. The proppant is any one or more of sorbitol, mannitol, trehalose, and lactose.

2. The lyophilized composition according to claim 1, characterized in that, The pH value of the solution after reconstitution of the lyophilized composition is 2.5–5.0; Preferably, the pH value is 3.0 to 5.

0.

3. The lyophilized composition according to claim 1, characterized in that, The mass ratio of the proppant to the compound of formula (I), calculated as irinotecan, is 1 to 80:

1.

4. The lyophilized composition according to claim 1, characterized in that, The pH adjuster is an acid and / or a base; wherein the base is any one or more of sodium hydroxide, potassium hydroxide, and sodium bicarbonate, and the acid is any one or more of hydrochloric acid and phosphoric acid.

5. The lyophilized composition according to claim 1, characterized in that, The proppant is mannitol, sorbitol, or trehalose; Preferably, the proppant is mannitol.

6. The freeze-dried composition according to any one of claims 1-5, characterized in that, The lyophilized composition is contained in a vial containing 10 to 50 mg of the compound of formula (I) as irinotecan.

7. The freeze-dried composition according to claim 6, characterized in that, The compound of formula (I) has a mass of 50 mg based on irinotecan and a mass of 1875 mg based on the proppant.

8. The freeze-dried composition according to claim 6, characterized in that, The lyophilized composition is contained in a vial, comprising 10 mg of the polymeric targeted anticancer conjugate molecule of formula (I) as irinotecan and 375 mg of the support agent.

9. A lyophilized composition of a polymeric targeted anticancer conjugate, characterized in that, The compound containing formula (I) has a mass of 50 mg (based on irinotecan) and 1875 mg (based on mannitol); the pH of the lyophilized composition after reconstitution is 3.0–5.

0.

10. A lyophilized composition of a polymeric targeted anticancer conjugate, characterized in that, The compound containing formula (I) has a mass of 10 mg (based on irinotecan) and 375 mg mannitol; the pH of the lyophilized composition after reconstitution is 3.0–5.

0.

11. A method for preparing the freeze-dried composition according to any one of claims 1-10, characterized in that, The process includes the following steps: mixing the support agent, water for injection, and the compound shown in formula (Ⅰ) according to the prescribed amount, adjusting the pH value, adding water for injection to the full volume, and freeze-drying to obtain the final product.

12. The preparation method according to claim 11, characterized in that, It includes the following steps: ① Mix the water for injection with the proppant. ② Add the prescribed amount of the compound shown in formula (Ⅰ) and mix well; ③ Adjust the pH value to around 4, add water for injection to the total volume, mix well, and obtain an intermediate solution. The pH value of the intermediate solution is between 3.0 and 4.

5. ④ Freeze-dry the intermediate solution to obtain the final product.

13. The preparation method according to claim 11, characterized in that, The freeze-drying process comprises three stages: pre-freezing, primary drying, and secondary drying. The pre-freezing temperature is -45℃ to 0℃, and the duration is 4 to 9 hours. The primary drying temperature is -35℃ to -5℃, the vacuum degree is 0.15 to 0.30 mbar, and the duration is 39.5 to 95 hours. The secondary drying temperature is 15℃ to 30℃, the vacuum degree is 0 to 0.30 mbar, and the duration is 12 to 23 hours.

14. Use of the lyophilized composition according to any one of claims 1-10 in the preparation of an antitumor drug.

15. The application as described in claim 14, wherein the tumor is selected from gastric cancer, pancreatic cancer, small cell lung cancer, colon cancer, breast cancer, lung adenocarcinoma, liver cancer, nasopharyngeal carcinoma, malignant glioma, lymphoma, kidney cancer, ovarian cancer, head and neck cancer, and squamous cell carcinoma.

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