Pharmaceutical composition containing Rubitedin as well as preparation method and application of pharmaceutical composition

Abstract

The invention relates to a pharmaceutical composition containing Rubitedin as well as a preparation method and application of the pharmaceutical composition. The pharmaceutical composition containing Rubitedin is a freeze-dried composition, and the freeze-dried composition comprises Rubitedin, a buffer agent derived from inorganic acid and a proppant. According to the present invention, the active component Rubitedin of the pharmaceutical composition can be completely dissolved, the stability of the pH value of the pharmaceutical composition during the storage process can be ensured, the quality and the stability of the active component of the pharmaceutical composition are not affected, the impurity content is low, the pharmaceutical composition can be stored for a long time, and the pharmaceutical composition has important application prospects in the treatment of cancer and other related diseases. The preparation method of the pharmaceutical composition is easy and convenient to operate, low in production cost and beneficial to large-scale production, and helps are provided for large-scale application of pharmaceutical preparations.

Description

A pharmaceutical composition containing rubitidine, and its preparation method and application

[0001] The present invention claims priority to the Chinese patent application filed with the China Patent Office on December 22, 2022, with application number 202211667008.4 and invention name “A pharmaceutical composition containing rubitidine, its preparation method and application”, all disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition containing rubitidine, a preparation method thereof, and an application thereof. Background Art

[0003] Lung cancer is a disease in which malignant (cancer) cells form in the lung tissue. The two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). At the time of diagnosis, SCLC accounts for approximately 13%-15% of all lung cancers. However, SCLC is a more aggressive type of lung cancer, with cancer cells that tend to grow rapidly and metastasize more easily to other parts of the body. The most common treatment regimen currently involves administering cisplatin or carboplatin and etoposide. However, patients often develop resistance to chemotherapy and relapse.

[0004] Lubinectedin (CAS No.: 497871-47-3) is a derivative of the marine compound ET-736, isolated from the sea squirt Ecteinacidia turbinata. The hydrogen atoms in ET-736 are replaced by methoxy groups. Its structure is shown below. In addition to its direct effects on cancer cells, lurbinectedin can also inhibit the transcription and production of certain cytokines in tumor-associated macrophages that are critical for tumor growth. Lubinectedin is indicated for the treatment of adult patients with SCLC whose disease has progressed during or after platinum-based chemotherapy.

[0005] However, rubitidine is a complex compound with limited solubility in water. Furthermore, it is unstable and rapidly degrades at room temperature (25°C). It can only be stored for one month at 5°C, so it can only be stored at -20°C for a long time. This greatly limits its clinical application. Therefore, it is extremely necessary to develop a rubitidine formulation with good stability, stable efficacy, and long-term storage.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide a pharmaceutical composition containing rubitidine.

[0008] The second object of the present invention is to provide a method for preparing a pharmaceutical composition containing rubitidine;

[0009] The third object of the present invention is to provide use of a pharmaceutical composition containing rubitidine in the preparation of anti-tumor drugs.

[0010] To achieve the above object, the technical solution of the present invention is:

[0011] A first aspect of the present invention provides a pharmaceutical composition containing rubitidine, wherein the pharmaceutical composition is a lyophilized composition, comprising: rubitidine, a buffer derived from an inorganic acid, and a support. The buffer derived from an inorganic acid is selected from a combination of an inorganic acid and an inorganic acid salt or a combination of an inorganic acid and a base.

[0012] Furthermore, the buffering agent derived from an inorganic acid is selected from a combination of phosphoric acid and a phosphate, a combination of hydrochloric acid and an alkali, a combination of sulfuric acid and an alkali, and a combination of phosphoric acid and an alkali, or a combination of phosphoric acid and a phosphate, a combination of hydrochloric acid and an alkali, and a combination of sulfuric acid and an alkali, wherein the alkali is any one of sodium carbonate, potassium carbonate, NH4OH, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium bicarbonate; wherein the phosphate comprises a hydrate of phosphate.

[0013] Preferably, the buffering agent derived from an inorganic acid is selected from a combination of phosphoric acid and sodium dihydrogen phosphate, a combination of phosphoric acid and potassium dihydrogen phosphate, a combination of hydrochloric acid and sodium hydroxide, a combination of sulfuric acid and sodium hydroxide, or a combination of phosphoric acid and sodium dihydrogen phosphate, a combination of phosphoric acid and potassium dihydrogen phosphate, a combination of hydrochloric acid and sodium hydroxide, or a combination of sulfuric acid and sodium hydroxide.

[0014] More preferably, the buffering agent derived from an inorganic acid is selected from a combination of phosphoric acid and potassium dihydrogen phosphate, a combination of phosphoric acid and sodium dihydrogen phosphate, or a combination of phosphoric acid and potassium dihydrogen phosphate.

[0015] Furthermore, in the pharmaceutical composition, the support agent is a disaccharide selected from any one of sucrose, trehalose, and lactose. Preferably, the support agent is sucrose.

[0016] Furthermore, in the stock solution of the freeze-dried composition before freeze-drying, the concentration of rubitidine is 0.4-0.6 mg / mL, preferably, the concentration of rubitidine is 0.5 mg / mL.

[0017] Furthermore, in the pharmaceutical composition, the molar ratio of rubitidine to proppant is 1:440 to 1:480, preferably, the molar ratio of rubitidine to proppant is 1:450 to 1:470, more preferably, the molar ratio of rubitidine to proppant is 1:455 to 1:465. Even more preferably, the molar ratio of rubitidine to proppant is 1:458.58.

[0018] Preferably, in the pharmaceutical composition, the support agent is sucrose, and the molar ratio of rubitidine to sucrose is 1:458.58, and the corresponding mass ratio is 1:200.

[0019] Furthermore, in the pharmaceutical composition, the pH value of the original solution of the freeze-dried composition before freeze-drying is 3 to 5. Preferably, the pH value of the original solution of the freeze-dried composition before freeze-drying is 3.5 to 4.5.

[0020] Furthermore, the pharmaceutical composition consists of rubitidine, phosphoric acid, potassium dihydrogen phosphate, sucrose, potassium hydroxide, and water. The concentration of rubitidine is 0.4-0.6 mg / mL, and the pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5.

[0021] Furthermore, the ingredients of each 80 mL of the pharmaceutical composition are as follows: .

[0022] Furthermore, the pharmaceutical composition consists of rubitidine, phosphoric acid, sodium dihydrogen phosphate, sucrose, and water. The concentration of rubitidine is 0.4-0.6 mg / mL, and the pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5.

[0023] Furthermore, the ingredients of each 80 mL of the pharmaceutical composition are as follows: .

[0024] The second aspect of the present invention provides a method for preparing a pharmaceutical composition containing rubitidine, comprising mixing rubitidine, a buffer, a support and water, and adjusting the pH value to obtain the pharmaceutical composition.

[0025] Furthermore, the above preparation method includes a freeze-drying process after pH adjustment. The freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying. The pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, with a vacuum degree of 0.05 to 0.5 mbar; and the secondary drying temperature is -25 to 45°C, with a vacuum degree of 0.01 to 0.5 mbar.

[0026] Preferably, the vacuum degree of the secondary drying is 0.05-0.5 mbar.

[0027] Furthermore, the time required for the pre-freezing is 0.5 to 8 hours, the time required for the primary drying (first drying) is 50 to 120 hours, and the time required for the secondary drying (second drying) is 24 to 65 hours.

[0028] Furthermore, the preparation method of the pharmaceutical composition can be selected from any one of the following three preparation methods:

[0029] Preparation method 1:

[0030] 1) mixing rubitidine with an inorganic acid;

[0031] 2) adding water, alkali / inorganic acid salt;

[0032] 3) Add proppant and adjust pH value to obtain;

[0033] Preparation method 2:

[0034] 1) mixing rubitidine with an inorganic acid;

[0035] 2) mixing alkali / inorganic acid salt, proppant, and water and adjusting the pH value;

[0036] 3) mixing the solution obtained in step 1) with the solution obtained in step 2), and adjusting the pH value to obtain;

[0037] Preparation method three:

[0038] 1) mixing an inorganic acid, an inorganic acid salt and rubitidine;

[0039] 2) Mix the proppant with water and adjust the pH value;

[0040] 3) mixing the solution obtained in step 1) with the solution obtained in step 2), and adjusting the pH value to obtain the product.

[0041] Furthermore, the preparation method of the pharmaceutical composition also includes a freeze-drying process after adjusting the pH value, and the freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying; the pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, and the vacuum degree is 0.1 to 0.5 mbar; the secondary drying temperature is -25 to 25°C, and the vacuum degree is 0.01 to 0.5 mbar.

[0042] Preferably, the vacuum degree of the secondary drying is 0.05-0.5 mbar.

[0043] Furthermore, the time required for the pre-freezing is 0.5 to 8 hours, the time required for the primary drying (first drying) is 35 to 50 hours, and the time required for the secondary drying (second drying) is 28 hours.

[0044] Preferably, the pre-freezing temperature is -40 to 5°C; and the primary drying temperature is -40 to -25°C.

[0045] Furthermore, the preparation method of the pharmaceutical composition also includes a freeze-drying process after adjusting the pH value, and the freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying; the pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, and the vacuum degree is 0.05 to 0.5 mbar; the secondary drying temperature is -25 to 45°C, and the vacuum degree is 0.01 to 0.5 mbar.

[0046] Preferably, the vacuum degree of the secondary drying is 0.05-0.5 mbar.

[0047] Furthermore, the time required for the pre-freezing is 0.5 to 8 hours, the time required for the primary drying (first drying) is 50 to 120 hours, and the time required for the secondary drying (second drying) is 24 to 65 hours. Preferably, the time required for the primary drying (first drying) is 50 to 100 hours, and the time required for the secondary drying (second drying) is 24 to 46 hours.

[0048] A third aspect of the present invention provides use of a pharmaceutical composition containing rubitidine in the preparation of an anti-tumor drug.

[0049] In the pharmaceutical composition provided by the present invention, by selecting excipients such as a buffer and a support agent, the pharmaceutical active ingredient, rubitidine, maintains good stability during lyophilization. This also solves the problem of poor solubility of rubitidine in water, thereby obtaining a rubitidine pharmaceutical composition that meets the requirements of intravenous infusion and can be stably stored. This pharmaceutical composition shows important application prospects in the preparation of anti-tumor drugs.

[0050] The present invention utilizes a combination of an inorganic acid and an inorganic acid salt or a combination of an inorganic acid and a base as a buffer, thereby ensuring that the active ingredient rubitidine can be completely dissolved during the preparation process of the pharmaceutical composition, and can ensure that the pH value of the pharmaceutical composition is stable during storage without affecting the quality and stability of the active ingredient of the pharmaceutical composition. The impurity content is low, the composition can be stored for a long time, and the osmotic pressure meets the requirements (260 to 330 mOsmol / kg) for intravenous infusion of drugs (≥100 mL).

[0051] The preparation method of the pharmaceutical composition provided by the present invention is simple to operate, has low production cost, is conducive to large-scale production, and provides assistance for the large-scale application of pharmaceutical preparations. Specific implementation plan

[0052] The following describes the embodiments of the present invention, but the present invention is not limited thereto. The present invention is not limited to the various structures described below, and various modifications can be made within the scope of the invention. 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.

[0053] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0054] In the present invention, “ / ” means “and” or “or”.

[0055] In this specification, a numerical range expressed using "numerical value A to numerical value B" or "numerical value A - numerical value B" means a range including the endpoints numerical values ​​A and B.

[0056] In this specification, the use of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0057] Unless otherwise stated, in this manual, if specific conditions are not specified, the experiments were conducted according to conventional conditions or those recommended by the manufacturer. Reagents or instruments used without manufacturer indication are commercially available conventional products.

[0058] In this specification, the units used are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0059] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "embodiments," etc., mean that the specific elements (e.g., features, structures, properties, and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0060] The concentrations of phosphoric acid, sulfuric acid, hydrochloric acid, and sodium hydroxide used in the examples of the present invention are all 0.1 mol / L. For example, when using 0.1 mol / L phosphoric acid, if 3.44 mL of phosphoric acid is used in the prescription, the theoretical corresponding molar number is 0.344 mmol, and the weight is 0.344 mmol × 97.99 g / mol = 33.71 mg.

[0061] Example 1: Prescription 1

[0062] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a combination of phosphoric acid / potassium dihydrogen phosphate as a buffer, phosphoric acid / potassium hydroxide as a pH adjuster, sucrose as a support agent, and water for injection as a solvent. The specific formula composition and dosage are shown in Table 1:

[0063] Table 1 Prescription information

[0064] Preparation method:

[0065] 1. Take 33.71 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0066] 2. Add 70% water for injection to the drug solution, stir evenly, then add 544 mg of potassium dihydrogen phosphate to the drug solution and stir to dissolve;

[0067] 3. Add 8 g of sucrose to the solution obtained in step 2, stir to dissolve, and then adjust the pH to 4.0 ± 0.2 with phosphoric acid solution or potassium hydroxide solution;

[0068] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0069] The above solution was freeze-dried to prepare a lyophilized preparation, and the appearance, moisture content, and related substances were examined. This example freeze-dried the preparation using the lyophilization procedure 1 described in Example 12. The shelf stability of the lyophilized preparation was tested under accelerated conditions (25°C, 60% RH). The results are shown in Table 2:

[0070] Table 2 Stability study of the lyophilized preparation obtained from prescription 1 Note: ①“ / ” means not detected or less than 0.05%;

[0071] As shown in Table 2, using the combination of phosphoric acid and potassium dihydrogen phosphate as a buffer, the active ingredient rubitidine was completely dissolved in the solution. The lyophilized preparation prepared by freeze-drying met the standards in terms of appearance, moisture content, and related substances. The lyophilized preparation had good stability under accelerated conditions, and the total impurities remained essentially unchanged after being stored at 25°C and 60% RH for three months. This indicates that using the combination of potassium dihydrogen phosphate and phosphoric acid as a buffer for the rubitidine preparation can improve the stability of rubitidine during storage.

[0072] Example 2: Prescription 2

[0073] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a combination of phosphoric acid / sodium dihydrogen phosphate as a buffer, phosphoric acid / sodium hydroxide as a pH adjuster, sucrose as a support agent, and water for injection as a solvent. The specific composition and dosage of the second prescription are shown in Table 3:

[0074] Table 3 Prescription II information

[0075] Preparation method:

[0076] 1. Take 33.71 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0077] 2. Add 70% water for injection to the drug solution, stir evenly, then add 480 mg of sodium dihydrogen phosphate to the drug solution and stir to dissolve;

[0078] 3. Add 8 g of sucrose to the solution obtained in step 2, stir to dissolve, and then adjust the pH to 4.0 ± 0.2 with phosphoric acid solution or sodium hydroxide solution;

[0079] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0080] The above solution was freeze-dried to prepare a lyophilized preparation, and the appearance, moisture content, and related substances were examined. This example freeze-dried the preparation using the freeze-drying procedure 1 described in Example 12. The shelf stability of the lyophilized preparation was tested under accelerated conditions (25°C, 60% RH). The results are shown in Table 4.

[0081] Table 4 Stability study of the lyophilized preparation obtained from prescription 2 Note: ①“ / ” means not detected or less than 0.05%;

[0082] As shown in Table 4, using the combination of sodium dihydrogen phosphate and phosphoric acid as a buffer, the active ingredient rubitidine was completely dissolved in the solution. The freeze-dried preparation prepared by freeze-drying met the standards in terms of appearance, moisture content, and related substances. The freeze-dried preparation had good stability under accelerated conditions. After three months of storage at 25°C and 60% RH, the total impurity level remained essentially unchanged, decreasing from 0.41 to 0.47. This indicates that the combination of sodium dihydrogen phosphate and phosphoric acid as a buffer for the rubitidine preparation can improve the stability of rubitidine during storage.

[0083] Example 3: Prescription 3

[0084] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a hydrochloric acid / sodium hydroxide combination as a buffer, hydrochloric acid / sodium hydroxide as a pH adjuster, sucrose as a support agent, and water for injection as a solvent. The specific composition and dosage of the three prescriptions are shown in Table 5:

[0085] Table 5 Prescription 3 information

[0086] Preparation method:

[0087] 1. Take 12.54 mg of hydrochloric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0088] 2. Add 70% water for injection into the drug solution and stir evenly;

[0089] 3. Add 8 g of sucrose to the solution obtained in step 2, stir to dissolve, and then adjust the pH to 4.0 ± 0.2 with hydrochloric acid solution or sodium hydroxide solution;

[0090] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0091] The above solution was freeze-dried to prepare a lyophilized formulation of Rubitidine. The appearance, moisture content, and related substances were examined. This example freeze-dried the formulation using the freeze-drying procedure 1 described in Example 12. The shelf stability of the freeze-dried formulation was tested under accelerated conditions (25°C, 60% RH). The results are shown in Table 6:

[0092] Table 6 Stability study of the lyophilized preparation obtained from prescription 3 Note: ①“ / ” means not detected or less than 0.05%;

[0093] As shown in Table 6, using the combination of hydrochloric acid and sodium hydroxide as a buffer, the active ingredient rubitidine was completely dissolved in the solution. The lyophilized preparation prepared by lyophilization met the standards in terms of appearance, moisture content, and related substances. The lyophilized preparation had good stability under accelerated conditions. After three months at 25°C and 60% RH, the total impurities decreased from 0.48 to 0.69, with minimal change in total impurities. This indicates that the combination of hydrochloric acid and sodium hydroxide as a buffer for the rubitidine preparation can ensure the stability of rubitidine during storage.

[0094] Example 4: Prescription 4

[0095] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a sulfuric acid / sodium hydroxide combination as a buffer, sulfuric acid / sodium hydroxide as a pH adjuster, sucrose as a support agent, and water for injection as a solvent. The specific composition and dosage of the fourth prescription are shown in Table 7:

[0096] Table 7 Prescription IV information

[0097] Preparation method:

[0098] 1. Take 33.71 mg of sulfuric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0099] 2. Add 70% water for injection into the drug solution and stir evenly;

[0100] 3. Add 8 g of sucrose to the solution obtained in step 2, stir to dissolve, and then adjust the pH to 4.0 ± 0.2 with sulfuric acid solution or sodium hydroxide solution;

[0101] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0102] The above solution was freeze-dried to prepare a lyophilized formulation of Rubitidine, and the appearance, moisture content, and related substances were examined. This example freeze-dried the formulation using the freeze-drying procedure 1 described in Example 12. The shelf stability of the lyophilized formulation was tested under accelerated conditions (25°C, 60% RH). The results are shown in Table 8.

[0103] Table 8 Stability study of the lyophilized preparation obtained from prescription 4 Note: ①“ / ” means not detected or less than 0.05%.

[0104] As shown in Table 8, using the combination of sulfuric acid and sodium hydroxide as a buffer, the active ingredient rubitidine was completely dissolved in the solution. The lyophilized preparation prepared by lyophilization met the standards in terms of appearance, moisture content, and related substances. The lyophilized preparation exhibited good stability under accelerated conditions. After three months at 25°C and 60% RH, the total impurities decreased from 0.67 to 0.89, with minimal change in total impurities. This indicates that the combination of sulfuric acid and sodium hydroxide, as a buffer for the rubitidine preparation, can also ensure the stability of rubitidine during storage.

[0105] Example 5: Prescription 5

[0106] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a combination of phosphoric acid and sodium dihydrogen phosphate as a buffer, sucrose as a support agent, and water for injection as a solvent. The specific composition and dosage of the fifth formula are shown in Table 9:

[0107] Table 9 Prescription V Information

[0108] Preparation method:

[0109] 1. Take 11.5 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0110] 2. Take 70% water for injection, add 8g sucrose and 294mg sodium dihydrogen phosphate, and stir to dissolve;

[0111] 3. Add all the solution obtained in step 1 to the solution obtained in step 2 and stir evenly. The pH of the resulting solution is 4.0 ± 0.2;

[0112] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0113] The above solution is freeze-dried to prepare a lyophilized preparation of Rubitidine;

[0114] The freeze drying in this embodiment is carried out using the following procedure: .

[0115] Example 6: Prescription 6

[0116] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a combination of phosphoric acid / sodium dihydrogen phosphate as a buffer, sodium hydroxide as a pH adjuster, sucrose as a support agent, and water for injection as a solvent. The specific composition and dosage of the sixth formula are shown in Table 10:

[0117] Table 10 Prescription VI Information

[0118] Preparation method:

[0119] 1. Take 33.71 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0120] 2. Take 70% water for injection, add 8g sucrose and 480mg sodium dihydrogen phosphate, and stir to dissolve;

[0121] 3. Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and adjust the pH value to 4.0±0.2 with sodium hydroxide solution;

[0122] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0123] The above solution was freeze-dried to prepare a rubitidine freeze-dried preparation.

[0124] The freeze drying in this embodiment is carried out using the following procedure: .

[0125] Example 7: Prescription 7

[0126] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a combination of phosphoric acid and potassium dihydrogen phosphate as a buffer, sodium hydroxide as a pH adjuster, sucrose as a support agent, and water for injection as a solvent. The specific composition and dosage of the formula are shown in Table 11:

[0127] Table 11 Prescription VII Information

[0128] Preparation method:

[0129] 1. Take 23.71 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0130] 2. Take 70% water for injection, add 8g sucrose and 544mg potassium dihydrogen phosphate, and stir to dissolve;

[0131] 3. Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and adjust the pH value to 4.0±0.2 with sodium hydroxide solution;

[0132] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0133] The above solution was freeze-dried to prepare a freeze-dried preparation.

[0134] The freeze drying in this embodiment is carried out using the following procedure: .

[0135] Example 8: Prescription 8

[0136] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a phosphoric acid / sodium hydroxide combination buffer, sucrose as a support agent, phosphoric acid as a pH adjuster, and water for injection as a solvent. The specific formula composition and dosage are shown in Table 12:

[0137] Table 12 Prescription VIII Information

[0138] Preparation method:

[0139] 1. Take 127.1 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0140] 2. Take 70% water for injection, add 8g sucrose and 51mg sodium hydroxide, and stir to dissolve;

[0141] 3. Add all the solution obtained in step 1 to the solution obtained in step 2, stir evenly, and adjust the pH to 4.0±0.2 with phosphoric acid;

[0142] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0143] The above solution is further freeze-dried to prepare a lyophilized preparation.

[0144] The freeze drying in this embodiment is carried out using the following procedure: .

[0145] Example 9: Prescription 9

[0146] The rubitidine pre-lyophilization solution was prepared using rubitidine as the active ingredient, a phosphoric acid / sodium hydroxide combination as a buffer, sucrose as a support agent, and water for injection as a solvent. The specific composition and dosage of the formula are shown in Table 13:

[0147] Table 13 Prescription 9 Information

[0148] Preparation method:

[0149] 1. Take 139.1 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0150] 2. Take 70% water for injection, add 8g sucrose and 51mg sodium hydroxide, and stir to dissolve;

[0151] 3. Add all the solution obtained in step 1 to the solution obtained in step 2 and stir evenly. The pH of the resulting solution is 4.0 ± 0.2;

[0152] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0153] The above solution is further freeze-dried to prepare a lyophilized preparation.

[0154] The freeze drying in this embodiment is carried out using the following procedure: .

[0155] Reference example one

[0156] Rubitidine pre-lyophilized solution was prepared using rubitidine as the active ingredient, a lactic acid / sodium hydroxide combination as a buffer, sucrose as a support agent, and water for injection as a solvent. The specific formulation composition and dosage are shown in Table 14:

[0157] Table 14 Prescription information for reference example 1

[0158] Preparation method:

[0159] 1. Take 45 mg of lactic acid, add 40 mg of lubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0160] 2. Take 70% water for injection, add 8g sucrose, 51mg sodium hydroxide, and 176mg lactic acid, and stir to dissolve;

[0161] 3. Add all the solution obtained in step 1 to the solution obtained in step 2 and stir evenly;

[0162] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0163] The above solution is further freeze-dried to prepare a lyophilized preparation.

[0164] The freeze drying in this embodiment is carried out using the following procedure: .

[0165] Example 10: Stability Study of the Freeze-Dried Preparations Obtained from Prescriptions 5 to 9 and Reference Example 1

[0166] The appearance, moisture content, and related substances of the lyophilized preparations obtained from Prescriptions 5 to 9 and Reference Example 1 were examined. The shelf stability of the lyophilized preparations under accelerated conditions (25°C / 60% RH, 40°C) was tested. The results are shown in Table 15:

[0167] Table 15 Stability study of the lyophilized preparations obtained from prescriptions 5 to 9 and reference example 1

[0168] Note: ② Impurities A, B, and C are known specific impurities in the quality standard of the reference preparation. Impurity A has an RRT of 0.78, impurity B has an RRT of 1.2, and impurity C has an RRT of 2.0.

[0169] As shown in Table 15, the impurities in the rubitidine freeze-dried composition prepared in Reference Example 1, using a lactic acid / sodium hydroxide combination as a buffer, increased from 0.20 to 0.49 after storage at 40°C for one month. The stability of Formulations 6 and 7 of the present invention was comparable to that of Reference Example 1, while the stability of Formulation 9 was slightly better than that of Reference Example 1. The stability of Formulations 5 and 8 was significantly better than that of Reference Example 1. Overall, the stability of the formulations of the present invention was superior to that of Reference Example 1, ensuring the stability of rubitidine during storage.

[0170] Example 11: Preparation methods of different pre-lyophilized solutions

[0171] Taking prescription 1 as an example, three different methods for preparing the pre-lyophilized solution were designed:

[0172] ●The first preparation method:

[0173] See Example 1 for details.

[0174] ●The second preparation method:

[0175] 1. Take 33.71 mg of phosphoric acid, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0176] 2. Take 544 mg of potassium dihydrogen phosphate and 8 g of sucrose and add them to 70% water for injection. Stir until completely dissolved. Adjust the pH to 4.0 ± 0.2 with phosphoric acid solution or potassium hydroxide solution.

[0177] 3. Add the solution obtained in step 1 to the solution obtained in step 2, mix well, and adjust the pH to 4.0±0.2 with phosphoric acid solution or potassium hydroxide solution.

[0178] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0179] ●The third preparation method:

[0180] 1. Take 33.71 mg of phosphoric acid and 544 mg of potassium dihydrogen phosphate, add 40 mg of rubitidine, and stir until the drug is completely dissolved to obtain a drug solution;

[0181] 2. Take 8g of sucrose and add it to 70% water for injection. Stir until completely dissolved. Use phosphoric acid solution or potassium hydroxide solution to adjust the pH to 4.0±0.2.

[0182] 3. Add the solution obtained in step 1 to the solution obtained in step 2, mix well, and adjust the pH to 4.0 ± 0.2 with phosphoric acid solution or potassium hydroxide solution;

[0183] 4. Adjust the above solution to the total weight and fill half of the container with a stopper.

[0184] The three solutions were freeze-dried to prepare freeze-dried preparations, and their appearance, moisture content, and related substances were examined. The shelf stability of the freeze-dried preparations was tested under accelerated conditions (25°C, 60% RH). The results are shown in Table 16:

[0185] Table 16 Stability study of lyophilized preparations obtained by different preparation methods

[0186] In addition, the appearance of the lyophilized preparation was also investigated, and the results are shown in Table 17:

[0187] Table 17 Appearance of freeze-dried preparations obtained by different preparation methods

[0188] As shown in Tables 16 and 17, the preparations prepared by the three preparation methods did not show significant changes in properties and related substances after being placed under accelerated conditions for 3 months, and no significant differences were observed between the groups. Among them, the moisture content and appearance of preparation method 1 were slightly better than those of the other two groups. To ensure better product quality, preparation method 1 can be preferred as the preparation method for the pre-lyophilization solution.

[0189] Example 12: Different freeze-drying procedures

[0190] The pre-lyophilization solution was prepared according to the formulation and preparation method of Example 1, and lyophilized according to the following three lyophilization procedures.

[0191] Table 18 Freeze-drying procedure 1

[0192] Table 19 Freeze-drying procedure 2

[0193] Table 20 Freeze-drying procedure three

[0194] The appearance, moisture content, and related substances of the freeze-dried preparation were examined. The shelf stability of the freeze-dried preparation was tested under accelerated conditions (25°C, 60% RH). The results are shown in Table 21:

[0195] Table 21 Stability study of lyophilized preparations obtained by different lyophilization procedures

[0196] In addition, the appearance of the lyophilized preparation was also investigated, and the results are shown in Table 22:

[0197] Table 22 Appearance of freeze-dried preparations obtained by different freeze-drying procedures

[0198] The results in Tables 21 and 22 show that the preparations prepared by the three freeze-drying procedures showed no significant changes in properties and related substances after being placed under accelerated conditions for 3 months, and no significant differences were observed between the groups. Among them, the moisture content and appearance of freeze-drying procedure 1 were slightly better than those of the other two groups. To ensure better product quality, freeze-drying procedure 1 can be preferred.

[0199] Example 13: Different freeze-drying procedures

[0200] The pre-lyophilized solution was prepared using the formulation and preparation method of Example 5, and lyophilized using the lyophilization procedure 4 in Table 23:

[0201] Table 23 Freeze-drying procedure 4

[0202] The appearance, moisture content, and related substances of the freeze-dried preparation obtained by freeze-drying procedure 4 were examined. The results are shown in Table 24:

[0203] Table 24 Stability study of the lyophilized preparation obtained by lyophilization procedure 4 Note: ① “ / ” indicates not detected; ② Impurities A, B, and C are known specific impurities in the quality standard of the reference preparation, with RRT of impurity A being 0.78, impurity B being 1.2, and impurity C being 2.0.

[0204] As shown in Table 24, the freeze-dried preparation obtained by freeze-drying procedure 4 did not show any significant changes in properties and related substances when placed under accelerated conditions (40°C, 60°C) for 10 or 30 days, and the moisture content was greatly reduced, resulting in a freeze-dried preparation of better quality.

[0205] While various embodiments of the present disclosure have been described above, the above descriptions are illustrative, non-exhaustive, and not intended to be limiting of the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or improvements to existing technologies, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A pharmaceutical composition containing rubitidine, characterized in that: The pharmaceutical composition is a freeze-dried composition, which comprises: rubitidine, a buffer derived from an inorganic acid, and a support.

2. The pharmaceutical composition according to claim 1, wherein The buffering agent derived from an inorganic acid is a combination of an inorganic acid and an inorganic acid salt or a combination of an inorganic acid and a base.

3. The pharmaceutical composition according to claim 2, wherein The combination of the inorganic acid and the inorganic acid salt is a combination of phosphoric acid and a phosphate; the combination of the inorganic acid and the base is a combination of hydrochloric acid and a base, a combination of sulfuric acid and a base, or a combination of phosphoric acid and a base.

4. The pharmaceutical composition according to claim 3, wherein The base is any one of sodium carbonate, potassium carbonate, NH4OH, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium bicarbonate.

5. The pharmaceutical composition according to claim 1, wherein The proppant is a disaccharide selected from any one of sucrose, trehalose and lactose.

6. The pharmaceutical composition according to claim 1, wherein In the stock solution of the freeze-dried composition before freeze-drying, the concentration of rubitidine is 0.4 to 0.6 mg / mL.

7. The pharmaceutical composition according to claim 1, wherein The molar ratio of rubidin to proppant is 1:440 to 1:

480.

8. The pharmaceutical composition according to claim 1, wherein The pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5.

9. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition consists of rubitidine, phosphoric acid, potassium dihydrogen phosphate, sucrose, potassium hydroxide and water. The concentration of rubitidine is 0.4-0.6 mg / mL, and the pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5.

10. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition consists of rubitidine, phosphoric acid, sodium dihydrogen phosphate, sucrose and water. The concentration of rubitidine is 0.4-0.6 mg / mL, and the pH value of the original solution of the freeze-dried composition before freeze-drying is 3-5.

11. The pharmaceutical composition according to claim 9, wherein The ingredients of each 80mL pharmaceutical composition are as follows:

12. The pharmaceutical composition according to claim 10, wherein The ingredients of each 80mL pharmaceutical composition are as follows:

13. The method for preparing the pharmaceutical composition according to any one of claims 1 to 12, wherein: The method comprises the following steps: mixing rubitidine, a buffer derived from an inorganic acid, a proppant and water, and adjusting the pH value to obtain the product.

14. The preparation method according to claim 13, wherein: Any of the following preparation methods: Preparation method 1: 1) mixing rubitidine with an inorganic acid; 2) adding water, alkali / inorganic acid salt; 3) Add proppant and adjust pH value to obtain; Preparation method 2: 1) mixing rubitidine with an inorganic acid; 2) mixing alkali / inorganic acid salt, proppant, and water and adjusting the pH value; 3) mixing the solution obtained in step 1) with the solution obtained in step 2), and adjusting the pH value to obtain; Preparation method three: 1) mixing an inorganic acid, an inorganic acid salt and rubitidine; 2) Mix the proppant with water and adjust the pH value; 3) mixing the solution obtained in step 1) with the solution obtained in step 2), and adjusting the pH value to obtain the product.

15. The preparation method according to claim 13, characterized in that: After adjusting the pH value, a freeze-drying process is also included, and the freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying; the pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, and the vacuum degree is 0.1 to 0.5 mbar; the secondary drying temperature is -25 to 25°C, and the vacuum degree is 0.01 to 0.5 mbar; preferably, the vacuum degree of the secondary drying is 0.05 to 0.5 mbar.

16. The preparation method according to claim 13, wherein: After adjusting the pH value, a freeze-drying process is also included, and the freeze-drying process is divided into three stages: pre-freezing, primary drying, and secondary drying; the pre-freezing temperature is -50 to 5°C; the primary drying temperature is -40 to -10°C, and the vacuum degree is 0.05 to 0.5 mbar; the secondary drying temperature is -25 to 45°C, and the vacuum degree is 0.01 to 0.5 mbar; preferably, the vacuum degree of the secondary drying is 0.05 to 0.5 mbar.

17. Use of the pharmaceutical composition according to any one of claims 1 to 12 in the preparation of anti-tumor drugs.