Tolvaptan sodium phosphate freeze-dried composition

Abstract

The invention provides a tolvaptan sodium phosphate freeze-dried composition. The tolvaptan sodium phosphate freeze-dried composition comprises tolvaptan sodium phosphate, a filling agent and a buffering agent, the composition further comprises a pH regulator. The invention also provides a preparation method of the tolvaptan sodium phosphate freeze-dried composition. The tolvaptan sodium phosphate freeze-dried composition provided by the invention has the advantages of low moisture content, good stability and simple and convenient preparation process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and specifically relates to a lyophilized composition containing tolvaptan sodium phosphate. Background Technology

[0002] Tolvaptan is an angiotensin V2 receptor antagonist. Its tablet form has been approved in China, the United States, Japan, and Europe for the treatment of hyponatremia caused by congestive heart failure, cirrhosis, and insufficiency of antidiuretic hormone secretion syndrome. However, tolvaptan has poor water solubility, belongs to the BCSIV class of drugs, and has low solubility and low permeability, resulting in low bioavailability in vivo. This imposes many limitations on its dosage form and route of administration.

[0003] WO2007 / 074915 discloses a class of tolvaptan prodrugs with excellent water solubility, and specifically discloses the tolvaptan sodium phosphate prodrug represented by formula (I).

[0004]

[0005] Chinese patent CN113645954A discloses a freeze-dried composition and an aqueous solution composition, which comprises a compound represented by formula (I) and a disaccharide, wherein the disaccharide is at least one selected from sucrose, maltose, lactose and trehalose.

[0006] In March 2022, Otsuka Pharmaceutical developed tolvaptan sodium phosphate for injection. Approved in Japan for fluid retention in heart failure that is not adequately controlled by other diuretics (such as loop diuretics). Studies show that tolvaptan sodium phosphate is rapidly hydrolyzed into the active ingredient tolvaptan after intravenous injection, providing a new treatment option for patients who cannot take tolvaptan orally. Summary of the Invention

[0007] The purpose of this invention is to provide a novel lyophilized composition containing tolvaptan sodium phosphate, based on existing technology.

[0008] In a first aspect, the present invention provides a tolvaptan sodium phosphate lyophilized composition, characterized in that the lyophilized composition comprises tolvaptan sodium phosphate, a filler, and a buffer; further, the lyophilized composition also comprises a pH adjuster.

[0009] The filler is selected from one or a combination of sucrose, mannitol, glucose, cellobiose, sodium chloride, lactulose, fructooligosaccharides, maltodextrin, fructose, L-arginine, L-threonine, maltitol, dextran 20, dextran 40, lactose, trehalose, maltose, and tromethorphan; preferably, the filler is selected from one or a combination of mannitol, fructooligosaccharides, L-arginine, and maltitol; more preferably, the filler is mannitol.

[0010] The mass ratio of tolvaptan sodium phosphate to filler is 1:(0.5-10); preferably 1:(0.9-6); more preferably 1:(2-5).

[0011] The buffer is a phosphate buffer, selected from one or a combination of anhydrous disodium hydrogen phosphate, disodium hydrogen phosphate hydrate, anhydrous sodium dihydrogen phosphate, and sodium dihydrogen phosphate hydrate; preferably, the phosphate buffer is selected from a combination of disodium hydrogen phosphate hydrate and sodium dihydrogen phosphate hydrate or a combination of anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate hydrate; more preferably, the phosphate buffer is selected from a combination of disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate monohydrate or a combination of anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate.

[0012] The pH adjuster is sodium hydroxide and / or phosphoric acid.

[0013] In this invention, sodium hydroxide and / or phosphoric acid are generally prepared as aqueous solutions to adjust pH, but the direct use of solid sodium hydroxide and / or liquid phosphoric acid should not be excluded from the scope of protection of this invention.

[0014] In some embodiments, the sodium hydroxide solution is prepared by dissolving 0.2g of sodium hydroxide in 50ml of water for injection.

[0015] In some embodiments, the phosphoric acid solution is prepared by adding 30 ml of water for injection to every 0.5 ml of phosphoric acid and dissolving it.

[0016] In this invention, the tolvaptan sodium phosphate is tolvaptan disodium phosphate salt, having the structural formula shown in formula (I):

[0017]

[0018] A second aspect of the present invention provides a method for preparing the tolvaptan sodium phosphate lyophilized composition described in the first aspect of the present invention, characterized by comprising the following steps:

[0019] (1) Dissolve tolvaptan sodium phosphate, filler and buffer in water for injection;

[0020] (2) Adjust the pH of the solution obtained in step (1) to 8.0 to 9.0, preferably 8.5 to 9.0, using a pH adjuster;

[0021] (3) Filter the solution obtained in step (2), and freeze-dry the filtrate to obtain the tolvaptan sodium phosphate freeze-dried composition.

[0022] Preferably, in step (3), the solution obtained in step (2) is filtered using a microporous membrane; more preferably, the solution obtained in step (2) is filtered using a 0.22 μm microporous membrane.

[0023] Preferably, the tolvaptan sodium phosphate lyophilized composition provided by the present invention is obtained by lyophilizing the filtrate obtained in step (3) into pharmaceutical containers.

[0024] Preferably, each pharmaceutical container contains 8–25 mg of tolvaptan sodium phosphate.

[0025] In some implementations, each pharmaceutical container contains 21.847 mg of tolvaptan sodium phosphate.

[0026] In some implementations, each pharmaceutical container contains 10.924 mg of tolvaptan sodium phosphate.

[0027] In this invention, the 16mg lyophilized formulation refers to a formulation containing 21.847mg of tolvaptan sodium phosphate per bottle.

[0028] In this invention, the 8mg lyophilized formulation refers to a formulation containing 10.924mg of tolvaptan sodium phosphate per bottle.

[0029] The pharmaceutical container described in this invention is preferably an amber or colorless glass vial with a resilient stopper and a rolled-edge aluminum cap, or any amber or colorless container suitable for immediate-use systems. The pharmaceutical container described in this invention includes, but is not limited to, ampoules or vials, with vials being preferred.

[0030] In some implementations, step (3) of the freeze-drying method includes the following steps:

[0031] (a) Freezing: Cool from room temperature to -40 to -50°C within 2 hours and maintain for 1.5 to 2.5 hours;

[0032] (b) First drying: Pre-evacuate to a vacuum of less than or equal to 0.1 mbar, raise the temperature to -20 to -30°C within 2 hours and maintain it for 10 to 11 hours; raise the temperature to -15 to -5°C within 2 hours and maintain it for 7 to 9 hours; raise the temperature to 5 to 15°C within 2 hours and maintain it for 6 to 8 hours.

[0033] (c) Drying: Apply ultimate vacuum, raise the temperature to 35-45℃ within 2 hours, and maintain it for 8-11 hours.

[0034] Preferably, the lyophilized composition of the present invention can be in the form of a lyophilized powder for injection.

[0035] Preferably, the residual moisture content of the tolvaptan sodium phosphate lyophilized composition of the present invention is not higher than 3% by mass.

[0036] In this invention, the term "room temperature" refers to 15–25°C.

[0037] A third aspect of the present invention provides a tolvaptan sodium phosphate solution for intravenous infusion, characterized in that the tolvaptan sodium phosphate lyophilized composition described in the first aspect of the present invention is dissolved in physiological saline or glucose injection to obtain the tolvaptan sodium phosphate solution for intravenous infusion.

[0038] Beneficial effects:

[0039] The tolvaptan sodium phosphate lyophilized composition provided by the present invention has the advantages of low moisture content, good stability and simple preparation process. Detailed Implementation

[0040] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0041] Example 1

[0042] prescription:

[0043] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Mannitol 22.778 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0044] Preparation method:

[0045] Weigh the prescribed amounts of tolvaptan sodium phosphate, mannitol, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate monohydrate, dissolve them in water for injection, adjust the pH of the solution to approximately 8.5 with an appropriate amount of sodium hydroxide (or phosphoric acid), and bring each vial to a final volume of 2.14 ml with water. Filter the solution through a 0.22 μm filter membrane and fill it into 7 ml lyophilization vials, with a volume of 2.14 ml per vial. Half-stop the vial with a rubber stopper. Freeze the solution using a vacuum freeze dryer, freezing at -40°C, drying once at -25°C to 10°C, and then desorbing at 40°C. After drying, tighten the rubber stopper under vacuum, remove the vial from the vacuum freeze dryer, and then screw on an aluminum cap to obtain the finished formulation.

[0046] Example 2

[0047] prescription:

[0048] Preparation method: Same as in Example 1.

[0049] Example 3

[0050] prescription:

[0051] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Mannitol 68.334 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0052] Preparation method: Same as in Example 1.

[0053] Example 4

[0054] prescription:

[0056] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Mannitol 45.556 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0058] Preparation method: Same as in Example 1.

[0059] Example 5

[0060] Example 5-1: Using the formula of Example 4 with a mannitol dosage of 91.112 mg / bottle, a solution was prepared before lyophilization. The pH was adjusted to 8.0 with an appropriate amount of sodium hydroxide (or phosphoric acid). Then, the lyophilized formulations were prepared according to the preparation method of Example 1.

[0061] Example 5-2: Using the formula of Example 4 with a mannitol dosage of 91.112 mg / bottle, prepare a solution before lyophilization, adjust the pH to 8.5 with an appropriate amount of sodium hydroxide (or phosphoric acid), and then prepare lyophilized formulations according to the preparation method of Example 1.

[0062] Examples 5-3: Using the formula of Example 4 with a mannitol dosage of 91.112 mg / bottle, prepare a solution before lyophilization, adjust the pH to 9.0 with an appropriate amount of sodium hydroxide (or phosphoric acid), and then prepare lyophilized formulations according to the preparation method of Example 1.

[0063] Example 6

[0064] prescription:

[0065] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 glucose 22.530 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0066] Preparation method: Refer to Example 1, but replace mannitol with glucose.

[0067] Example 7

[0068] prescription:

[0069] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Cellobiose 42.800 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0070] Preparation method: Refer to Example 1, but replace mannitol with cellobiose.

[0071] Example 8

[0072] prescription:

[0073] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Sodium chloride 3.654 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0074] Preparation method: Refer to Example 1, but replace mannitol with sodium chloride.

[0075] Example 9

[0076] prescription:

[0077] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 lactulose 42.800 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0078] Preparation method: Refer to Example 1, but replace mannitol with lactulose.

[0079] Example 10

[0080] prescription:

[0081] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Fructooligosaccharides 83.350 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0082] Preparation method: Refer to Example 1, but replace mannitol with fructooligosaccharides.

[0083] Example 11

[0084] prescription:

[0085] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 maltodextrin 85.600 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0086] Preparation method: Refer to Example 1, but replace mannitol with maltodextrin.

[0087] Example 12

[0088] prescription:

[0089] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 fructose 22.530 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0090] Preparation method: Refer to Example 1, but replace mannitol with fructose.

[0091] Example 13

[0092] prescription:

[0093] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 L-arginine 21.780 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0094] Preparation method: Refer to Example 1, but replace mannitol with L-arginine.

[0095] Example 14

[0096] prescription:

[0097] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 L-threonine 14.890 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0098] Preparation method: Refer to Example 1, but replace mannitol with L-threonine.

[0099] Example 15

[0100] prescription:

[0101]

[0102]

[0103] Preparation method: Refer to Example 1, but replace mannitol with maltitol.

[0104] Example 16

[0105] prescription:

[0106] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Dextran 20 300.000 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0107] Preparation method: Refer to Example 1, but replace mannitol with dextran 20.

[0108] Example 17

[0109] prescription:

[0110] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Dextran 40 300.000 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0111] Preparation method: Refer to Example 1, but replace mannitol with dextran 40.

[0112] Example 18

[0113] prescription:

[0114] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 lactose 45.050 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0115] Preparation method: Refer to Example 1, but replace mannitol with lactose.

[0116] Example 19

[0117] prescription:

[0118] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Trehalose 42.800 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0119] Preparation method: Refer to Example 1, but replace mannitol with trehalose.

[0120] Example 20

[0121] prescription:

[0122] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 maltose 42.800 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0123] Preparation method: Refer to Example 1, but replace mannitol with maltose.

[0124] Example 21

[0125] prescription:

[0126] Components Dosage per bottle / mg Tolvaptan sodium phosphate 21.847 Tromethamine 15.150 Sodium hydrogen phosphate dodecahydrate 19.260 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0127] Preparation method: Refer to Example 1, but replace mannitol with tromethamine.

[0128] Example 22

[0129] prescription:

[0130] Components Dosage per bottle / mg Tolvaptan sodium phosphate 10.924 Mannitol 68.334 disodium hydrogen phosphate 7.634 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0131] Preparation method:

[0132] Weigh the prescribed amounts of tolvaptan sodium phosphate, mannitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate monohydrate, dissolve them in water for injection, adjust the pH of the solution to approximately 8.5 with an appropriate amount of sodium hydroxide (or phosphoric acid), and bring each vial to a final volume of 2.14 ml with water. Filter the solution through a 0.22 μm filter membrane and fill it into 10 ml lyophilization vials, with a volume of 2.14 ml per vial. Half-stop the vial with a rubber stopper. Freeze the solution using a vacuum freeze dryer, freezing at -40°C, drying once at -25°C to 10°C, and then desorbing at 40°C. After drying, tighten the rubber stopper under vacuum, remove the vial from the freeze dryer, and then screw on an aluminum cap to obtain the finished formulation.

[0133] Example 23

[0134] prescription:

[0135] Components Dosage per bottle / mg Tolvaptan sodium phosphate 10.924 Mannitol 51.251 disodium hydrogen phosphate 7.634 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0136] Preparation method: Same as in Example 22.

[0137] Example 24

[0138] prescription:

[0139] Components Dosage per bottle / mg Tolvaptan sodium phosphate 10.924 Mannitol 34.167 disodium hydrogen phosphate 7.634 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0140] Preparation method: Same as in Example 22.

[0141] Example 25

[0142] prescription:

[0143] Components Dosage per bottle / mg Tolvaptan sodium phosphate 10.924 Mannitol 34.167 disodium hydrogen phosphate 7.634 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0144] Preparation method:

[0145] Weigh the prescribed amounts of tolvaptan sodium phosphate, mannitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate monohydrate, dissolve them in water for injection, adjust the pH of the solution to approximately 8.5 with an appropriate amount of sodium hydroxide (or phosphoric acid), and bring the volume of each vial to 1.07 ml with water. Filter the solution through a 0.22 μm filter membrane and fill it into 5 ml lyophilization vials, with a filling volume of 1.07 ml / vial. Half-stop the vial with a rubber stopper. Freeze the solution using a vacuum freeze dryer, freezing at -40°C, drying once at -25°C to 10°C, and then desorbing at 40°C. After drying, tighten the rubber stopper under vacuum, remove the vial from the vacuum freeze dryer, and then screw on an aluminum cap to obtain the finished formulation.

[0146] Comparative Examples 1-2

[0147] prescription:

[0148]

[0149] Preparation method:

[0150] Weigh the prescribed amounts of tolvaptan sodium phosphate, sucrose (or sucrose-free), disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate monohydrate, dissolve them in water for injection, adjust the pH of the solution to approximately 8.5 with an appropriate amount of sodium hydroxide (or phosphoric acid), and bring each vial to a final volume of 2.14 ml with water. Filter the solution through a 0.22 μm filter membrane and fill it into 7 ml lyophilization vials, with a volume of 2.14 ml per vial. Half-stop the vial with a rubber stopper. Freeze the solution using a vacuum freeze dryer, freezing at -40°C, drying once at -25°C to 10°C, and then desorbing at 40°C. After drying, tighten the rubber stopper under vacuum, remove the vial from the vacuum freeze dryer, and then screw on an aluminum cap to obtain the finished formulation.

[0151] Comparative Example 3

[0152] prescription:

[0153] Components Dosage per bottle / mg Tolvaptan sodium phosphate 10.924 sucrose 42.800 disodium hydrogen phosphate 7.634 Sodium dihydrogen phosphate monohydrate 0.321 Sodium hydroxide Appropriate amount Phosphoric acid Appropriate amount

[0154] Preparation method: Refer to Example 22, but replace mannitol with sucrose.

[0155] Test Example 1: Screening and Stability Study of Mannitol Dosage

[0156] The lyophilized formulations prepared according to the formulations in Examples 1-4 were subjected to stability studies by being placed at 60°C for 30 days. Samples were taken at 0, 10, 20, and 30 days for testing. Appearance, moisture content, tolvaptan content, and increase in tolvaptan were used as test indicators to screen the mannitol dosage in the 16mg lyophilized formulation. Lyophilized formulations prepared according to the formulations in Comparative Examples 1-2 and commercially available original formulations (batch number: 2H97STA1, 16mg specification) were placed as comparisons. The stability study results are shown in Table 1.

[0157] Table 1. Stability data of mannitol formulation screening

[0158]

[0159]

[0160] The test results show that:

[0161] During the 60℃ stability testing, the appearance of the 16mg mannitol-containing lyophilized formulation was significantly affected by the amount of mannitol used. After 30 days of testing, when the amount of mannitol was low (e.g., ≤45.556mg / vial), the formulation melted or shrank significantly in volume; when the amount of mannitol was high (e.g., ≥68.334mg / vial), the formulation had a better appearance. The 16mg mannitol-containing lyophilized formulation had lower moisture content than the original formulation, which is more conducive to moisture control. During the testing, the increase in the related substance tolvaptan was affected by the mannitol content; the increase in tolvaptan increased with the increase in mannitol usage.

[0162] Test Example 2

[0163] To further investigate the stability of the lyophilized formulation when mannitol was used as the filler, a new batch of lyophilized formulation (different batch from Test Example 1) was prepared according to the formulation of Example 3. Stability was assessed by placing the formulation under accelerated conditions (40°C, RH 75%) for 6 months. Samples were taken at 0 days, 3 months, and 6 months for testing. Appearance, moisture content, tolvaptan content, and the increase in tolvaptan were used as test indicators. A lyophilized formulation prepared according to the formulation of Comparative Example 1 (different batch from Test Example 1) and a commercially available original formulation (batch number: 2H97STA1, 16mg specification) were used as comparisons. The stability test results are shown in Table 2.

[0164] Table 2

[0165] Test Example 3: Screening of pH Value and Stability Study of Solution Before Lyophilization

[0166] The lyophilized formulations prepared in Examples 5-1, 5-2, and 5-3 were placed at 60°C for 30 days for stability testing. Samples were taken at day 0 and day 30 for testing. The increase in appearance, moisture content, and the related substance tolvaptan was used as the detection indicators. The pH value of the solution before lyophilization was also screened. The results of the stability test are shown in Table 3.

[0167] Table 3. Stability screening data based on pH value of the solution before lyophilization.

[0168]

[0169]

[0170] The test results show that:

[0171] During the 60℃ stability testing, the appearance of the lyophilized formulations with different pH values ​​of the solution before lyophilization remained unchanged; their moisture content decreased slightly, with no significant difference; the increase in the related substance tolvaptan was greatly affected by the pH value of the solution before lyophilization, with a slightly lower pH value of the solution before lyophilization resulting in a slightly higher increase in tolvaptan.

[0172] Test Example 4: Stability Study of Lyophilized Formulation After Reconstitution

[0173] Referring to the reconstitution method in the original drug's instructions, the lyophilized formulation prepared according to the prescription in Example 3 was dissolved in 50 mL of 0.9% sodium chloride injection or 5% glucose injection. The appearance, pH value, and osmotic pressure of the reconstituted solution all met the standards in the original drug's approval report.

[0174] The solutions, after being dissolved and reconstituted with 50 ml of 0.9% sodium chloride injection or 5% glucose injection, were stored in sodium chloride injection bottles or glucose injection bottles. Samples were taken at 0, 4 h, 8 h, 24 h, and 28 h to examine their compatibility stability at 2-8℃ and 30℃. The results showed that at 2-8℃ and 30℃, there were no significant changes in the appearance, pH value, content, and related substances of the solutions at each sampling point within 28 h. Visible foreign matter and insoluble particles met the pharmacopoeia requirements.

[0175] Test Example 5: Screening and Data of Freeze-drying Process

[0176] Using the formulation from Example 1, the lyophilized formulation was prepared according to lyophilization process 1 in Table 4, as follows:

[0177] Freezing control: Cool from room temperature to -40°C within 2 hours and maintain for 2 hours.

[0178] First drying: Pre-evacuate to 0.1 mbar, raise the temperature to -25°C within 2 hours and maintain it for 10 hours; raise the temperature to -10°C within 2 hours and maintain it for 8 hours; raise the temperature to 10°C within 2 hours and maintain it for 6 hours.

[0179] Analysis and drying: Apply ultimate vacuum, raise the temperature to 40°C within 2 hours, and maintain it for 11 hours.

[0180] The moisture content of the sample was 2.978%, which is comparable to the moisture content of the commercially available original reagent.

[0181] Further investigation of the freeze-drying process was conducted, and freeze-dried formulations were prepared according to freeze-drying processes 1-6 using the formulation from Example 3. Upon removal from the freeze-drying chamber, the freeze-dried formulations prepared according to processes 1-4 were plump and did not shrink, while the freeze-dried formulations prepared according to processes 5 and 6 showed signs of shrinkage or even melting.

[0182] Table 4 Freeze-drying process

[0183]

[0184] Test Example 6: Screening and Stability Study of Other Fillers

[0185] The lyophilized formulations prepared according to the formulations in Examples 6-21 were subjected to stability studies at 60°C for 30 days. Samples were taken at 0, 10, 20, and 30 days for testing. Appearance, moisture content, tolvaptan content, and the increase in tolvaptan were used as test indicators to screen for other fillers. The lyophilized formulation prepared in Comparative Example 1 and the commercially available original formulation (batch number: 2H97STA1, 16mg specification) were placed together for comparison. The stability study results are shown in Table 5.

[0186] Table 5. Stability data for other fillers.

[0187]

[0188]

[0189]

[0190] The test results show that:

[0191] During the 60℃ stability testing process, the appearance of the lyophilized formulations prepared according to the formulations of Examples 10, 13, 15 and 19 remained unchanged, but the moisture content increased. The content of the related substance tolvaptan was less or equivalent to that of the original formulation. It is also feasible to use fructooligosaccharides, L-arginine, maltitol or trehalose as fillers.

[0192] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing description of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A tolvaptan sodium phosphate lyophilized composition, characterized in that, The lyophilized composition comprises tolvaptan sodium phosphate, a filler, and a buffer; furthermore, the lyophilized composition also comprises a pH adjuster.

2. The lyophilized composition according to claim 1, characterized in that, The filler is selected from one or a combination of sucrose, mannitol, glucose, cellobiose, sodium chloride, lactulose, fructooligosaccharides, maltodextrin, fructose, L-arginine, L-threonine, maltitol, dextran 20, dextran 40, lactose, trehalose, maltose, and tromethamine. Preferably, the filler is selected from one or a combination of mannitol, fructooligosaccharides, L-arginine, and maltitol; more preferably, the filler is mannitol. The mass ratio of tolvaptan sodium phosphate to filler is 1:(0.5-10); preferably 1:(0.9-6); more preferably 1:(2-5).

3. The lyophilized composition according to claim 1, characterized in that, The buffer is a phosphate buffer, which is selected from one or a combination of anhydrous disodium hydrogen phosphate, disodium hydrogen phosphate hydrate, anhydrous sodium dihydrogen phosphate, and sodium dihydrogen phosphate hydrate. Preferably, the phosphate buffer is selected from a combination of disodium hydrogen phosphate hydrate and sodium dihydrogen phosphate hydrate or a combination of anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate hydrate; More preferably, the phosphate buffer is selected from a combination of disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate monohydrate or a combination of anhydrous disodium hydrogen phosphate and sodium dihydrogen phosphate monohydrate.

4. The lyophilized composition according to claim 1, characterized in that, The pH adjuster is sodium hydroxide and / or phosphoric acid.

5. The lyophilized composition according to claim 1, characterized in that, The residual moisture content in the freeze-dried composition is not higher than 3% by mass.

6. A method for preparing the freeze-dried composition according to any one of claims 1 to 5, characterized in that, Includes the following steps: (1) Dissolve tolvaptan sodium phosphate, filler and buffer in water for injection; (2) Adjust the pH of the solution obtained in step (1) to 8.0 to 9.0, preferably 8.5 to 9.0, using a pH adjuster; (3) Filter the solution obtained in step (2), and freeze-dry the filtrate to obtain the freeze-dried composition.

7. The method according to claim 6, characterized in that, In step (3), the solution obtained in step (2) is filtered using a microporous membrane, preferably using a 0.22 μm microporous membrane.

8. The method according to claim 6, characterized in that, The filtrate obtained in step (3) is dispensed into pharmaceutical containers and freeze-dried. Each pharmaceutical container contains 8-25 mg of tolvaptan sodium phosphate. The pharmaceutical container is a vial.

9. The method according to claim 6, characterized in that, The freeze-drying method in step (3) includes the following steps: (a) Freezing: Cool from room temperature to -40 to -50°C within 2 hours and maintain for 1.5 to 2.5 hours; (b) First drying: Pre-evacuate to a vacuum of less than or equal to 0.1 mbar, raise the temperature to -20 to -30°C within 2 hours and maintain it for 10 to 11 hours; raise the temperature to -15 to -5°C within 2 hours and maintain it for 7 to 9 hours; raise the temperature to 5 to 15°C within 2 hours and maintain it for 6 to 8 hours. (c) Drying: Apply ultimate vacuum, raise the temperature to 35-45°C within 2 hours, and maintain it for 8-11 hours.

10. A tolvaptan sodium phosphate solution for intravenous infusion, characterized in that, The solution is prepared by dissolving the lyophilized composition according to any one of claims 1 to 5 in physiological saline or glucose injection.

Images