Lyophilized composition containing tolvaptan sodium phosphate and preparation method for lyophilized composition

Abstract

The present invention provides a lyophilized composition containing tolvaptan sodium phosphate and a preparation method for the lyophilized composition. One or more of maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, polyethylene glycol, xylitol, or sorbitol is / are used as a lyoprotectant, so that the problem in the prior art that lyophilized compositions containing tolvaptan sodium phosphate are difficult to satisfy both high stability and high clarity; provided a tolvaptan sodium phosphate-containing composition which satisfies both high stability and high clarity, has a high dissolution rate and is easy to apply, reducing generation of impurities; in addition, in the preparation and long-term storage process, better stability is achieved, the opalescence and turbidity of liquid medicine during reconstitution and redissolution are avoided, dissolution is easier, and safe application of the product is facilitated.

Description

A lyophilized composition containing tolvaptan sodium phosphate and its preparation method Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a lyophilized composition containing tolvaptan sodium phosphate, and a method for preparing the composition. Background Technology

[0002] Tolvaptan is a non-peptide angiotensin V2 receptor antagonist that counteracts the antidiuretic effect of abnormally increased AVP on the kidneys in heart failure, improving water retention and hyponatremia in heart failure patients. It is currently widely used to treat heart failure, cirrhosis, syndrome of abnormal antidiuretic hormone secretion, polycystic kidney disease, and other related conditions.

[0003] Tolvaptan has poor water solubility. Therefore, developing a tolvaptan drug that is easily administered intravenously for patients who cannot take oral medication is of great significance in order to improve its solubility. For example, patent CN101346390A discloses a water-soluble benzodiazepine... The compound and its pharmaceutical composition specifically disclose the tolvaptan prodrug, tolvaptan sodium phosphate. Although the prodrug has good water solubility, the stability of tolvaptan sodium phosphate is poor due to the easy dissociation of the phosphate group. During the preparation and storage of the composition, it is easy to dissociate back into tolvaptan, affecting the efficacy of the drug. Furthermore, it may generate turbidity and insoluble foreign matter during reconstruction, which has a significant impact on clinical safety.

[0004] In response, patent CN113645954A discloses a compound containing benzo[a]aza ... The lyophilized composition of the compound, specifically a lyophilized composition containing tolvaptan sodium phosphate, improves the stability of the tolvaptan sodium phosphate composition and reduces the formation of tolvaptan by adding disaccharides (e.g., sucrose, maltose, lactose, or trehalose). However, while this approach effectively inhibits the formation of insoluble tolvaptan in the composition, as the amount of disaccharide increases, foaming and slight turbidity occur during reconstitution, requiring prolonged standing for degassing. This results in excessively long preparation times and significant inconvenience for use. Summary of the Invention

[0005] The present application aims to solve the problem that the stability of the raw material drug of tolvaptan sodium phosphate is insufficient in the prior art, and the clarity of the obtained lyophilized composition is poor after adding a protective agent, and the phenomenon of opalescence, foaming and turbidity is easy to occur, so it is difficult to balance the high stability and high clarity of the tolvaptan sodium phosphate composition, and the present application provides a tolvaptan sodium phosphate composition which can simultaneously satisfy high stability and high clarity, has a faster dissolution speed, is convenient to administer, reduces the generation of impurities, and has better stability during preparation and long-term storage, and solves the opalescence and turbidity of the drug solution during reconstitution.

[0006] Another object of the present application is to provide a preparation method of the above-mentioned lyophilized composition containing tolvaptan sodium phosphate.

[0007] The technical scheme of the present application is as follows:

[0008] A lyophilized composition containing tolvaptan sodium phosphate is prepared by using the raw material drug of tolvaptan sodium phosphate, sodium phosphate, sodium phosphate, a lyophilization protective agent and water for injection to prepare a drug solution, filtering and sterilizing, filling, and then lyophilizing to obtain the finished product; in the preparation process of the drug solution, a pH regulator is used to adjust the pH value to 7.5-10.0, wherein the lyophilization protective agent is one or more of maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide or polyethylene glycol.

[0009] In the present application, the structural formula of the raw material drug of tolvaptan sodium phosphate is as follows:

[0010] For the present application, the pH regulator is phosphoric acid and / or sodium hydroxide. In the preparation process of the drug solution, the pH regulator is used to adjust the pH value to 7.5-10.0. Preferably, in the preparation process of the drug solution, the pH regulator is used to adjust the pH value to 8.5-9.0. More preferably, the pH regulator is used to adjust the pH value to 8.8-8.9.

[0011] In the present application, one or more of maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide or polyethylene glycol is used as the lyophilization protective agent, which solves the problem that the prior art lyophilized composition containing tolvaptan sodium phosphate is difficult to simultaneously satisfy high stability and high clarity, and provides a tolvaptan sodium phosphate composition which can simultaneously satisfy high stability and high clarity, has a faster dissolution speed, is convenient to administer, reduces the generation of impurities, and has better stability during preparation and long-term storage, solves the opalescence and turbidity of the drug solution during reconstitution, is easier to dissolve, and is beneficial to the safe administration of the product.

[0012] In a preferred embodiment, the lyoprotectant is one or more of maltitol, raffinose, dextran, stachyose or polyethylene glycol.

[0013] Further, the lyoprotectant is maltitol, raffinose or polyethylene glycol.

[0014] In a preferred embodiment, the lyophilized composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of solution: tolvaptan sodium phosphate 1-25 mg, sodium phosphate monobasic 0.05-0.8 mg, sodium phosphate dibasic 5.0-30.0 mg, and a lyoprotectant 20-250 mg.

[0015] In a more preferred embodiment, the lyophilized composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of solution: tolvaptan sodium phosphate 2-22 mg, sodium phosphate monobasic 0.1-0.5 mg, sodium phosphate dibasic 10.0-26.0 mg, and a lyoprotectant 30.0-200 mg.

[0016] In a particularly preferred embodiment, the lyophilized composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of solution: tolvaptan sodium phosphate 4-20 mg, sodium phosphate monobasic 0.16-0.32 mg, sodium phosphate dibasic 14.4-24.0 mg, and a lyoprotectant 40-180 mg.

[0017] For example, the lyophilized composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, and maltitol 40 mg.

[0018] The lyophilized composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, and maltitol 80 mg.

[0019] The lyophilized composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, and maltitol 160 mg.

[0020] The lyophilized composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, and raffinose 40 mg.

[0021] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and raffinose 80mg.

[0022] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and raffinose 160mg.

[0023] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 4mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 16.0mg, and raffinose 40mg.

[0024] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 16.0mg, and raffinose 40mg.

[0025] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 20mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 24.0mg, and raffinose 40mg.

[0026] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.16mg, disodium hydrogen phosphate 16.0mg, and raffinose 40mg.

[0027] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and dextran 40mg.

[0028] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and stachyose 40mg.

[0029] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of medicinal liquid: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and arabinogalactan 40mg.

[0030] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of the medicinal solution: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and fructose oligomer 40mg.

[0031] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of the medicinal solution: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and galactose oligomer 40mg.

[0032] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of the medicinal solution: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and isomaltulose oligomer 40mg.

[0033] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of the medicinal solution: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and polyethylene glycol 400 40mg.

[0034] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of the medicinal solution: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, polyethylene glycol 400 20mg, and dextran 40mg.

[0035] The freeze-dried composition containing tolvaptan sodium phosphate provided by the present application contains the following components by weight per 2ml of the medicinal solution: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, maltitol 160mg, and polyethylene glycol 2000 20mg.

[0036] The present application also provides a preparation method of the freeze-dried composition containing tolvaptan sodium phosphate described above, which comprises the following steps:

[0037] (1) Dissolve sodium dihydrogen phosphate and disodium hydrogen phosphate in part of water for injection, add a freeze-drying protective agent during stirring, and then add tolvaptan sodium phosphate after uniform stirring, and continuously stir until completely dissolved;

[0038] (2) Adjust the pH value of the solution obtained in step (1) to 7.5-10.0 by using a pH adjuster, add the remaining water for injection to constant volume, and stir to obtain a medicinal solution;

[0039] (3) After the preparation of the medicinal solution is completed, perform sterilization filtration, filling, and freeze-drying to obtain the finished product.

[0040] For the present application, in step (1), the amount of water for injection added is 75-95% of the total amount, preferably 90%.

[0041] For the present application, in step (2), the pH adjusting agent is phosphoric acid and / or sodium hydroxide, and in the preparation of the medicinal solution, the pH adjusting agent is used to adjust the pH value to 7.5-10.0. Preferably, in the preparation of the medicinal solution, the pH adjusting agent is used to adjust the pH value to 8.5-9.0. More preferably, the pH adjusting agent is used to adjust the pH value to 8.8-8.9.

[0042] In step (3), the process of filter sterilization is as follows: the medicinal solution is first filtered through a 0.45 μm PTFE filter membrane, and then through a 0.22 μm PTFE filter membrane.

[0043] For the present application, in step (3), the process of freeze-drying is as follows:

[0044] (1) Pre-freezing: the filled medicinal solution is cooled to -55°C to -45°C, the cooling time is 2-5 hours, and the holding time is 1-6 hours;

[0045] (2) Sublimation drying: the vacuum is controlled at 10-20 Pa, the temperature is raised to -10°C to 0°C, the raising time is 1-3 hours, and the holding time is 3-15 hours; the temperature is further raised to 0°C to 10°C, the raising time is 2-8 hours, and the holding time is 1-10 hours;

[0046] (3) Desorption drying: the vacuum is controlled at 1-5 Pa, the temperature is raised to 20°C to 40°C, the raising time is 3-6 hours, and the holding time is 5-10 hours.

[0047] In a preferred embodiment, the process of freeze-drying is as follows:

[0048] (1) Pre-freezing: the filled medicinal solution is cooled to -50°C, the cooling time is 3 hours, and the holding time is 3 hours;

[0049] (2) Sublimation drying: the vacuum is controlled at 10-20 Pa, the temperature is raised to -10°C to 0°C, the raising time is 2 hours, and the holding time is 6 hours; the temperature is further raised to 0°C to 10°C, the raising time is 6 hours, and the holding time is 3 hours;

[0050] (3) Desorption drying: the vacuum is controlled at 1-5 Pa, the temperature is raised to 30°C, the raising time is 4 hours, and the holding time is 6 hours.

[0051] A lyophilized composition containing tolvaptan sodium phosphate, comprising tolvaptan sodium phosphate and a lyophilization protective agent, wherein the lyophilization protective agent is one or more of maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, polyethylene glycol, xylitol or sorbitol.

[0052] The weight ratio of tolvaptan sodium phosphate and the lyophilization protective agent is 2-24:10-80, preferably 2-22:15-70, and more preferably 8-16:20-60.

[0053] In the present application, one or more of maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, polyethylene glycol, xylitol or sorbitol is used as the lyophilization protective agent to solve the problem that the prior art lyophilized composition containing tolvaptan sodium phosphate cannot simultaneously satisfy high stability and high clarity, and to provide a tolvaptan sodium phosphate composition that can simultaneously satisfy high stability and high clarity, has a faster dissolution speed, is easy to administer, reduces the generation of impurities, has better stability during preparation and long-term storage, solves the phenomenon of opalescence and turbidity of the drug solution during reconstitution, is easier to dissolve, and is conducive to the safe administration of the product.

[0054] For the present application, the pH adjusting agent is phosphoric acid and / or sodium hydroxide. Preferably, the pH of the drug solution is adjusted to 8.0-9.0 using the pH adjusting agent during preparation of the drug solution.

[0055] In a preferred embodiment, a lyophilized composition containing tolvaptan sodium phosphate is prepared by mainly using tolvaptan sodium phosphate, sodium phosphate dibasic or sodium phosphate dibasic hydrate, sodium phosphate monobasic or sodium phosphate monobasic hydrate, a lyophilization protective agent and water for injection to prepare a drug solution, filtering and sterilizing, filling, and lyophilizing to obtain the finished product. The pH of the drug solution is adjusted to 8.0-9.0 using a pH adjusting agent during preparation of the drug solution.

[0056] In the present application, the sodium phosphate monobasic hydrate is sodium phosphate monobasic monohydrate or sodium phosphate monobasic dihydrate, and the sodium phosphate dibasic hydrate is sodium phosphate dibasic monohydrate, sodium phosphate dibasic dihydrate, sodium phosphate dibasic heptahydrate or sodium phosphate dibasic dodecahydrate.

[0057] In a preferred embodiment, the present application provides a lyophilized composition containing sodium frusemide phosphate, which contains the following components by weight per 2 ml of the medicinal liquid: 2-24 mg of sodium frusemide phosphate, 0.05-1.0 mg of sodium phosphate dibasic dihydrate, 5-30 mg of sodium phosphate dibasic dodecahydrate, and 10-80 mg of a lyophilization protective agent; or, 1-25 mg of sodium frusemide phosphate, 0.05-0.8 mg of sodium phosphate dibasic, 5.0-30.0 mg of sodium phosphate dibasic, and 20-250 mg of a lyophilization protective agent.

[0058] In a more preferred embodiment, the present application provides a lyophilized composition containing sodium frusemide phosphate, which contains the following components by weight per 2 ml of the medicinal liquid: 2-22 mg of sodium frusemide phosphate, 0.1-0.5 mg of sodium phosphate dibasic dihydrate, 10-24 mg of sodium phosphate dibasic dodecahydrate, and 15-70 mg of a lyophilization protective agent; or, 2-22 mg of sodium frusemide phosphate, 0.1-0.5 mg of sodium phosphate dibasic, 10.0-26.0 mg of sodium phosphate dibasic, and 30.0-200 mg of a lyophilization protective agent.

[0059] In a particularly preferred embodiment, the present application provides a lyophilized composition containing sodium frusemide phosphate, which contains the following components by weight per 2 ml of the medicinal liquid: 8-16 mg of sodium frusemide phosphate, 0.15-0.45 mg of sodium phosphate dibasic dihydrate, 16-22 mg of sodium phosphate dibasic dodecahydrate, and 20-60 mg of a lyophilization protective agent; or, 4-20 mg of sodium frusemide phosphate, 0.16-0.32 mg of sodium phosphate dibasic, 14.4-24.0 mg of sodium phosphate dibasic, and 40-180 mg of a lyophilization protective agent.

[0060] For example, the present application provides a lyophilized composition containing sodium frusemide phosphate, which contains the following components by weight per 2 ml of the medicinal liquid: 8 mg of sodium frusemide phosphate, 0.32 mg of sodium phosphate dibasic, 14.4 mg of sodium phosphate dibasic, and 40 mg of maltitol.

[0061] The present application provides a lyophilized composition containing sodium frusemide phosphate, which contains the following components by weight per 2 ml of the medicinal liquid: 8 mg of sodium frusemide phosphate, 0.32 mg of sodium phosphate dibasic, 14.4 mg of sodium phosphate dibasic, and 80 mg of maltitol.

[0062] The present application provides a lyophilized composition containing sodium frusemide phosphate, which contains the following components by weight per 2 ml of the medicinal liquid: 8 mg of sodium frusemide phosphate, 0.32 mg of sodium phosphate dibasic, 14.4 mg of sodium phosphate dibasic, and 160 mg of maltitol.

[0063] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and raffinose 40mg.

[0064] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and raffinose 80mg.

[0065] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and raffinose 160mg.

[0066] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 4mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 16.0mg, and raffinose 40mg.

[0067] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 16.0mg, and raffinose 40mg.

[0068] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 20mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 24.0mg, and raffinose 40mg.

[0069] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 8mg, sodium dihydrogen phosphate 0.16mg, disodium hydrogen phosphate 16.0mg, and raffinose 40mg.

[0070] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and dextran 40mg.

[0071] The freeze-dried composition containing sodium phosphate of tolvaptan provided by the present application contains the following components by weight per 2ml of medicinal liquid: sodium phosphate of tolvaptan 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, and stachyose 40mg.

[0072] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of arabinogalactan.

[0073] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of fructooligosaccharide.

[0074] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of galactooligosaccharide.

[0075] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of isomaltulose.

[0076] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of polyethylene glycol 400.

[0077] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of polyethylene glycol 400.

[0078] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of polyethylene glycol 2000.

[0079] The present application provides a lyophilized composition containing sodium phosphate of tolvaptan, and each 2ml of the medicinal liquid contains the following components by weight: 8mg of sodium phosphate of tolvaptan, 0.32mg of sodium dihydrogen phosphate, 14.4mg of disodium hydrogen phosphate, 40mg of polyethylene glycol 2000.

[0080] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 16 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, and maltitol 40 mg.

[0081] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, and xylitol 40 mg.

[0082] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 16 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, and xylitol 40 mg.

[0083] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, and sorbitol 40 mg.

[0084] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 16 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, and sorbitol 40 mg.

[0085] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.15 mg, sodium phosphate dibasic dodecahydrate 18 mg, and maltitol 40 mg.

[0086] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.45 mg, sodium phosphate dibasic dodecahydrate 18 mg, and maltitol 40 mg.

[0087] The freeze-dried composition containing tolvaptan sodium phosphate according to the present application contains the following components by weight per 2 ml of the drug solution: tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, and sorbitol 20 mg.

[0088] The application provides a lyophilized composition containing tolvaptan sodium phosphate, and each 2ml of the medicine solution contains the following components by weight: tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate dihydrate 0.3mg, disodium hydrogen phosphate dodecahydrate 18mg, sorbitol 60mg.

[0089] The application also provides a preparation method of the lyophilized composition containing tolvaptan sodium phosphate.

[0090] (1) Dissolve sodium dihydrogen phosphate or sodium dihydrogen phosphate hydrate and disodium hydrogen phosphate or disodium hydrogen phosphate hydrate in part of water for injection, and add tolvaptan sodium phosphate and a lyophilization protective agent during stirring, and continuously stir until completely dissolved;

[0091] (2) Adjust the pH value of the solution obtained in step (1) to 8.0-9.0 by using a pH regulator, add the remaining water for injection to constant volume, and stir to obtain a medicine solution;

[0092] (3) After the preparation of the medicine solution is completed, sterilization filtration is carried out, and the medicine solution is filled and lyophilized to obtain a finished product.

[0093] For the application, the amount of water for injection added in step (1) is 70-90% of the total amount, and preferably 80%.

[0094] For the application, in step (1), the sodium dihydrogen phosphate hydrate is sodium dihydrogen phosphate monohydrate or sodium dihydrogen phosphate dihydrate; and the disodium hydrogen phosphate hydrate is disodium hydrogen phosphate monohydrate, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate heptahydrate or disodium hydrogen phosphate dodecahydrate.

[0095] For the application, in step (2), the pH regulator is phosphoric acid and / or sodium hydroxide, and the pH value of the medicine solution is adjusted to 8.0-9.0 by using the pH regulator during the preparation of the medicine solution.

[0096] In step (3), the sterilization filtration process is as follows: the medicine solution is first filtered through a 0.45μm PTFE filter membrane, and then filtered through a 0.22μm PTFE filter membrane.

[0097] For the application, in step (3), the lyophilization process is as follows:

[0098] 1) Pre-freezing: the medicine solution with a half stopper after filling is placed in a freeze dryer, cooled to-12℃ to-8℃, kept for 1-6 hours, continuously cooled to-50℃ to-40℃, and kept for 1-6 hours;

[0099] 2) Sublimation drying: control the vacuum to be 10-25Pa, heat to-15℃ to 0℃, keep for 4-10 hours; continuously heat to 0℃ to 15℃, and keep for 6-12 hours;

[0100] 3) Sublimation drying: control the vacuum at 1-10 Pa, and raise the temperature to 35-45℃, and keep for 3-10 hours.

[0101] In a preferred solution, in step (3), the freeze-drying process is as follows:

[0102] 1) Pre-freezing: place the half-corked medicine liquid after filling in the freeze dryer, and lower the temperature to -10℃, keep for 2 hours, and continue to lower the temperature to -45℃, keep for 2 hours;

[0103] 2) Sublimation drying: control the vacuum at 15 Pa, and raise the temperature to -10℃, keep for 6 hours; continue to raise the temperature to 10℃, keep for 10 hours;

[0104] 3) Elution drying: control the vacuum at 5 Pa, and raise the temperature to 40℃, keep for 5 hours.

[0105] In a preferred solution, in step (3), the freeze-drying process is as follows:

[0106] 1) Pre-freezing: place the half-corked medicine liquid after filling in the freeze dryer, and lower the temperature to -10℃, keep for 2 hours, and continue to lower the temperature to -45℃, keep for 4 hours;

[0107] 2) Sublimation drying: control the vacuum at 15 Pa, and raise the temperature to -5℃, keep for 6 hours; continue to raise the temperature to 5℃, keep for 8 hours;

[0108] 3) Elution drying: control the vacuum at 5 Pa, and raise the temperature to 40℃, keep for 5 hours.

[0109] In a preferred solution, in step (3), the freeze-drying process is as follows:

[0110] 1) Pre-freezing: place the half-corked medicine liquid after filling in the freeze dryer, and lower the temperature to -10℃, keep for 2 hours, and continue to lower the temperature to -45℃, keep for 4 hours;

[0111] 2) Sublimation drying: control the vacuum at 20 Pa, and raise the temperature to -2℃, keep for 6 hours; continue to raise the temperature to 2℃, keep for 8 hours;

[0112] 3) Elution drying: control the vacuum at 3 Pa, and raise the temperature to 40℃, keep for 5 hours.

[0113] The technical solution of the present application has the following advantages:

[0114] The present application uses one or more of maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, polyethylene glycol, xylitol or sorbitol as a lyophilization protective agent, solves the problem that the lyophilized composition containing tolvaptan sodium phosphate in the prior art is difficult to simultaneously meet high stability and high clarity, and provides a composition of tolvaptan sodium phosphate which can simultaneously meet high stability and high clarity, has a faster dissolution speed, is convenient to administer, reduces the generation of impurities, has better stability during preparation and long-term storage, solves the phenomenon of opalescence and turbidity of the drug solution during reconstitution, is easier to dissolve, and is beneficial to the safe administration of the product. BRIEF DESCRIPTION OF DRAWINGS

[0115] Figure 1 is a comparison chart of the dissolution of the compositions obtained in Examples 1-10 and Comparative Examples 1-2 after reconstitution;

[0116] Figure 2 is a comparison chart of the dissolution of the compositions obtained in Examples 13-17 after reconstitution;

[0117] Figure 3 is a comparison chart of the appearance of the drug solution prepared before lyophilization in Examples 1-4, Example 9 and Comparative Example 5 after being placed at 60°C for 7 days. DETAILED DESCRIPTION

[0118] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0119] The tolvaptan sodium phosphate used in the present application can be prepared by the method disclosed in the prior art patent CN101346390A.

[0120] Examples 1-10

[0121] A lyophilized composition containing tolvaptan sodium phosphate is made from the following components by weight, and the components and weights in Examples 1-10 are shown in Table 1.

[0122] Table 1 Components and amounts

[0123] The preparation method of the lyophilized composition in Example 1 is as follows:

[0124] (1) Dissolve sodium dihydrogen phosphate and disodium hydrogen phosphate in 90% of the total amount of water for injection, add maltitol during stirring, and then add tolvaptan sodium phosphate after uniform stirring, and continue stirring until complete dissolution;

[0125] (2) Adjust the pH of the solution obtained in step (1) to 8.8-8.9 using phosphoric acid and / or sodium hydroxide, add the remaining water for injection to make up to 2 mL, and stir to obtain a medicinal solution;

[0126] (3) After the medicinal solution is prepared, the medicinal solution is first filtered through a 0.45 μm PTFE filter membrane, then filtered through a 0.22 μm PTFE filter membrane for sterilization, and then filled into a corresponding vial, and the product is obtained after lyophilization.

[0127] The lyophilization process is as follows:

[0128] 1) Pre-freezing: the filled medicinal solution is cooled to -50°C, the cooling time is 3 hours, and the holding time is 3 hours;

[0129] 2) Sublimation drying: control the vacuum at 10-20 Pa, and raise the temperature to -10°C-0°C, the temperature raising time is 2 hours, and the holding time is 6 hours; continue to raise the temperature to 0°C-10°C, the temperature raising time is 6 hours, and the holding time is 3 hours;

[0130] 3) Desorption drying: control the vacuum at 1-5 Pa, and raise the temperature to 30°C, the temperature raising time is 4 hours, and the holding time is 6 hours.

[0131] In the preparation process, compared with Example 1, the difference of Examples 2-10 is that the maltitol is replaced by raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltulose, polyethylene glycol, and polyethylene glycol and dextran, respectively.

[0132] Comparative Examples 1-4

[0133] A lyophilized composition containing tolvaptan sodium phosphate is made from the following components by weight. The components and weights of Comparative Examples 1-4 are shown in Table 2.

[0134] Table 2 Components and amounts

[0135] The preparation method of the lyophilized composition in Comparative Example 1 is as follows:

[0136] (1) Dissolve sodium dihydrogen phosphate and disodium hydrogen phosphate in 90% of the total amount of water for injection, and add sucrose during stirring. After stirring uniformly, add tolvaptan sodium phosphate, and continue stirring until completely dissolved;

[0137] (2) Adjust the pH of the solution obtained in step (1) to 8.8-8.9 using phosphoric acid and / or sodium hydroxide, add the remaining water for injection to make up to 2 mL, and stir to obtain a medicinal solution;

[0138] (3) After the preparation of the liquid medicine, the liquid medicine is first filtered through a 0.45 μm PTFE filter membrane, and then filtered through a 0.22 μm PTFE filter membrane for sterilization and filtration, and then filled into the corresponding penicillin bottles, and then freeze-dried to obtain the finished product.

[0139] The freeze-drying process is as follows:

[0140] 1) Pre-freezing: the filled liquid medicine is cooled to -50°C, the cooling time is 3 hours, and the holding time is 3 hours;

[0141] 2) Sublimation drying: control the vacuum at 10-20 Pa, and raise the temperature to -10°C-0°C, the temperature raising time is 2 hours, and the holding time is 6 hours; continue to raise the temperature to 0°C-10°C, the temperature raising time is 6 hours, and the holding time is 3 hours;

[0142] 3) Desorption drying: control the vacuum at 1-5 Pa, and raise the temperature to 30°C, the temperature raising time is 4 hours, and the holding time is 6 hours.

[0143] In the preparation process, the difference between Comparative Example 1 and Comparative Examples 2-4 is that sucrose is replaced by trehalose, mannitol and cellobiose in turn.

[0144] Example 11: Stability comparison of the freeze-dried compositions obtained in the foregoing Examples 1-10 and Comparative Examples 1-4

[0145] The freeze-dried compositions prepared in the foregoing Examples 1-10 and Comparative Examples 1-4 are respectively placed at a high temperature of 60°C, and the changes in properties and related substances are compared, the related substances are detected by HPLC and the data are given by area normalization method, as shown in Table 3.

[0146] Table 3: Test results of influencing factors of Examples 1-10 and Comparative Examples 1-4

[0147] The results in Table 3 show that the freeze-dried products prepared by adding maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltulose, polyethylene glycol 400, and polyethylene glycol 400 and dextran as freeze-drying protectants in Examples 1-10 have lower impurities and high thermal stability, which are better than Comparative Examples 3 and 4 using mannitol and cellobiose, and are comparable to Comparative Examples 1 and 2 using sucrose and trehalose. Therefore, it can be shown that the freeze-dried compositions prepared in all the above examples of the present application have high stability.

[0148] Example 12: Reconstitution comparison of the freeze-dried compositions obtained in the foregoing Examples 1-10 and Comparative Examples 1-2

[0149] To the freeze-dried composition prepared in the foregoing Examples 1-10 and Comparative Examples 1-2, 4 mL of normal saline was added, respectively, and the time at which the composition was fully dissolved and the bubbling and turbidity completely disappeared was recorded, respectively, as the reconstitution time. The reconstituted solution was compared with the turbidity standard solution, and the recorded reconstitution time and clarity are shown in Table 4, and the images of the obtained solutions are shown in FIG. 1.

[0150] Table 4 Comparison of reconstitution of Examples 1-10 and Comparative Examples 1-2

[0151] The results of Table 4 and FIG. 1 show that the finished products prepared in Examples 1-10 have good dissolution and defoaming speed, and the reconstituted solution of the finished products has no obvious opalescence. Compared with the opalescence that is difficult to disappear in Comparative Examples 1 and 2, Examples 1-10 have a more optimal dissolution effect.

[0152] In combination with Table 3 above, it can be confirmed that the freeze-dried composition prepared in the foregoing Examples 1-10 has good stability and high solubility.

[0153] Examples 13-17:

[0154] A freeze-dried composition containing tolvaptan sodium phosphate is prepared from the following components by weight, and the components and weights of Examples 1-10 are shown in Table 5.

[0155] Table 5 Components and amounts

[0156] The preparation method is the same as that of Example 1, except that the type or amount of the corresponding protective agent is changed.

[0157] Example 18: Comparison of stability of different freeze-dried compositions in the foregoing Examples 13-17

[0158] The compositions prepared in the foregoing Examples 13-17 were freeze-dried and placed at a high temperature of 60°C, respectively, and the changes in properties and related substances were compared. The related substances were detected by HPLC and data were given by area normalization, and are shown in Table 6.

[0159] Table 6 Results of influence factor test of Examples 13-17

[0160] In combination with Table 3 and Table 6, increasing the amounts of maltitol and raffinose from 2% to 4% and 8% can further improve the thermal stability to a certain extent.

[0161] Example 19: Comparison of reconstitution of different freeze-dried compositions in the foregoing Examples 13-17

[0162] To the freeze-dried composition prepared in the foregoing Examples 13-17, 4 mL of normal saline was added, respectively, and the time when the composition was fully dissolved and the bubbling and turbidity completely disappeared was recorded, respectively, as the reconstitution time. The reconstituted solution was compared with the turbidity standard solution. The recorded reconstitution time and clarity are shown in Table 7, and the solution images obtained are shown in Fig. 2.

[0163] Table 7 Comparison of reconstitution of Examples 13-17

[0164] The results in Table 7 and Fig. 2 show that, in Examples 13-17, the use amount of the freeze-drying protectant is increased from 2% to 4% and 8%, and the prepared finished product still has good dissolution effect and does not cause the difficult-to-eliminate bubbling, turbidity and opalescence phenomenon.

[0165] In combination with Table 6 above, it can be confirmed that the freeze-dried composition prepared in the above Examples 13-17 can achieve high stability and high solubility at the same time even at a higher use amount of the freeze-drying protectant.

[0166] Examples 20-23

[0167] A freeze-dried composition containing tolvaptan sodium phosphate is prepared from the following components by weight, and the components and weights in Examples 20-23 are shown in Table 8.

[0168] Table 8 Components and amounts

[0169] The preparation method of the freeze-dried composition in Example 20 is as follows:

[0170] (1) Dissolve sodium dihydrogen phosphate and disodium hydrogen phosphate in 90% of the total amount of water for injection, add raffinose during stirring, and then add tolvaptan sodium phosphate after uniform stirring, and continue stirring until completely dissolved;

[0171] (2) Adjust the pH value of the solution obtained in step (1) to 8.8-8.9 using phosphoric acid and / or sodium hydroxide, add the remaining water for injection to make up to 2 mL, and stir to obtain a solution;

[0172] (3) After the solution is prepared, the solution is first filtered through a 0.45 μm PTFE filter membrane, and then filtered through a 0.22 μm PTFE filter membrane for sterilization filtration, and then filled into the corresponding vials, and the finished product is obtained after freeze-drying.

[0173] The freeze-drying process is as follows:

[0174] 1) Pre-freezing: The filled solution is cooled to -50°C, the cooling time is 3 hours, and the holding time is 3 hours;

[0175] 2) Sublimation drying: control the vacuum at 10-20 Pa, raise the temperature to -10℃-0℃, the temperature raising time is 2 hours, and the holding time is 6 hours; continue to raise the temperature to 0℃-10℃, the temperature raising time is 6 hours, and the holding time is 3 hours;

[0176] 3) Desorption drying: control the vacuum at 1-5 Pa, raise the temperature to 30℃, the temperature raising time is 4 hours, and the holding time is 6 hours.

[0177] In the preparation process, compared with Example 20, the difference of Examples 21-23 lies in the amount of sodium tolvaptan phosphate, disodium hydrogen phosphate and disodium hydrogen phosphate.

[0178] The freeze-dried composition prepared in Examples 20-23 is basically equivalent to the freeze-dried composition prepared in Example 2 in terms of stability and reconstitution effect, can simultaneously meet high stability and high clarity, reduces the generation of impurities, and has better stability during preparation and long-term storage, solves the phenomenon of opalescence and turbidity of the drug solution during reconstitution, is easier to dissolve, and is conducive to the safe administration of the product.

[0179] Comparative Example 5

[0180] A freeze-dried composition containing sodium tolvaptan phosphate, 1 ml of the drug solution contains the following components by weight: sodium tolvaptan phosphate 4 mg, sodium dihydrogen phosphate 0.16 mg, disodium hydrogen phosphate 7.2 mg, lactose 20 mg;

[0181] The preparation method of the freeze-dried composition in Comparative Example 5 is as follows:

[0182] (1) Dissolve sodium dihydrogen phosphate and disodium hydrogen phosphate in 90% of the total amount of water for injection, add lactose during stirring, and then add sodium tolvaptan phosphate after stirring uniformly, and continue stirring until completely dissolved;

[0183] (2) Adjust the pH value of the solution obtained in step (1) to 8.8-8.9 with phosphoric acid and / or sodium hydroxide, add the remaining water for injection to 2 mL, and stir to obtain the drug solution;

[0184] (3) After the preparation of the drug solution is completed, the drug solution is first filtered through a 0.45 μm PTFE filter membrane, and then filtered through a 0.22 μm PTFE filter membrane for sterilization filtration, and then filled into the corresponding vials, and the finished product is obtained after freeze-drying.

[0185] Among them, the freeze-drying process is as follows:

[0186] (1) Pre-freezing: cool the filled drug solution to -50℃, the cooling time is 3 hours, and the holding time is 3 hours;

[0187] (2) Sublimation drying: control the vacuum at 10-20 Pa, raise the temperature to -10-0°C, the temperature raising time is 2 hours, and the maintaining time is 6 hours; continue to raise the temperature to 0-10°C, the temperature raising time is 6 hours, and the maintaining time is 3 hours;

[0188] (3) Desorption drying: control the vacuum at 1-5 Pa, raise the temperature to 30°C, the temperature raising time is 4 hours, and the maintaining time is 6 hours.

[0189] Example 24

[0190] Comparison of liquid stability: comparison of stability of drug solution in the presence of different lyophilization protectants

[0191] The drug solution obtained after preparation in Examples 1-4, Example 9 and Comparative Example 5 was filtered through 0.45 μm PTFE filter membrane and 0.22 μm PTFE filter membrane in turn, and the amount of tolvaptan generated under the condition of being placed at 60°C for 7 days was compared, and the results are shown in Table 9, and the image of the drug solution is shown in Figure 3.

[0192] Table 9 Properties and related substances of different drug solutions under the condition of being placed at 60°C for 7 days

[0193] As can be seen from the results of Table 9 and Figure 3, compared with lactose, the drug solution has good stability before lyophilization when the lyophilization protectant is maltitol, raffinose, dextran, stachyose or polyethylene glycol 400, and can tolerate long time high temperature without obvious degradation or change in properties.

[0194] The above results can show that the addition of maltitol, raffinose, dextran, stachyose or polyethylene glycol 400 not only makes the lyophilized product have high stability and high solubility, but also makes the drug solution have high stability, which is beneficial to the implementation of large-scale production.

[0195] Examples 25-34

[0196] A lyophilized composition containing tolvaptan sodium phosphate is made from the following components by weight, and the components and weights of Examples 25-34 are shown in Table 10.

[0197] Table 10 Components and amounts

[0198] The preparation method of the lyophilized composition in Example 25 is as follows:

[0199] (1) Dissolve disodium hydrogen phosphate dihydrate and disodium hydrogen phosphate dodecahydrate in a total amount of 80% water for injection, fully stir until completely dissolved, and add tolvaptan sodium phosphate and maltitol during stirring, continue to stir until completely dissolved;

[0200] (2) Adjust the pH of the solution obtained in step (1) to 8.0-9.0 with sodium hydroxide and / or phosphoric acid, add the remaining water for injection to make up to 2 mL, and stir to obtain a medicinal solution;

[0201] (3) After the medicinal solution is prepared, the medicinal solution is first filtered through a 0.45 μm PTFE filter membrane, then filtered through a 0.22 μm PTFE filter membrane for sterilization, and then filled into a corresponding vial, and the product is obtained after lyophilization.

[0202] The lyophilization process is as follows:

[0203] 1) Pre-freezing: the half-closed medicinal solution after filling is placed in a freeze dryer, cooled to -10°C, maintained for 2 hours, and then cooled to -45°C, maintained for 2 hours;

[0204] 2) Sublimation drying: control the vacuum at 15 Pa, and heat to -10°C for 6 hours; continue to heat to 10°C for 10 hours;

[0205] 3) Desorption drying: control the vacuum at 5 Pa, and heat to 40°C for 5 hours.

[0206] In the sample preparation process, compared with Example 25, the difference between Examples 26-27 and Examples 33-34 is that the maltitol is replaced by xylitol and sorbitol, respectively, and the preparation method of the other examples is the same as that of Example 25.

[0207] Example 35 differs from Example 25 in that the specific lyophilization process is different:

[0208] The lyophilization process is as follows:

[0209] (1) Pre-freezing: the half-closed medicinal solution after filling is placed in a freeze dryer, cooled to -10°C, maintained for 2 hours, and then cooled to -45°C, maintained for 4 hours;

[0210] (2) Sublimation drying: control the vacuum at 15 Pa, and heat to -5°C for 6 hours; continue to heat to 5°C for 8 hours;

[0211] (3) Desorption drying: control the vacuum at 5 Pa, and heat to 40°C for 5 hours.

[0212] Example 36 differs from Example 25 in that the specific lyophilization process is different:

[0213] The lyophilization process is as follows:

[0214] (1) Pre-freezing: the half-closed medicinal solution after filling is placed in a freeze dryer, cooled to -10°C, maintained for 2 hours, and then cooled to -45°C, maintained for 4 hours;

[0215] (2) Sublimation drying: control the vacuum at 20 Pa, and raise the temperature to -2°C for 6 hours; continue to raise the temperature to 2°C for 8 hours;

[0216] (3) Desorption drying: control the vacuum at 3 Pa, and raise the temperature to 40°C for 5 hours.

[0217] Comparative Examples 6-7

[0218] A lyophilized composition containing tolvaptan sodium phosphate is prepared from the following components by weight, and the components and weights of Comparative Examples 6-7 are shown in Table 11.

[0219] Table 11 Components and amounts

[0220] The preparation method of the lyophilized composition in Comparative Example 6 is as follows:

[0221] (1) Dissolve disodium hydrogen phosphate dihydrate and disodium hydrogen phosphate dodecahydrate in a total amount of 80% of water for injection, and fully stir until completely dissolved. During stirring, add tolvaptan sodium phosphate and maltose, and continue to stir until completely dissolved;

[0222] (2) Adjust the pH of the solution obtained in step (1) to 8.0-9.0 using sodium hydroxide and / or phosphoric acid, add the remaining water for injection to make up to 2 mL, and stir to obtain a medicinal solution;

[0223] (3) After the medicinal solution is prepared, the medicinal solution is first filtered through a 0.45 μm PTFE filter membrane, and then filtered through a 0.22 μm PTFE filter membrane for sterilization filtration, and is filled into the corresponding Schott bottles. After lyophilization, the finished product is obtained.

[0224] In the process of lyophilization, the process is as follows:

[0225] 1) Pre-freezing: place the medicinal solution with a half stopper after filling in the lyophilizer, and reduce the temperature to -10°C for 2 hours, and continue to reduce the temperature to -45°C for 2 hours;

[0226] 2) Sublimation drying: control the vacuum at 15 Pa, and raise the temperature to -10°C for 6 hours; continue to raise the temperature to 10°C for 10 hours;

[0227] 3) Desorption drying: control the vacuum at 5 Pa, and raise the temperature to 40°C for 5 hours.

[0228] In the preparation method, compared with Example 25, the difference between Comparative Examples 6-7 is that the maltitol is replaced by maltose and sucrose in turn. The preparation methods of the other comparative examples are the same as those of Example 25.

[0229] Example 35: Stability comparison of the lyophilized compositions obtained in the preceding Examples 25-34 and Comparative Examples 6-7

[0230] The lyophilized compositions prepared in the preceding Examples 25-34 and Comparative Examples 6-7 were placed in light at 60°C, and the changes in their properties and the changes in the related substances were compared. The related substances were detected by HPLC and the data were given by area normalization. The results are shown in Table 12.

[0231] Table 12: Results of the influence factor test of Examples 25-34 and Comparative Examples 6-7

[0232] As shown in Table 13, Examples 25-27 added maltitol, xylitol and sorbitol, respectively, Examples 28-29 adjusted the amount of sodium phosphate monobasic dihydrate, Examples 30-31 adjusted the amount of maltitol, Examples 32-34 added maltitol, xylitol and sorbitol, respectively, under the adjustment of the amount of active ingredient, and Examples 35-36 adjusted the parameters in the lyophilization process. The samples prepared in the above Examples had a stability comparable to that of Comparative Examples 6 and 7 using maltose and sucrose, which indicated that the products in all the above Examples had high stability.

[0233] Example 34: Reconstitution comparison of the lyophilized compositions obtained in the preceding Examples 25-34 and Comparative Examples 6-7

[0234] Table 14: Reconstitution comparison of Examples 25-34 and Comparative Examples 6-7

[0235] As shown in Table 14, Examples 25-27 added maltitol, xylitol and sorbitol, respectively, Examples 28-29 adjusted the amount of sodium phosphate monobasic dihydrate, Examples 30-31 adjusted the amount of maltitol, Examples 32-34 added maltitol, xylitol and sorbitol, respectively, under the adjustment of the amount of active ingredient, and Examples 35-36 adjusted the parameters in the lyophilization process. The samples prepared in the above Examples had good dissolution and defoaming speed and the drug solution after reconstitution of the finished product had no obvious opalescence. However, Comparative Examples 6 and 7 had opalescence that was difficult to disappear.

[0236] The above merely describes preferred embodiments of the present application, and is not intended to limit the present application in any form. Although the present application has been disclosed with the preferred embodiments as above, it is not intended to limit the present application. Any person skilled in the art can make some changes or modifications to the above disclosed methods and technical contents to make equivalent embodiments with equivalent changes, without departing from the technical solution of the present application. Any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present application, without departing from the technical solution of the present application, still belongs to the scope of the technical solution of the present application.

Claims

1. A lyophilized composition comprising tolvaptan sodium phosphate, characterized in that, The pharmaceutical solution is prepared from tolvaptan sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, freeze-drying protective agent and water for injection, filtered and sterilized, filled, and freeze-dried to obtain the finished product; in the preparation process of the pharmaceutical solution, the pH value thereof is adjusted to 7.5-10.0 by a pH regulator, wherein the freeze-drying protective agent is one or more of maltitol, raffinose, dextran, stachyose, arabinogalactan, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide and polyethylene glycol.

2. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 1, characterized in that, The pharmaceutical solution contains the following components by weight per 2ml: tolvaptan sodium phosphate 1-25mg, sodium dihydrogen phosphate 0.05-0.8mg, disodium hydrogen phosphate 5.0-30.0mg, freeze-drying protective agent 20-250mg; the pH regulator is phosphoric acid and / or sodium hydroxide; and the pH value thereof is adjusted to 8.5-9.0 by the pH regulator.

3. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 3, characterized in that, The pharmaceutical solution contains the following components by weight per 2ml: tolvaptan sodium phosphate 2-22mg, sodium dihydrogen phosphate 0.1-0.5mg, disodium hydrogen phosphate 10.0-26.0mg, freeze-drying protective agent 30.0-200mg; and the pH value thereof is adjusted to 8.8-8.9 by the pH regulator.

4. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 3, characterized in that, The pharmaceutical solution contains the following components by weight per 2ml: tolvaptan sodium phosphate 4-20mg, sodium dihydrogen phosphate 0.16-0.32mg, disodium hydrogen phosphate 14.4-24.0mg, freeze-drying protective agent 40-180mg.

5. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 4, characterized in that, The pharmaceutical solution contains the following components by weight per 2ml: Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, maltitol 40mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, maltitol 80mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, maltitol 160mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, raffinose 40mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, raffinose 80mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, raffinose 160mg; Tolvaptan sodium phosphate 4mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 16.0mg, raffinose 40mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 16.0mg, raffinose 40mg; Tolvaptan sodium phosphate 20mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 24.0mg, raffinose 40mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.16mg, disodium hydrogen phosphate 16.0mg, raffinose 40mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, dextran 40mg; Tolvaptan sodium phosphate 8mg, sodium dihydrogen phosphate 0.32mg, disodium hydrogen phosphate 14.4mg, stachyose 40mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, arabinogalactan 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, fructooligosaccharide 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, galactooligosaccharide 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, isomaltooligosaccharide 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, polyethylene glycol 400 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, polyethylene glycol 400 20 mg, dextran 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, maltitol 160 mg, polyethylene glycol 2000 20 mg.

6. A process for the preparation of the lyophilized composition containing sodium tolvaptan phosphate according to claim 1, characterized in that, It comprises the following steps: (1) Dissolve sodium phosphate monobasic and sodium phosphate dibasic in part of water for injection, add the freeze-drying protective agent during stirring, and then add tolvaptan sodium phosphate after uniform stirring, and continuously stir until completely dissolved; (2) Adjust the pH value of the solution obtained in step (1) to 7.5-10.0 by using a pH adjuster, add the remaining water for injection to constant volume, and stir to obtain a medicinal solution; (3) After the preparation of the medicinal solution is completed, perform sterilization filtration, fill, and freeze-dry to obtain the finished product.

7. The process for preparing a lyophilized composition containing sodium tolvaptan phosphate according to claim 6, characterized by, In step (1), the amount of water for injection added is 75-95% of the total amount; in step (2), the pH adjuster is phosphoric acid and / or sodium hydroxide; and the pH value is adjusted to 8.5-9.0 by using the pH adjuster.

8. The process for preparing a lyophilized composition containing sodium tolvaptan phosphate according to claim 7, characterized by, In step (1), the amount of water for injection added is 90% of the total amount; in step (2), the pH value is adjusted to 8.8-8.9 by using the pH adjuster.

9. The process for preparing a lyophilized composition containing sodium tolvaptan phosphate according to claim 6, characterized by, In step (3), the freeze-drying process is as follows: 1) Pre-freezing: cool the filled medicinal solution to -55℃ to -45℃, the cooling time is 2-5 hours, and the holding time is 1-6 hours; 2) Sublimation drying: control the vacuum to be 10-20 Pa, warm up to -10℃ to 0℃, the warming-up time is 1-3 hours, and the holding time is 3-15 hours; continue to warm up to 0℃ to 10℃, the warming-up time is 2-8 hours, and the holding time is 1-10 hours; 3) Desorption drying: control the vacuum to be 1-5 Pa, warm up to 20℃ to 40℃, the warming-up time is 3-6 hours, and the holding time is 5-10 hours.

10. The process for preparing a lyophilized composition containing sodium tolvaptan phosphate according to claim 9, characterized by, The freeze-drying process is as follows: 1) Pre-freezing: cool the filled medicinal solution to -50℃, the cooling time is 3 hours, and the holding time is 3 hours; 2) Sublimation drying: control the vacuum to be 10-20 Pa, warm up to -10℃ to 0℃, the warming-up time is 2 hours, and the holding time is 6 hours; continue to warm up to 0℃ to 10℃, the warming-up time is 6 hours, and the holding time is 3 hours; 3) Desiccation: control the vacuum at 1-5 Pa, and raise the temperature to 30℃, the temperature rising time is 4 hours, and the holding time is 6 hours.

11. A lyophilized composition comprising sodium trovafloxacin phosphate, characterized in that, The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection.

12. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 11, characterized in that, The weight ratio of the tolvaptan sodium phosphate and the freeze-drying protective agent is 2-24:10-80.

13. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 11, characterized in that, The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection.

14. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 13, characterized in that, The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection.

15. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 14, characterized in that, The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection.

16. The lyophilized composition containing sodium trovafloxacin phosphate according to claim 15, characterized in that, The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by mixing tolvaptan sodium phosphate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate monobasic hydrate, sodium phosphate dibasic hydrate, and water for injection. The tolvaptan sodium phosphate and the freeze-drying protective agent are prepared by Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, raffinose 160 mg; Tolvaptan sodium phosphate 4 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 16.0 mg, raffinose 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 16.0 mg, raffinose 40 mg; Tolvaptan sodium phosphate 20 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 24.0 mg, raffinose 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.16 mg, sodium phosphate dibasic 16.0 mg, raffinose 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, dextran 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, stachyose 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, arabinogalactan 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, fructooligosaccharide 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, galactooligosaccharide 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, isomaltooligosaccharide 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, polyethylene glycol 400 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, polyethylene glycol 400 20 mg, dextran 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic 0.32 mg, sodium phosphate dibasic 14.4 mg, maltitol 160 mg, polyethylene glycol 2000 20 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, maltitol 40 mg; Tolvaptan sodium phosphate 16 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, maltitol 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, xylitol 40 mg; Tolvaptan sodium phosphate 16 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, xylitol 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, sorbitol 40 mg; Tolvaptan sodium phosphate 16 mg, sodium phosphate monobasic dihydrate 0.3 mg, sodium phosphate dibasic dodecahydrate 18 mg, sorbitol 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate monobasic dihydrate 0.15 mg, sodium phosphate dibasic dodecahydrate 18 mg, maltitol 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate dibasic dihydrate 0.45 mg, sodium phosphate dibasic twelve hydrate 18 mg, maltitol 40 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate dibasic dihydrate 0.3 mg, sodium phosphate dibasic twelve hydrate 18 mg, sorbitol 20 mg; Tolvaptan sodium phosphate 8 mg, sodium phosphate dibasic dihydrate 0.3 mg, sodium phosphate dibasic twelve hydrate 18 mg, sorbitol 60 mg.

17. A process for the preparation of a lyophilized composition containing sodium tolvaptan phosphate according to claim 11, characterized in that, Comprising the following steps: (1) Dissolve sodium phosphate dibasic or sodium phosphate dibasic hydrate and sodium phosphate dibasic or sodium phosphate dibasic hydrate in part of water for injection, add tolvaptan sodium phosphate and lyophilization protectant during stirring, continue stirring until completely dissolved; (2) Adjust the pH value of the solution obtained in step (1) to 8.0-9.0 with a pH adjuster, add the remaining water for injection to constant volume, and stir to obtain a liquid medicine; (3) After the preparation of the liquid medicine is completed, sterilization filtration is carried out, and then the product is obtained after filling and lyophilization.

18. A process for preparing a lyophilized composition containing sodium tolvaptan phosphate according to claim 17, characterized by, In step (1), the amount of water for injection added is 70-90% of the total amount; the sodium phosphate dibasic hydrate is sodium phosphate dibasic monohydrate or sodium phosphate dibasic dihydrate; the sodium phosphate dibasic hydrate is sodium phosphate dibasic monohydrate, sodium phosphate dibasic dihydrate, sodium phosphate dibasic seven hydrate or sodium phosphate dibasic twelve hydrate; in step (2), the pH adjuster is phosphoric acid and / or sodium hydroxide.

19. A process for preparing a lyophilized composition containing sodium tolvaptan phosphate according to claim 17, characterized by, In step (3), the process of lyophilization is as follows: 1) Pre-freezing: place the half-capped liquid medicine after filling in the lyophilizer, cool to -12℃ to -8℃, keep for 1-6 hours, continue to cool to -50℃ to -40℃, keep for 1-6 hours; 2) Sublimation drying: control the vacuum to 10-25 Pa, warm up to -15℃ to 0℃, keep for 4-10 hours; continue to warm up to 0℃ to 15℃, keep for 6-12 hours; 3) Sublimation drying: control the vacuum to 1-10 Pa, warm up to 35℃ to 45℃, keep for 3-10 hours.

20. A process for preparing a lyophilized composition containing sodium tolvaptan phosphate according to claim 19, characterized by, In step (3), the process of lyophilization is as follows: 1) Pre-freezing: place the half-capped liquid medicine after filling in the lyophilizer, cool to -10℃, keep for 2 hours, continue to cool to -45℃, keep for 2 hours; 2) Sublimation drying: control the vacuum to 15 Pa, warm up to -10℃, keep for 6 hours; continue to warm up to 10℃, keep for 10 hours; 3) Analytical drying: control the vacuum to 5 Pa, warm up to 40℃, keep for 5 hours; Or, 1) Pre-freezing: place the half-capped liquid medicine after filling in the lyophilizer, cool to -10℃, keep for 2 hours, continue to cool to -45℃, keep for 4 hours; 2) Sublimation drying: control the vacuum to 15 Pa, warm up to -5℃, keep for 6 hours; continue to warm up to 5℃, keep for 8 hours; 3) Analytical drying: control the vacuum to 5 Pa, warm up to 40℃, keep for 5 hours; Or, 1) Pre-freezing: place the half-capped liquid medicine after filling in the lyophilizer, cool to -10℃, keep for 2 hours, continue to cool to -45℃, keep for 4 hours; 2) Sublimation drying: control the vacuum at 20 Pa, and raise the temperature to -2°C, keep for 6 hours; continue to raise the temperature to 2°C, keep for 8 hours; 3) Desorption drying: control the vacuum at 3 Pa, and raise the temperature to 40°C, keep for 5 hours.

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