CN106551898A - A kind of Vonoprazan fumarate compositionss and preparation method thereof - Google Patents

Abstract

The present invention relates to a kind of Vonoprazan fumarate compositionss and preparation method thereof.The compositionss include Vonoprazan fumarate, solubilizing agent, buffer agent, pH adjusting agent, solvent, wherein, solubilizing agent can dramatically increase Vonoprazan fumarate dissolubility, compositionss good stability, buffer agent and pH adjusting agent, compositionss stability is added to significantly change.Meanwhile, present invention also offers the method for preparing above-mentioned Vonoprazan fumarate compositionss, the method simple economy, it is adaptable to industrialized production.

Description

A kind of vonoprazan fumarate composition and its preparation method

technical field

The invention relates to a fumaric acid vonoprazan composition, in particular to a safe and stable fumaric acid vonoprazan composition containing substituted β-cyclodextrin and a preparation method thereof, belonging to the technical field of pharmacy.

Background technique

Vonoprazan fumarate (Vonoprazan fumarate) used to be code-named TAK-438, which is a new type of gastric acid secretion inhibitor developed by Takeda Corporation of Japan. In the last step of secretion, by inhibiting the binding of K ⁺ to H ⁺ -K ⁺ -ATPase (proton pump), it also has an early termination effect on gastric acid secretion. Vonorazan fumarate was first launched in Japan in 2014 under the trade name Takecab.

The chemical name of vonoprazan fumarate is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylformazan Amine fumaric acid monosalt, the structural formula is as follows:

Currently, the marketed dosage form of vonoprazan fumarate is tablet, and no other dosage form has been disclosed yet. Since the tablet is an oral preparation, it has poor compliance for patients with dysphagia, children, and the elderly; and for patients with acute gastritis and gastric ulcer who need a rapid onset of action, the tablet cannot meet the clinical needs of a rapid onset of action. Therefore, it is of great significance to develop new dosage forms of vonoprazan fumarate, such as injections, to provide treatment options for more patients who have medication needs but are difficult to use tablets to administer or achieve curative effect.

Vonoprazan fumarate is slightly soluble in water. Due to its poor water solubility, it is difficult to meet the requirement of injection for drug solubility. Therefore, there are great challenges in the development of injection dosage forms.

Prior art CN 201410154778.8 discloses the new water-soluble organic acid salt of Wonorazan and the injection of the water-soluble organic acid salt and its preparation method, but this type of new water-soluble organic acid salt and the active ingredient fuma Compared with vonoprazan fumarate, its effect has not been supported by clinical experiments and pharmaceutical practice, and there is no technical means and effect to increase the water solubility of vonoprazan fumarate, and the injection uses 100 ° C steam Sterilize for 30 minutes. This method is not terminal sterilization and cannot achieve a better sterilization effect. Therefore, it is of great significance to improve the water solubility of vonoprazan fumarate through an appropriate method, and to develop a composition and injection of vonoprazan fumarate suitable for injection and a preparation method thereof.

Contents of the invention

Summary of the invention

The first aspect of the present invention provides a composition containing substituted β-cyclodextrin vonoprazan fumarate, and the substituted β-cyclodextrin can increase the solubility of vonoprazan fumarate in water.

The second aspect of the present invention provides a vonoprazan fumarate injection prepared from the composition of the first aspect. The injection is safe and effective, has good storage stability, and brings new medication options for special groups of people who are not suitable for oral administration. To meet the clinical needs of patients with acute gastritis and gastric ulcer who need rapid onset of action.

The third aspect of the present invention provides a method for preparing vonoprazan fumarate injection described in the second aspect. The method is simple and easy, can be sterilized by terminal sterilization, has good stability and high safety, and is suitable for Industrial production.

The fourth aspect of the present invention also provides a solution for infusion of vonoprazan fumarate and a preparation method thereof.

Definition of Terms

The term "comprising" or "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

Specific parameters of "terminal sterilization method": damp heat sterilization, 121°C, 12min to 15min.

In the context of the present invention, all numbers disclosed herein are approximations, whether or not the word "about" or "approximately" is used. The value of each figure may have a difference of less than 10% or a reasonable difference considered by those skilled in the art, such as a difference of 1%, 2%, 3%, 4% or 5%.

Detailed description of the invention

Based on the deficiencies of the prior art, after in-depth investigation and research, the present invention selects substituted β-cyclodextrin as a solubilizer to form an inclusion complex with vonorazan fumarate, on the one hand, replaces β-cyclodextrin to increase fumaric acid The solubility of vonoprazan in water and the stability of the solution meet the solubility requirements for preparation of injections; on the one hand, vonoprazan fumarate injection is further prepared from the clathrate, which has high bioavailability and effective Fast, safe, and good drug compliance for special populations; on the other hand, the combination of substituted β-cyclodextrin and vonoprazan fumarate is used in the preparation process of injections, the solution is stable, and can be used in terminal Sterilization is sterilized, and the sterilization is thorough.

The invention provides a vonoprazan fumarate composition, which contains vonoprazan fumarate and a solubilizer, wherein the solubilizer is a substituted β-cyclodextrin, Tween 80, phospholipids, and porol Sham or any combination of them. The solubilizer can increase the solubility of vonoprazan fumarate in water.

In some embodiments the solubilizing agent is a substituted β-cyclodextrin.

A composition containing vonoprazan fumarate and substituted β-cyclodextrin, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin Arginine, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin or any combination thereof. In some embodiments, hydroxypropyl-beta-cyclodextrin; in some embodiments, sulfobutyl ether-beta-cyclodextrin.

A composition of vonoprazan fumarate, wherein the composition is an clathrate.

A composition containing vonoprazan fumarate and a solubilizer, which can be prepared into a liquid preparation of vonoprazan fumarate, which can be, but not limited to, a spray, a suspension, a solution, an injection . In some embodiments, the liquid formulation is an injection.

The invention provides a vonoprazan fumarate inclusion compound, which contains vonoprazan fumarate and substituted β-cyclodextrin, and the substituted β-cyclodextrin can increase the concentration of vonoprazan fumarate in Solubility in water.

An inclusion compound containing vonoprazan fumarate and substituted β-cyclodextrin, wherein the weight ratio of vornorazan fumarate to substituted β-cyclodextrin is 1:1 to 1:20 . In some embodiments it is 1:3; in some embodiments it is 1:5; in some embodiments it is 1:10.

An inclusion compound containing vonoprazan fumarate and substituted β-cyclodextrin, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin Dextrin, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin, or any combination thereof. In some embodiments, hydroxypropyl-beta-cyclodextrin; in some embodiments, sulfobutyl ether-beta-cyclodextrin.

An inclusion compound containing vonoprazan fumarate and substituted β-cyclodextrin, which can be prepared into a liquid preparation of vonoprazan fumarate, which can be, but not limited to, a spray or a suspension , solution, injection. In some embodiments, the liquid formulation is an injection.

The invention provides a vonoprazan fumarate injection, which comprises vonoprazan fumarate and substituted β-cyclodextrin.

A vonoprazan fumarate injection, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin Arginine, methyl-β-cyclodextrin, or any combination thereof. In some embodiments, hydroxypropyl-beta-cyclodextrin; in some embodiments, sulfobutyl ether-beta-cyclodextrin.

A vonoprazan fumarate injection, wherein the injection is a ready-to-use liquid injection.

A vonoprazan fumarate injection, wherein the weight ratio of the vonoprazan fumarate to the total volume of the injection is 0.05% to 10% (W/V, g/mL). In some embodiments it is 0.4%.

A vonoprazan fumarate injection, wherein the weight ratio of the substituted β-cyclodextrin relative to the total volume of the injection is 0.4% to 20% (W/V, g/mL). In some embodiments it is 0.8%; in some embodiments it is 1.2%; in some embodiments it is 2%.

A fumarate vonoprazan injection, wherein the weight ratio of the fumarate vonoprazan to the substituted β-cyclodextrin is 1:1 to 1:20. In some embodiments it is 1:3; in some embodiments it is 1:5; in some embodiments it is 1:10.

In some embodiments, the vonoprazan fumarate injection further includes a solvent, a pH regulator, and a buffer. Wherein, the solvent is water. Wherein, the pH regulator comprises hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogen phosphate, calcium carbonate or magnesium hydroxide; in some embodiments, the pH regulator is sodium hydroxide. Wherein, the buffer is acetic acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, malic acid, benzoic acid or any combination thereof; in some embodiments, the buffer is tartaric acid; in some embodiments, the buffer is citric acid monohydrate.

A vonoprazan fumarate injection, wherein the weight ratio of the buffering agent to the total volume of the injection is 0.1% to 3% (W/V, g/mL). In some embodiments it is 0.4%.

A vonoprazan fumarate injection, wherein the pH of the injection ranges from 3.0 to 9.0, and in some embodiments is 4.23.

A vonoprazan fumarate injection, wherein the pH of the injection ranges from 3.0 to 6.0.

A vonoprazan fumarate injection, wherein the pH of the injection ranges from 4.0 to 5.0, and in some embodiments is 4.14.

In some embodiments, a vonoprazan fumarate injection comprising:

1) Vonorazan fumarate 0.05%-10%;

2) Hydroxypropyl-β-cyclodextrin 0.4%-20%;

3) 0.1%-3% citric acid monohydrate;

4) Appropriate amount of NaOH;

5) Purified water.

In some embodiments, a vonoprazan fumarate injection comprising:

1) Vonorazan fumarate 0.05%-10%;

2) Hydroxypropyl-β-cyclodextrin 0.4%-20%;

3) Tartaric acid 0.1%-3%;

4) Appropriate amount of NaOH;

5) Purified water.

In some embodiments, a vonoprazan fumarate injection comprising:

1) Vonorazan fumarate 0.05%-10%;

2) 0.4%-20% of sulfobutyl ether-β-cyclodextrin;

3) 0.1%-3% citric acid monohydrate;

4) Appropriate amount of NaOH;

5) Purified water.

In some embodiments, a vonoprazan fumarate injection comprising:

1) Vonorazan fumarate 0.05%-10%;

2) 0.4%-20% of sulfobutyl ether-β-cyclodextrin;

3) Tartaric acid 0.1%-3%;

4) Appropriate amount of NaOH;

5) Purified water.

The present invention also provides a method for preparing the above-mentioned vonoprazan fumarate injection, the method comprising dissolving buffer and substituted β-cyclodextrin in purified water, and using a pH regulator to adjust the pH to 4.0-5.0 , add vonoprazan fumarate, stir to dissolve, add purified water to make up the volume, measure the pH value of the final solution, bottle, stopper, cap, and terminally sterilize.

In some embodiments, the above-mentioned vonoprazan fumarate injection can be prepared according to the following method:

1) The buffering agent of the prescribed amount is dissolved in purified water of 50%-90% of the prescribed amount to form a buffer solution;

2) Add the prescribed amount of substituted β-cyclodextrin to the buffer solution, stir until completely dissolved, and adjust the pH to 4.5 with a pH regulator;

3) Add vonoprazan fumarate to the system, stir to dissolve, add purified water to constant volume, and measure the pH value of the final solution;

4) Bottling, stoppering, capping, terminal sterilization at 121°C for 12min-15min.

In another aspect, the present invention provides a solution for infusion of vonoprazan fumarate.

A solution for infusion of vonoprazan fumarate, wherein the weight ratio of the vonoprazan fumarate to the total volume of the infusion solution is 0.005% to 10% (W/V, g/mL). In some embodiments it is 0.0107%; in some embodiments it is 0.053%; in some embodiments it is 0.0053%.

A solution for vonoprazan fumarate infusion, comprising vonoprazan fumarate and a buffer, wherein the buffer is acetic acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, anticyclone Blood acid, malic acid, benzoic acid, or any combination thereof. In some embodiments, the buffer is tartaric acid.

A solution for infusion of vonoprazan fumarate, wherein the weight ratio of the contained buffering agent relative to the total volume of the solution for infusion is 0.001% to 3% (W/V, g/mL). In some embodiments it is 0.0053%; in some embodiments it is 0.053%.

A solution for vonoprazan fumarate infusion, which also contains an isotonic regulator. Wherein, the isotonic regulator is sodium chloride, glucose, mannitol, sorbitol, glycerin and the like. In some embodiments, the isotonicity adjusting agent is sodium chloride; in some embodiments, the isotonicity adjusting agent is dextrose. Wherein, the osmotic pressure of the solution is adjusted to 260mosm/L to 320mosm/L.

A solution for infusion of vonoprazan fumarate, wherein the pH value of the solution for infusion is in the range of 3.0 to 6.0. In some embodiments it is 4.5.

The present invention also provides a method for preparing a solution for infusion of vonoprazan fumarate, the method comprising dissolving an isotonic regulator in purified water, adding vonoprazan fumarate and a buffer, stirring and dissolving , use a pH regulator to adjust the pH to 3.0-6.0, add purified water to constant volume, and measure the pH value of the final solution.

In some embodiments, the above-mentioned solution for infusion of vonoprazan fumarate can be prepared according to the following method:

1) The isotonicity regulator of prescription quantity is dissolved in the purified water of prescription quantity 50%-90%;

2) Add the prescribed amount of buffer and stir to dissolve;

3) Add vonoprazan fumarate to the system, stir and dissolve, and use a pH regulator to adjust the pH to 4.5;

4) Add purified water to make up to volume, and measure the pH value of the final solution.

The fumaric acid vonoprazan composition provided by the present invention can increase the solubility of fumaric acid vonoprazan in water, meet the requirement of being prepared into injections, and can be sterilized by terminal sterilization method, the sterilization is thorough, and the Injection safety; the provided vonoprazan fumarate injection is a new dosage form, which can meet the clinical needs of patients with acute gastritis and gastric ulcer who need rapid action, and can solve the drug administration problem of patients with dysphagia. The safety is high and the stability is good; the preparation method provided is simple and easy, and is suitable for industrial production.

The vonoprazan fumarate infusion solution provided by the invention has a simple and easy preparation method and is suitable for industrial production.

detailed description

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

In the present invention, min means minute, h means hour, mg means milligram, g means gram, mL means milliliter, W means weight, and V means volume.

Example 1: Solubilization of Vonoprazan Fumarate Using Hydroxypropyl-β-Cyclodextrin (HP-β-CD).

Add a certain volume (about 75% of the final volume of the solution) of purified water into the beaker, add hydroxypropyl-β-cyclodextrin, stir and dissolve with a magnetic stirrer; after the hydroxypropyl-β-cyclodextrin dissolves, , add voronoprazan fumarate, stir, visually observe the dissolution of voronoprazan fumarate, stir until voronoprazan fumarate is completely dissolved; add purified water to make up to 20 mL. A short-term stability study was carried out on the solution (the stability storage condition is to first place the sample at 40° C. for a certain period of time, and then place the sample at 60° C. for a certain period of time). The prescription is shown in Table 1-1.

Table 1-1

Results of Example 1: After stirring for 20 minutes, the API was completely dissolved. The results of short-term stability studies confirmed that the solution remained stable when the solution was placed at 40°C for 80 hours, and then placed at 60°C for 72 hours. The results of the stability study are shown in Table 1-2.

Table 1-2

Example 1 Conclusion: When the mass ratio of HP-β-CD to API is 10:1, the API can be effectively solubilized; and the obtained solution remains stable at 60°C for 72 hours after being placed at 40°C for 80 hours.

Example 2: Different dosages of HP-β-CD solubilized vonoprazan fumarate.

Add a certain volume (about 75% of the final volume of the solution) of purified water into two beakers, add different amounts of HP-β-CD respectively, stir and dissolve with a magnetic stirrer; after the HP-β-CD dissolves, Add voronoprazan fumarate, stir, visually observe the dissolution of voronoprazan fumarate, stir until voronoprazan fumarate is completely dissolved; add purified water to make up to 20mL. See Table 2-1 and 2-2 for the prescription.

table 2-1

Table 2-2

Results of Example 2: When the amount of HP-β-CD is 240 mg, that is, when the mass ratio to API is 3:1, the API is added to the HP-β-CD solution, stirred for 60 minutes, and the API is completely dissolved; when the HP-β-CD The dosage is 400mg, that is, when the mass ratio of API to API is 5:1, API is added to HP-β-CD solution, stirred for 20min, and API is completely dissolved.

Example 2 Conclusion: The ratio of HP-β-CD to API is reduced to 3:1, which can still effectively solubilize API.

Example 3: Solubilization of vonoprazan fumarate by HP-β-CD in different buffer solutions.

Add a certain volume (about 75% of the final volume of the solution) of purified water to the two beakers, then add the prescribed amount of citric acid monohydrate or tartaric acid, stir and dissolve with a magnetic stirrer, and use 2% (w/w) NaOH Adjust the pH of the solution to 4.5; add HP-β-CD, stir and dissolve with a magnetic stirrer; add fumaric acid vonoprazan, stir with a magnetic stirrer, visually observe the dissolution of fumaric acid vonoprazan, and stir until fumaric acid vonoprazan Norazan is completely dissolved; make up to 20 mL with purified water, and measure the pH. See Table 3-1 and 3-2 for the prescription. The short-term stability of the solution is studied (the stability storage condition is to first place the sample at 40°C for a certain period of time, and then place the sample at 60°C for a certain period of time).

Table 3-1

Table 3-2

Results of Example 3: After stirring for 60 minutes, the API was completely dissolved in the solution. The pH values of the final solutions of the two samples were 4.22 and 4.23 respectively; the results of the preliminary stability study showed that the content of related substances in the solutions remained basically unchanged when the two solutions were placed at 40°C for 24 hours and then at 60°C for 24 hours. See Table 3-3 and 3-4 for the contents of relevant substances.

Example 3 Conclusion: When the mass ratio of HP-β-CD to API is 3:1, the API can be effectively solubilized in different buffer solutions, and the buffer has no obvious effect on the dissolution rate; the obtained solution is placed at 40°C for 24 hours, and then It is stable at 60°C for 24h.

Table 3-3 Stability data of HP-β-CD fumaric acid vonoprazan (3:1) solution (pH4.22) containing citric acid monohydrate

Table 3-4 Stability data of HP-β-CD fumarate vonoprazan (3:1) solution (pH4.23) containing tartrate

Example 4: Solubilization of vonoprazan fumarate by HP-β-CD in different buffer solutions.

Add a certain volume (accounting for about 75% of the final volume of the solution) of purified water in four beakers respectively, add different amounts of HP-β-CD or tartaric acid or citric acid monohydrate, stir and dissolve with a magnetic stirrer; tartaric acid Or adjust the pH value to 4.5 with 2% (w/w) NaOH after dissolving citric acid monohydrate; after dissolving HP-β-CD, add vonoprazan fumarate, stir, and visually observe the dissolution of vonoprazan fumarate Stir until vonoprazan fumarate is completely dissolved; add purified water to make the volume to 20mL, and measure the pH value of the final solution. See Table 4-1 and 4-2 for prescriptions.

Table 4-1

Table 4-2

Example 5: Solubilization of vonoprazan fumarate by sulfobutyl ether-β-cyclodextrin (SBE-β-CD)

Add a certain volume (about 75% of the final volume of the solution) of purified water into two beakers, add different amounts of SBE-β-CD respectively, and stir and dissolve with a magnetic stirrer; after the SBE-β-CD dissolves, Add voronoprazan fumarate, stir, visually observe the dissolution of voronoprazan fumarate, stir until voronoprazan fumarate is completely dissolved; add purified water to make up to 20 mL. See Table 5-1 and 5-2 for the prescription.

Table 5-1

Table 5-2

Results of Example 5: When the amount of SBE-β-CD is 240 mg, that is, when the mass ratio of SBE-β-CD to API is 3:1, the API is added to the SBE-β-CD solution, stirred for 60 minutes, and the API is completely dissolved; when SBE-β-CD The dosage is 400mg, that is, when the mass ratio of API to API is 5:1, API is added to the SBE-β-CD solution, stirred for 20min, and API is completely dissolved.

Example 5 Conclusion: When the mass ratio of SBE-β-CD to API is 3:1 or above, API can be effectively solubilized.

Example 6: Solubilization of vonoprazan fumarate by SBE-β-CD in different buffer solutions.

Add a certain volume (about 75% of the final volume of the solution) of purified water to the two beakers, then add the prescribed amount of citric acid monohydrate or tartaric acid, stir and dissolve with a magnetic stirrer, and use 2% (w/w) NaOH Adjust the pH of the solution to 4.5; add SBE-β-CD, stir and dissolve with a magnetic stirrer; add fumaric acid vonoprazan, stir with a magnetic stirrer, visually observe the dissolution of fumaric acid vonoprazan, and stir until fumaric acid vonoprazan Norazan is completely dissolved; make up to 20 mL with purified water, and measure the pH. See Table 6-1, 6-2 for the prescription. The short-term stability of the solution is studied (the stability storage condition is to first place the sample at 40°C for a certain period of time, and then place the sample at 60°C for a certain period of time).

Table 6-1

Table 6-2

Results of Example 6: After stirring for 60 minutes, the API was completely dissolved in the solution. The pH values of the final solutions of the two samples were 4.14 (citric acid monohydrate) and 4.21 (tartaric acid) respectively; the results of the preliminary stability study showed that the two solutions were placed at 40°C for 24h, and then placed at 60°C for 24h, the content of related substances in the solution Basically unchanged. See Table 6-3 and 6-4 for relevant substance content.

Example 6 Conclusion: When the mass ratio of SEB-β-CD to API is 3:1, it can effectively solubilize API in different buffer solutions, and has no obvious effect on the dissolution rate; the obtained solution is placed at 40°C for 24 hours, and then It was kept stable at 60°C for 24 hours.

Table 6-3 Stability data of citric acid monohydrate SBE-β-CD fumaric acid vonoprazan solution (pH4.14)

Table 6-4 Stability data of tartrate-containing SBE-β-CD fumaric acid vonoprazan solution (pH4.21)

Example 7: Stability of SBE-β-CD vonoprazan fumarate solution to sterilization conditions.

Add a certain volume (about 75% of the final volume of the solution) of purified water to four beakers, add different amounts of SBE-β-CD or tartaric acid or citric acid monohydrate, stir and dissolve with a magnetic stirrer; tartaric acid or After dissolving citric acid monohydrate, adjust the pH value to 4.5 with 2% (w/w) NaOH; after dissolving SBE-β-CD, add vonoprazan fumarate, stir, and visually observe the dissolution of vonoprazan fumarate , and stir until vonoprazan fumarate is completely dissolved; add purified water to make up to the target final volume, and measure the pH value of the final solution. Sterilize in a high-pressure steam sterilizer, and the sterilization condition is 121°C for 12min. See Table 7-1 to 7-5 for prescriptions.

Table 7-1 (No. 01)

Table 7-2 (No. 02)

Table 7-3 (No. 03)

Table 7-4 (No. 04)

Table 7-5 (No. 05)

Results of Example 7: The solutions of the low-concentration samples and the high-concentration samples before and after sterilization were clear and transparent, colorless solutions. The content of related substances in the solution increased slightly after sterilization; the amount of SBE-β-CD and the type of buffer had no significant effect on the content of related substances in the solution. See Table 7-5 for content of relevant substances.

Table 7-6

Example 7 Conclusion: 5 prescription sample solutions remained basically stable after being sterilized at 121° C. for 12 minutes.

Example 8: Study on long-term stability of SBE-β-CD vonoprazan fumarate solution

Add a certain volume (accounting for about 75% of the final volume of the solution) of purified water into the two beakers respectively, add the prescribed amount of SBE-β-CD respectively, stir and dissolve with a magnetic stirrer; add tartaric acid to stir and dissolve in 02; add Vonoprazan fumarate, stir, visually observe the dissolution of vonoprazan fumarate, stir until vonoprazan fumarate is completely dissolved; adjust the sample solution 01 and 02 with 2% (w/w) NaOH solution pH value to 4.5; add purified water to make up to 60mL, and measure the pH value of the final solution. Sterilize in a high-pressure steam sterilizer, and the sterilization condition is 121°C for 15 minutes. After sterilization, the samples were placed at 40°C, and the changes of related substances in the samples were detected at 1, 3, and 6 months respectively. See Table 8-1 and 8-2 for the prescription.

Table 8-1 (No. 01)

Table 8-2 (No. 02)

Embodiment 8 experimental result:

Table 8-3

The two samples were placed at 40°C for 6 months, and the impurity content only increased slightly.

Example 8 Conclusion: SBE-β-CD vonoprazan fumarate solution has good long-term stability.

Example 9: Preparation of Vonorazan Fumarate Infusion Solution

Add a certain volume (accounting for about 75% of the final volume of the solution) of purified water in two beakers respectively, add sodium chloride or glucose of the prescribed amount respectively, stir and dissolve with a magnetic stirrer; add the prescribed amount of tartaric acid and stir to dissolve; add Vonoprazan fumarate, stirring, visually inspecting the dissolution of vonoprazan fumarate, stirring until the complete dissolution of vonoprazan fumarate; using 2% (w/w) NaOH solution to adjust the pH value of the sample solution to 4.5; add purified water to make up to the target final volume, and measure the pH value of the final solution.

Table 9-1 (No. 01)

Table 9-2 (No. 02)

Table 9-3 (No. 03)

Table 9-4 (No. 04)

Experimental results of Example 9: the vonoprazan fumarate in the four samples was dissolved after being stirred for half an hour, and the obtained solution was clear, transparent and colorless; the solution could be sterilized by moist heat or by filtration.

It can be seen from the above results that Examples 1-7 respectively use substituted-β-cyclodextrin to prepare vonoprazan fumarate compositions or injections. In the stability test, the single and total impurities are basically the same. In the experiment of influencing factors, the single impurity and total impurity only increased slightly, and the trend of change was not obvious. Even after high-pressure steam sterilization, the content of simple impurity and total impurity changed little before and after sterilization, which was in line with the impurity content of injections. control standards. From the analysis of the stability test results, it can be concluded that the vonoprazan fumarate composition or injection of the present invention has good solubility and solution stability.

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

In the description of this specification, reference is made to descriptions of the terms "one embodiment", "some embodiments", "some implementations", "some implementations", "examples", "specific examples", or "some examples" etc. It means that a specific feature, structure, material or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (14)

1. A composition comprising vonoprazan fumarate and a solubilizer, wherein the solubilizer is substituted β-cyclodextrin, Tween 80, phospholipids, poloxamers or any combination thereof. 2. The composition according to claim 1, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin Cyclodextrin, methyl-beta-cyclodextrin, or any combination thereof. 3. An inclusion compound of vonoprazan fumarate, containing vonoprazan fumarate and a substituted β-cyclodextrin, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin Alcohol, sulfobutyl ether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin or any combination thereof. 4. The clathrate according to claim 3, which is further prepared into a liquid preparation of vonoprazan fumarate. 5. A vonoprazan fumarate injection, comprising vonoprazan fumarate and a substituted β-cyclodextrin, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin , sulfobutyl ether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin, or any combination thereof. 6. The injection according to claim 5, wherein the injection is a ready-to-use liquid injection. 7. The injection according to claim 5, wherein the ratio of the weight of the vonoprazan fumarate to the total volume of the injection is 0.05% to 10%. 8. The injection according to claim 5, wherein the ratio of the weight of the substituted β-cyclodextrin to the total volume of the injection is 0.4% to 20%. 9. The injection according to claim 5, wherein the weight ratio of vonoprazan fumarate to the substituted β-cyclodextrin is 1:1 to 1:20. 10. The injection according to any one of claims 5-9, which further comprises a pH regulator, a buffer and a solvent, wherein the pH regulator is hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogen phosphate, calcium carbonate or Magnesium hydroxide, the buffering agent is acetic acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, ascorbic acid, malic acid, benzoic acid or any combination thereof. 11. The injection according to claim 5, which has a pH value of 3.0 to 9.0. 12. The injection according to claim 10, wherein the weight ratio of the buffer to the total volume of the injection is 0.1% to 3%. 13. The injection according to claim 5, comprising sulfobutyl ether-β-cyclodextrin, citric acid monohydrate, sodium hydroxide and purified water, or comprising hydroxypropyl-β-cyclodextrin, lemon monohydrate acid, sodium hydroxide and purified water. 14. A method for preparing the injection according to any one of claims 5-13, comprising: 1) Add a certain volume of purified water into the container, then add the prescribed amount of buffer, and stir to dissolve; 2) adjust the pH to 4.0 to 5.0 with a pH regulator; 3) Add substituted β-cyclodextrin and stir to dissolve; 4) Add voronoprazan fumarate and stir until voronoprazan fumarate is completely dissolved; 5) Constant volume with purified water; 6) The solution in 5) is sterilized, and the sterilization condition is 121° C. for 12-15 minutes.