WO2018133009A1 - Vonoprazan fumarate composition and preparation method thereof - Google Patents

Abstract

The present invention relates to a vonoprazan fumarate composition and a preparation method thereof. The composition comprises vonoprazan fumarate, a solubilizer, a buffer, a pH control agent, and a solvent.

Description

Fumarate fumarate composition and preparation method thereof Technical field

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

Background technique

Vonoprazan fumarate, formerly known as TAK-438, is a novel gastric acid secretion inhibitor developed by Takeda, Japan. It has a fast-acting, strong and long-lasting inhibition of gastric acid secretion, and gastric acid in the stomach wall. In the final 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. Voronafu, a fumaric acid, was first launched in Japan in 2014 under the trade name Takecab.

The chemical name of vorolazan fumarate is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methyl A single amine salt of fumaric acid, the structural formula is as follows:

At present, the marketed dosage form of vorolazan fumarate is a tablet, and no other dosage forms have been disclosed. Since the tablets are oral preparations, the compliance is poor for patients with dysphagia, children, and the elderly; and for patients with acute gastritis and gastric ulcers that require rapid onset of action, the tablet does not meet the clinical needs for rapid onset of action. Therefore, the development of a new pharmaceutical formulation of vorolazin fumarate, such as injection, is of great significance for providing more therapeutic options for patients who have difficulty in using tablets or achieving therapeutic effects.

Voronazide fumarate is a slightly water-soluble substance, and because of its poor water solubility, it is difficult to meet the demand for injection solubility of the drug. Therefore, there are major challenges in the development of injectable dosage forms.

The prior art CN 201410154778.8 discloses a novel water-soluble organic acid salt of Voronazan and an injection of the water-soluble organic acid salt and a preparation method thereof, but the novel water-soluble organic acid salt and the active ingredient already on the market are rich in horses. Compared with the acid vorolazan, its effect has not been supported by clinical trials and medicinal practices, nor has it increased the water-soluble technical means and effects of vorolazan fumarate, and the injection uses 100 ° C steam. Sterilization for 30 minutes, this method is not terminal sterilization, and does not achieve a superior sterilization effect. Therefore, it has been important to improve the water solubility of vorolazan fumarate by an appropriate method, and to develop a vonolazan fumarate composition and an injection preparation suitable for injection use and a preparation method thereof.

Summary of the invention

Summary of invention

According to a first aspect of the present invention, there is provided a composition comprising a substituted β-cyclodextrin-containing vorolazan fumarate which is capable of increasing the solubility of vorolazan fumarate in water.

According to a second aspect of the present invention, there is provided a wonorazin fumarate injection prepared by the composition of the first aspect, which is safe and effective, has good storage stability, and brings new drug selection to a special group that is not suitable for oral administration. Meet the clinical needs of patients with acute gastritis and gastric ulcer who need rapid onset of action.

A third aspect of the present invention provides a method for preparing a fumarazin fumarate injection according to the second aspect, which is simple and easy to perform, can be sterilized by terminal sterilization, has good stability and high safety, and is suitable for the method. Industrial production.

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

Definition of Terms

The term "comprising" or "including" is an open-ended expression that includes the content of the invention, but does not exclude other aspects.

Specific parameters of the "Terminal Sterilization Method": moist heat sterilization, 121 ° C, 12 min to 15 min.

In the context of the present invention, all numbers disclosed herein are approximate, whether or not the words "about" or "about" are used. The value of each number may have a difference of less than 10% or a reasonable difference considered by those in the field, such as a difference of 1%, 2%, 3%, 4% or 5%.

Detailed description of the invention

Based on the deficiencies of the prior art, the present invention has been intensively investigated and studied, and the substituted β-cyclodextrin is used as a solubilizing agent to form an inclusion complex with vorolazan fumarate, and on the one hand, the β-cyclodextrin is substituted to increase fumaric acid. The solubility of vonolazan in water, the stability of the solution is good, and it satisfies the solubility requirement of the preparation into injection; on the one hand, the preparation of vorolazin fumarate is further prepared from the inclusion compound, and the bioavailability is high and the effect is effective. Fast, safe, and good drug compliance for special populations; on the other hand, the combination of β-cyclodextrin and vorolazan fumarate is used in the preparation process of injection, the solution stability is strong, and the terminal can be used. Sterilized by sterilization and thoroughly sterilized.

The present invention provides a vorolazan fumarate composition comprising vorolazan fumarate and a solubilizing agent, wherein the solubilizing agent is a substituted β-cyclodextrin, Tween 80, a phospholipid, a polox Sham or any combination of them. The solubilizer is capable of increasing the solubility of vorolazan fumarate in water.

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

A composition comprising vorolazan fumarate and a substituted β-cyclodextrin, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin Sperm, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin or any combination thereof. In some embodiments is hydroxypropyl-β-cyclodextrin; in some embodiments, sulfobutylether-β-cyclodextrin.

A vonorazanic fumaric acid composition, wherein the composition is an inclusion compound.

A composition comprising vorolazan fumarate and a solubilizing agent, which can be prepared as a liquid preparation of vorolazan 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 present invention provides a wornolazan fumarate inclusion complex comprising wortolazan fumarate and a substituted β-cyclodextrin capable of increasing the fumarate fumarate at Solubility in water.

An inclusion complex comprising vorolazan fumarate and a substituted β-cyclodextrin, wherein the weight ratio of the vorolazan fumarate to the substituted β-cyclodextrin is 1:1 to 1:20 . In some embodiments it is 1:3; in some embodiments 1:5; in some embodiments 1:10.

An inclusion complex comprising vorolazan fumarate and a substituted β-cyclodextrin, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutylether-β-ring Dextrin, hydroxyethyl-β-cyclodextrin, methyl-β-cyclodextrin or any combination thereof. In some embodiments is hydroxypropyl-β-cyclodextrin; in some embodiments, sulfobutylether-β-cyclodextrin.

An inclusion complex comprising vorolazan fumarate and a substituted β-cyclodextrin, which can be prepared as a liquid preparation of vorolazan 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 present invention provides a vorolazan fumarate injection comprising vonolazan fumarate and substituted β-cyclodextrin.

A vorolazan injection of fumaric acid, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin Refined, methyl-β-cyclodextrin or any combination thereof. In some embodiments is hydroxypropyl-β-cyclodextrin; in some embodiments, sulfobutylether-β-cyclodextrin.

A vorolazan injection of fumaric acid, wherein the injection is a ready-to-use liquid injection.

A vorolazan injection of fumaric acid, wherein the ratio of the weight of the vorolazan 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 vorolazan injection of fumaric acid, wherein the ratio of the weight of the substituted β-cyclodextrin contained to the total volume of the injection is from 0.4% to 20% (w/v, g/mL). In some embodiments it is 0.8%; in some embodiments 1.2%; in some embodiments 2%.

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

In some embodiments, the vorolazan fumarate injection further comprises a solvent, a pH adjuster, a buffer. Wherein the solvent is water. Wherein the pH adjusting agent comprises hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogen phosphate, calcium carbonate or magnesium hydroxide; in some embodiments, the pH adjusting agent is sodium hydroxide. Wherein 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; in some embodiments, the buffering agent Is tartaric acid; in some embodiments, the buffer is citric acid monohydrate.

A vorolazan fumarate injection, wherein the ratio of the weight of the buffer contained to the total volume of the injection is from 0.1% to 3% (w/v, g/mL). In some embodiments it is 0.4%.

A vorolazan injection of fumaric acid, wherein the injection has a pH in the range of 3.0 to 9.0, and in some embodiments, 4.23.

A vorolazan injection of fumaric acid, wherein the injection has a pH in the range of 3.0 to 6.0.

A vorolazan fumarate injection, wherein the injection has a pH in the range of 4.0 to 5.0, and in some embodiments 4.14.

In some embodiments, a fumarazin fumarate injection comprising:

1) Fumarate fumarate 0.05%-10%;

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

3) citric acid monohydrate 0.1%-3%;

4) NaOH amount;

5) Purified water.

In some embodiments, a fumarazin fumarate injection comprising:

1) Fumarate fumarate 0.05%-10%;

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

3) tartaric acid 0.1%-3%;

4) NaOH amount;

5) Purified water.

In some embodiments, a fumarazin fumarate injection comprising:

1) Fumarate fumarate 0.05%-10%;

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

3) citric acid monohydrate 0.1%-3%;

4) NaOH amount;

5) Purified water.

In some embodiments, a fumarazin fumarate injection comprising:

1) Fumarate fumarate 0.05%-10%;

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

3) tartaric acid 0.1%-3%;

4) NaOH amount;

5) Purified water.

The present invention also provides a method for preparing the above-mentioned vorolazin fumarate injection, which comprises dissolving a buffer, a substituted β-cyclodextrin in purified water, and adjusting the pH to 4.0-5.0 using a pH adjuster. Adding fumarate fumarate, stirring and dissolving, adding purified water to volume, measuring the pH value of the final solution, bottling, stoppering, capping, terminal sterilization.

In some embodiments, the above-described vorolazin fumarate injection can be prepared as follows:

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

2) adding a predetermined amount of substituted β-cyclodextrin to the buffer solution, stirring until completely dissolved, and adjusting the pH to 4.5 using a pH adjuster;

3) adding vorolazan fumaric acid to the system, stirring and dissolving, adding purified water to make up to volume, and measuring the pH value of the final solution;

4) bottling, stoppering, capping, 121 ° C, 12 min - 15 min terminal sterilization.

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

A solution of vorolazin fumarate infusion solution, wherein the ratio of the weight of the vorolazan 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 0.053%; in some embodiments 0.0053%.

A solution of vorolazin fumarate infusion containing wonolam fumarate and a buffer, wherein the buffer is acetic acid, citric acid monohydrate, succinic acid, adipic acid, tartaric acid, anti-ring Blood acid, malic acid, benzoic acid or any combination thereof. In some embodiments, the buffer is tartaric acid.

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

A solution of vorolazan fumarate infusion, which further comprises an isotonicity adjusting agent. Wherein, the isotonicity adjusting agent is sodium chloride, glucose, mannitol, sorbitol, glycerin or the like. In some embodiments, the isotonicity adjusting agent is sodium chloride; in some embodiments, the isotonicity adjusting agent is glucose. Among them, the solution osmotic pressure was adjusted to 260 mosm / L to 320 mosm / L.

A solution of inofazan fumarate infusion solution, wherein the infusion solution has a pH in the range of 3.0 to 6.0. In some embodiments it is 4.5.

The invention also provides a preparation method of a solution of vorolazin fumarate infusion, which comprises dissolving an isotonic regulator in purified water, adding vorolazan fumarate, a buffering agent, and stirring and dissolving. Adjust the pH to 3.0-6.0 with a pH adjuster, add purified water to volume, and measure the pH of the final solution.

In some embodiments, the above-described solution of vorolazin fumarate infusion can be prepared as follows:

1) The prescription amount of isotonicity adjusting agent is dissolved in purified water having a prescription amount of 50%-90%;

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

3) adding fumarate fumarate to the system, stirring and dissolving, adjusting the pH to 4.5 using a pH adjuster;

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

The wovonazin fumaric acid composition provided by the invention can increase the solubility of wortolazan fumarate in water, meet the requirement for preparation into an injection, and can be sterilized by terminal sterilization method, and the sterilization is thorough and improved. Injectables safety; the provided Norfolk fumarate injection is a new dosage form that meets the clinical need for rapid onset of action in patients with acute gastritis and gastric ulcer, and can solve the problem of drug delivery in patients with dysphagia. High safety and good stability; the preparation method is simple and easy to implement, and is suitable for industrial production.

The invention provides a solution for the infusion solution of fumarate fumarate, which is simple and easy to manufacture, and is suitable for industrial production.

detailed description

In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below by way of non-limiting embodiments.

The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.

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

Example 1: Solubilization of vorolazan fumarate using hydroxypropyl-β-cyclodextrin (HP-β-CD).

Add a certain volume (about 75% of the final volume of the solution) of purified water to the beaker, add hydroxypropyl-β-cyclodextrin, stir and dissolve with a magnetic stirrer; after dissolving hydroxypropyl-β-cyclodextrin Adding fumarate fumarate, stirring, visualizing the dissolution of vorolazan fumarate, stirring until the complete dissolution of fumarate fumarate; adding purified water to a volume of 20 mL. The solution was subjected to a short-term stability study (stability was placed by placing the sample at 40 ° C for a certain period of time and then placing the sample at 60 ° C for a certain period of time). See Table 1-1 for prescriptions.

Table 1-1

Results of Example 1: After stirring for 20 min, the API was completely dissolved. The results of the short-term stability study confirmed that the solution was allowed to stand at 40 ° C for 80 h, and the solution was allowed to stand at 60 ° C for 72 h, and the solution remained stable. The stability study results are shown in Table 1-2.

Table 1-2

Example 1 Conclusion: When the HP-β-CD to API mass ratio was 10:1, the API was effectively solubilized; and the obtained solution was allowed to stand at 40 ° C for 80 hours and then kept at 60 ° C for 72 hours to remain stable.

Example 2: Different amounts of HP-β-CD solubilized vorolazan fumarate.

Add a certain volume (about 75% of the final volume of the solution) of purified water to the two beakers, add different amounts of HP-β-CD, stir and dissolve with a magnetic stirrer; after HP-β-CD is dissolved, Adding fumarate fumarate, stirring, visualizing the dissolution of fumarate fumarate In this case, stir until the fumarate of fumaric acid is completely dissolved; add purified water to make up to 20 mL. See Table 2-1, 2-2 for prescriptions.

table 2-1

Table 2-2

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

Example 2 Conclusion: The HP-β-CD to API ratio reduced to 3:1 still effectively solubilized the API.

Example 3: Solubilization of vonolazan 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, add the prescribed amount of citric acid or tartaric acid, stir and dissolve with a magnetic stirrer, and use 2% (w/w) NaOH. The solution was adjusted to pH 4.5; HP-β-CD was added, and stirred by a magnetic stirrer; the fumarate fumarate was added, stirred by a magnetic stirrer, and the dissolution of the fumarate fumarate was visually observed and stirred until the fumaric acid was stirred. Nolazan was completely dissolved; make up to 20 mL with purified water and measure the pH. See Table 3-1,3-2 for prescriptions. The short-term stability of the solution was studied (stability was placed by placing the sample at 40 ° C for a certain period of time and then placing the sample at 60 ° C for a certain period of time).

Table 3-1

Table 3-2

Example 3 Results: After stirring for 60 min, 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 preliminary stability study showed that the two solutions were placed at 40 ° C for 24 h and then at 60 ° C for 24 h. The content of the relevant substances in the solution was basically unchanged. The relevant substances are shown in Table 3-3, 3-4.

Conclusion of Example 3: 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 significant effect on the dissolution rate; the obtained solution is placed at 40 ° C for 24 h, and then It was kept stable at 60 ° C for 24 h.

Table 3-3 Stability data of a solution of citric acid HP-β-CD fumarate (3:1) containing monohydrate (pH 4.22)

Table 3-4 Stability data for tartaric acid HP-β-CD fumarate (3:1) solution (pH 4.23)

Example 4: Solubilization of HP-β-CD to vorolazan fumarate in different buffer solutions.

Add a certain volume (about 75% of the final volume of the solution) of purified water to each of the four beakers, add different amounts of HP-β-CD or tartaric acid or citric acid monohydrate, stir and dissolve with a magnetic stirrer; tartaric acid Or citric acid monohydrate dissolved with 2% (w / w) NaOH to adjust the pH to 4.5; after HP-β-CD dissolved, add fumarate fumarate, stir, visually dissolve fumarate fumarate In the case, stir until the fumarate of fumaric acid was completely dissolved; add purified water to a volume of 20 mL, and measure the pH of the final solution. See Tables 4-1 and 4-2 for prescriptions.

Table 4-1

Table 4-2

Example 5: Sulfocyl ether-β-cyclodextrin (SBE-β-CD) solubilization of fumarate fumarate

Add a certain volume (about 75% of the final volume of the solution) of purified water to the two beakers, add different amounts of SBE-β-CD, stir and dissolve with a magnetic stirrer; after SBE-β-CD is dissolved, Adding fumarate fumarate, stirring, visualizing the dissolution of vorolazan fumarate, stirring until the complete dissolution of fumarate fumarate; adding purified water to a volume of 20 mL. See Table 5-1, 5-2 for prescriptions.

Table 5-1

Table 5-2

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

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

Example 6: Solubilization of SBE-β-CD to vorolazan fumarate in different buffer solutions.

Add a certain volume (about 75% of the final volume of the solution) of purified water to the two beakers, add the prescribed amount of citric acid or tartaric acid, stir and dissolve with a magnetic stirrer, and use 2% (w/w) NaOH. The solution was adjusted to pH 4.5; SBE-β-CD was added, and stirred by a magnetic stirrer; the fumarate fumarate was added, the magnetic stirrer was stirred, and the dissolution of the fumarate fumarate was visually observed and stirred until the fumaric acid was stirred. Nolazan was completely dissolved; make up to 20 mL with purified water and measure the pH. See Table 6-1, 6-2 for prescriptions. The short-term stability of the solution was studied (stability was placed by placing the sample at 40 ° C for a certain period of time and then placing the sample at 60 ° C for a certain period of time).

Table 6-1

Table 6-2

Example 6 Results: After stirring for 60 min, 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 preliminary stability study showed that the two solutions were placed at 40 ° C for 24 h and then at 60 ° C for 24 h. Basically unchanged. The relevant substances are shown in Table 6-3, 6-4.

Conclusion of Example 6: When the mass ratio of SEB-β-CD to API is 3:1, the API can be effectively solubilized in different buffer solutions, and the dissolution rate is not affected; the obtained solution is placed at 40 ° C for 24 h, and then Stable at 60 ° C for 24 h.

Table 6-3 Stability data of citric acid SBE-β-CD fumarate solution (pH 4.14) containing monohydrate

Table 6-4 Stability data of tartaric acid SBE-β-CD fumarate solution (pH 4.21)

Example 7: Stability of SBE-[beta]-CD fumarazin fumarate solution to sterilization conditions.

Add a volume of purified water (about 75% of the final volume of the solution) 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 the citric acid monohydrate was dissolved, the pH was adjusted to 4.5 with 2% (w/w) NaOH; after the SBE-β-CD was dissolved, the fumonazide fumarate was added, stirred, and the dissolution of the vorolazan fumarate was visually observed. Stir until the fumarate of fumaric acid is completely dissolved; add purified water to the final volume of the target, and measure the pH of the final solution. The autoclave was sterilized and the sterilization condition was 121 ° C for 12 min. See Tables 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)

Example 7 Results: Both the low concentration sample and the high concentration sample were clear and transparent before and after sterilization, and the colorless solution was obtained. After sterilization, the content of related substances in the solution increased slightly; the amount of SBE-β-CD and the type of buffer had no significant effect on the content of related substances in the solution. The relevant substances are shown in Table 7-5.

Table 7-6

Example 7 Conclusion: The five prescription sample solutions remained substantially stable after 12 minutes of sterilization at 121 °C.

Example 8: Long-term stability study of SBE-β-CD fumarazin fumarate solution

Add a certain volume (about 75% of the final volume of the solution) of purified water to the two beakers, add the prescribed amount of SBE-β-CD, stir and dissolve with a magnetic stirrer; add tartaric acid to dissolve and dissolve in 02; Fumarazin fumarate, stir, visualize the dissolution of vorolazan fumarate, stir until the complete dissolution of fumarate fumarate; adjust the sample solution 01, 02 with 2% (w/w) NaOH solution The pH was adjusted to 4.5; the purified water was added to a volume of 60 mL, and the pH of the final solution was measured. The autoclave was sterilized and the sterilization condition was 121 ° C for 15 min. After sterilization, the sample was placed at 40 ° C and the samples were tested for changes in the relevant substances at 1, 3, and 6 months. See Table 8-1, 8-2 for prescriptions.

Table 8-1 (No. 01)

Table 8-2 (No. 02)

Example 8 experimental results:

Table 8-3

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

Example 8 Conclusion: The long-term stability of the SBE-β-CD fumarazin fumarate solution was good.

Example 9: Preparation of a solution of vorolazin fumarate infusion solution

Add a certain volume (about 75% of the final volume of the solution) of purified water to the two beakers, add the prescribed amount of sodium chloride or glucose, stir and dissolve with a magnetic stirrer; add the prescription amount of tartaric acid to stir and dissolve; Venolazan fumarate, stir, visualize the dissolution of vorolazan fumarate, stir until the complete dissolution of fumarate fumarate; adjust the pH of the sample solution with 2% (w/w) NaOH solution to 4.5; Add purified water to the final volume of the target, and measure the pH of the final solution.

Table 9-1 (No. 01)

Table 9-2 (No. 02)

Table 9-3 (No. 03)

Table 9-4 (No. 04)

Example 9 Experimental results: The vanoramine fumarate in the four samples was dissolved after stirring for half an hour, and the obtained solution was clear and transparent, colorless; the solution was sterilized by moist heat sterilization or filtration.

It can be seen from the above results that Example 1 - Example 7 respectively used a substituted-β-cyclodextrin to prepare a vorolazin fumarate composition or an injection, and in the stability test, the single impurity and the total impurity content are substantially not In the influencing factors experiment, the single and total impurities only increased slightly, and the change trend was not obvious. Even after autoclaving, the content of single and total impurities before and after sterilization was small, which was consistent with the impurity content of the injection. Control standards. From the analysis of the results of the stability test, it was found that the fumarazin fumarate composition or the injection of the present invention has good solubility and solution stability.

The method of the present invention has been described by the preferred embodiments, and it is obvious that those skilled in the art can make modifications and/or changes and combinations of the methods and applications described herein to implement and apply the present technology. . Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

In the description of the present specification, reference is made to the descriptions of the terms "one embodiment", "some embodiments", "some embodiments", "some embodiments", "example", "specific examples", or "some examples", etc. The specific features, structures, materials, or characteristics described in connection with the embodiments or examples are included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.

Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims (14)

1. A composition comprising vorolazan fumarate and a solubilizing agent, wherein the solubilizing agent is a substituted β-cyclodextrin, Tween 80, a phospholipid, a poloxamer or any combination thereof.
2. The composition according to claim 1, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxyethyl-β-cyclodextrin. Refined, methyl-β-cyclodextrin or any combination thereof.
3. A vorolazin fumarate inclusion compound comprising vonolazan 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.
4. The clathrate according to claim 3, which is further prepared as a liquid preparation of vorolazan fumarate.
5. A vorolazine fumarate injection comprising vorolazan fumarate and a substituted β-cyclodextrin, wherein the substituted β-cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfonate Butyl 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 vorolazan 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 from 0.4% to 20%.
9. The injection according to claim 5, wherein the weight ratio of vorolazan fumarate to the substituted β-cyclodextrin is 1:1 to 1:20.
10. The injection according to any one of claims 5 to 9, further comprising a pH adjuster, a buffer, and a solvent, wherein the pH adjuster is hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogen phosphate, calcium carbonate or hydroxide Magnesium, 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 of from 3.0 to 9.0.
12. The injection according to claim 10, wherein the ratio of the weight of the buffer to the total volume of the injection is from 0.1% to 3%.
13. The injection according to claim 5, which comprises sulfobutylether-β-cyclodextrin, citric acid monohydrate, sodium hydroxide and purified water, or hydroxypropyl-β-cyclodextrin, citric acid monohydrate, Sodium hydroxide and purified water.
14. A method of preparing the injection of any one of claims 5-13, comprising:

    1) adding a certain volume of purified water to the container, adding a prescribed amount of buffering agent, stirring and dissolving;

    2) adjusting the pH to 4.0 to 5.0 with a pH adjuster;

    3) adding a substituted β-cyclodextrin, stirring and dissolving;

    4) Adding fumarate fumarate and stirring until the fumarate of fumaric acid is completely dissolved;

    5) Make up to volume with purified water;

    6) The solution in 5) is sterilized, and the sterilization condition is 121 ° C, 12 to 15 min.