A proton pump inhibitor composition and preparation method thereof

Abstract

The present invention relates to a proton pump inhibitor composition and a preparation method thereof. The composition comprises a proton pump inhibitor and an osmotic pressure regulator, and the composition does not need to be redissolved, can be used directly, has good stability and good safety. At the same time, the present invention also provides a method for preparing the above-mentioned proton pump inhibitor composition, which is simple, economical, and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a proton pump inhibitor composition and a preparation method thereof, in particular to a safe and stable proton pump inhibitor composition and a preparation method thereof, belonging to the technical field of pharmaceuticals. Background Art

[0002] Vonoprazan fumarate, formerly codenamed TAK-438, is a new type of proton pump inhibitor developed by Takeda Corporation of Japan. It has a rapid, strong and long-lasting inhibitory effect on gastric acid secretion. In the last step of gastric acid secretion in gastric parietal cells, it inhibits K + For H + -K + -ATPase (proton pump) binding action, stop gastric acid secretion, and achieve acid suppression effect. Vonola fumarate was first launched in Japan in 2014 under the trade name Takecab.

[0003] The chemical name of vonoprazan fumarate is 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine fumaric acid monosalt, and the structural formula is as follows:

[0004]

[0005] Currently, the marketed dosage form of vonoprazan fumarate is tablets, and no other dosage forms have been made public. Since tablets are oral preparations, patients with dysphagia, children, and the elderly have poor compliance when taking the medicine; and for patients with acute gastritis and gastric ulcers who need rapid onset of action, tablets cannot meet the clinical needs of 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 find it difficult to use tablets or achieve therapeutic effects.

[0006] Vonoprazan fumarate has poor water solubility and is slightly soluble in water, which makes it difficult to meet the drug solubility requirements of injections.

[0007] CN201510350087 records a freeze-dried powder injection preparation, including vonoprazan fumarate and an acidic freeze-drying protective agent. CN201610051170 records a small water injection liquid preparation and a freeze-dried powder injection, including vonoprazan and its salts, a pH regulator, a metal ion complexing agent, and an inorganic salt. CN201610714831 records a small water injection liquid preparation, including vonoprazan fumarate, substituted β-cyclodextrin, and a pH regulator. In order to increase the solubility of the active ingredient vonoprazan fumarate, the above documents all add a variety of excipients to the formulation to increase the stability of the solution, or require re-dissolution in clinical use, which increases the safety risk of medication.

[0008] Therefore, providing an injection that does not require reconstitution, can be used directly, and has good stability is very beneficial for improving medication safety and compliance. Summary of the invention SUMMARY OF THE INVENTION

[0010] The first aspect of the present invention provides a composition containing vonoprazan or a salt thereof, wherein the composition comprises an osmotic pressure regulator.

[0011] The second aspect of the present invention provides an injection prepared from the composition of the first aspect. The injection is safe and effective, has good storage stability, provides a new medication option for special groups of people who are not suitable for oral administration, and meets the clinical needs of patients with acute gastritis and gastric ulcers for rapid onset of action.

[0012] The third aspect of the present invention provides a method for preparing the injection described in the second aspect. The method is simple and easy to implement, can be sterilized by terminal sterilization, has good stability, high safety, and is suitable for industrial production.

[0013] Definition of terms

[0014] The term “comprise” or “include” is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0015] Specific parameters of “terminal sterilization method”: moist heat sterilization, 121°C, 12min to 30min.

[0016] In the context of the present invention, all the numbers disclosed herein are approximate values, regardless of whether the words "about" or "approximately" are used. The value of each number may vary by less than 10% or a reasonable difference considered by those skilled in the art, such as 1%, 2%, 3%, 4% or 5%.

[0017] In the present invention, min represents minute, h represents hour, mg represents milligram, g represents gram, mL represents milliliter, W represents weight, V represents volume, and mOsm / kg represents milliosmole / kilogram.

[0018] The dosage of the active ingredient or osmotic pressure regulator in the present invention is the ratio of the active ingredient or osmotic pressure regulator to the total volume of the injection, that is, W / V, g / 100mL. For example, 0.6% sodium chloride means that 100mL of solution contains 0.6g of sodium chloride. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention aims to provide an injection which does not require reconstitution, can be used directly and has good stability.

[0021] Based on the deficiencies of the prior art, the present invention, after in-depth investigation and research, directly dissolves vonoprazan or its salt in water, and no other excipients are added except for adding an osmotic pressure regulator and controlling the pH range of the resulting liquid. The resulting solution has good stability and meets the solubility requirements for preparing an injection; and has high bioavailability, rapid onset, good safety, and good compliance with medication for special populations. On the other hand, the vonoprazan composition of the present invention has strong solution stability during the process of preparing an injection, and can be sterilized by terminal sterilization, and the sterilization is thorough.

[0022] In a first aspect of the present invention, a composition is provided, wherein the active ingredient is vonoprazan or a salt thereof, and the composition comprises an osmotic pressure regulator. In some embodiments, the active ingredient of the composition is vonoprazan fumarate. When an osmotic pressure regulator is added to the composition and the composition is prepared into an injection, the requirements for the use of the injection are met, and the risks of injection pain, hemolysis, etc. caused by hypotonicity or hypertonicity are avoided.

[0023] The composition of the present invention can be prepared into a liquid preparation, and the liquid preparation can be but not limited to a spray, a suspension, a solution, or an injection. In some embodiments, the liquid preparation is an injection. In some embodiments, the liquid preparation is a ready-to-use liquid injection. In some embodiments, the liquid preparation is a large infusion of vonoprazan fumarate.

[0024] In some embodiments, the composition is a ready-to-use liquid injection, and the active ingredient is vonoprazan fumarate.

[0025] In some embodiments, the osmotic pressure adjusting agent comprises sodium chloride.

[0026] In some embodiments, according to the ratio of the weight of the osmotic pressure regulator to the total volume of the injection, the dosage range of the osmotic pressure regulator is 0.6%-1.0% (W / V, g / 100mL). In some embodiments, the dosage range of the osmotic pressure regulator is 0.7%-0.9%; in some embodiments, the dosage range of the osmotic pressure regulator is 0.6%-0.7%; in some embodiments, the dosage range of the osmotic pressure regulator is 0.6%-0.9%; in some embodiments, the dosage range of the osmotic pressure regulator is 0.7%-1.0%; in some embodiments, the dosage range of the osmotic pressure regulator is 0.9%-1.0%. In some embodiments, the dosage of the osmotic pressure regulator is 0.6%, 0.7%, 0.9%, or 1.0%.

[0027] In some embodiments, the osmotic pressure regulator is sodium chloride, and the dosage of the sodium chloride ranges from 0.6% to 1.0% (W / V, g / 100 mL) or 0.7% to 0.9% according to the ratio of the weight of the osmotic pressure regulator to the total volume of the injection. In some embodiments, the dosage of sodium chloride is 0.6%, 0.7%, 0.9%, or 1.0%.

[0028] The composition of the present invention may have a pH of 3.0-5.5. In some embodiments, the composition has a pH of 3.5-4.5; in some embodiments, the composition has a pH of 3.5-4.0; in some embodiments, the composition has a pH of 3.0-4.0; in some embodiments, the composition has a pH of 4.0-5.0; in some embodiments, the composition has a pH of 4.0-4.5. In some embodiments, the composition has a pH of 3.5; in some embodiments, the composition has a pH of 4.0; in some embodiments, the composition has a pH of 4.5; in some embodiments, the composition has a pH of 5.0.

[0029] In some embodiments, the injection pH is preferably 3.8-4.5. The injection pH is 3.8-4.2, and the stability is good. In some embodiments, the injection pH is 4.3; in some embodiments, the injection pH is 4.1.

[0030] When the composition of the present invention is prepared into an injection, the dosage of the active ingredient ranges from 0.0025% to 0.4% (W / V, g / 100 mL) according to the ratio of the weight of vonoprazan free base to the total volume of the injection. In some embodiments, the amount of active ingredient ranges from 0.005% to 0.1%; in some embodiments, the amount of active ingredient ranges from 0.01% to 0.1%; in some embodiments, the amount of active ingredient ranges from 0.005% to 0.01%; in some embodiments, the amount of active ingredient ranges from 0.005% to 0.02%; in some embodiments, the amount of active ingredient ranges from 0.005% to 0.04%; in some embodiments, the amount of active ingredient ranges from 0.005% to 0.1%; in some embodiments, the amount of active ingredient ranges from 0.01% to 0.02%; in some embodiments, the amount of active ingredient ranges from 0.01% to 0.04%; in some embodiments, the amount of active ingredient ranges from 0.02% to 0.04%; in some embodiments, the amount of active ingredient ranges from 0.02% to 0.1%; in some embodiments, the amount of active ingredient ranges from 0.04% to 0.1%. In some embodiments, the amount of active ingredient is 0.005%; in some embodiments, the amount of active ingredient is 0.02%; in some embodiments, the amount of active ingredient is 0.04%; in some embodiments, the amount of active ingredient is 0.01%; in some embodiments, the amount of active ingredient is 0.1%.

[0031] The composition of the present invention, the active ingredient is measured by weight of vonoprazan free base, and the single dose is 5 mg-20 mg. In some embodiments, the single dose of the active ingredient is 10 mg-20 mg; in some embodiments, the single dose of the active ingredient is 5 mg-10 mg. In some embodiments, the single dose of the active ingredient is 5 mg; in some embodiments, the single dose of the active ingredient is 10 mg; in some embodiments, the single dose of the active ingredient is 15 mg; in some embodiments, the single dose of the active ingredient is 20 mg.

[0032] In some embodiments, the osmotic pressure regulator in the composition is sodium chloride, and the amount of sodium chloride in each 100 mL of the composition is 0.6 g to 1.0 g.

[0033] In some embodiments, the composition comprises:

[0034] 1) Vonoprazan fumarate, dosage range is 0.005%-0.1% (W / V, g / 100mL);

[0035] 2) Sodium chloride, dosage range is 0.6%-1.0% (W / V, g / 100mL).

[0036] In some embodiments, the composition is vonoprazan fumarate injection, which comprises:

[0037] 1) Vonoprazan fumarate, dosage range is 0.005%-0.1% (W / V, g / 100mL);

[0038] 2) Sodium chloride, dosage range is 0.6%-1.0% (W / V, g / 100mL).

[0039] In some embodiments, the composition is vonoprazan fumarate injection, which comprises:

[0040] 1) Vonoprazan fumarate, dosage range is 0.01%-0.1% (W / V, g / 100mL);

[0041] 2) Sodium chloride, dosage range is 0.7%-0.9% (W / V, g / 100mL).

[0042] In some embodiments, the composition is a vonoprazan fumarate infusion solution, which comprises:

[0043] 1) Vonoprazan fumarate, dosage: 0.01% (W / V, g / 100mL);

[0044] 2) Sodium chloride, dosage: 0.9% (W / V, g / 100mL);

[0045] 3) Water for injection.

[0046] In some embodiments, the composition is a vonoprazan fumarate injection, which contains: vonoprazan fumarate, sodium chloride and water, and the pH range is 3.5-5.5; wherein the vonoprazan fumarate content ranges from 0.0025% to 0.4% (W / V, g / 100mL), and the sodium chloride content ranges from 0.6% to 1.0% (W / V, g / 100mL).

[0047] In some embodiments, the composition is a vonoprazan fumarate injection, which contains: vonoprazan fumarate, sodium chloride and water, and the pH range is 3.5-5.5; wherein the vonoprazan fumarate content ranges from 0.005% to 0.1% (W / V, g / 100mL), and the sodium chloride content ranges from 0.6% to 1.0% (W / V, g / 100mL).

[0048] In some embodiments, the composition is a vonoprazan fumarate injection, which contains: vonoprazan fumarate, sodium chloride and water, and the pH range is 3.5-5.5; wherein the vonoprazan fumarate content ranges from 0.01% to 0.1% (W / V, g / 100mL), and the sodium chloride content ranges from 0.7% to 0.9% (W / V, g / 100mL).

[0049] In some embodiments, the composition is a vonoprazan fumarate infusion, which contains vonoprazan fumarate, sodium chloride and water, and has a pH range of 3.5-5.5; wherein the vonoprazan fumarate content is 0.01% (W / V, g / 100mL), and the sodium chloride content is 0.9% (W / V, g / 100mL).

[0050] In some embodiments, the composition is a vonoprazan fumarate injection, which is composed of vonoprazan fumarate, sodium chloride and water, and has a pH range of 3.5-5.5; wherein the vonoprazan fumarate content ranges from 0.0025% to 0.4% (W / V, g / 100mL), and the sodium chloride content ranges from 0.6% to 1.0% (W / V, g / 100mL).

[0051] In some embodiments, the composition is a vonoprazan fumarate injection, which consists of vonoprazan fumarate, sodium chloride and water, and has a pH range of 3.5-5.5; wherein the vonoprazan fumarate content ranges from 0.005% to 0.1% (W / V, g / 100mL), and the sodium chloride content ranges from 0.6% to 1.0% (W / V, g / 100mL).

[0052] In some embodiments, the composition is a vonoprazan fumarate injection, which is composed of vonoprazan fumarate, sodium chloride and water, and has a pH range of 3.5-5.5; wherein the vonoprazan fumarate content ranges from 0.01% to 0.1% (W / V, g / 100mL), and the sodium chloride content ranges from 0.7% to 0.9% (W / V, g / 100mL).

[0053] In some embodiments, the composition is a vonoprazan fumarate infusion, which consists of vonoprazan fumarate, sodium chloride and water, and has a pH range of 3.5-5.5; wherein the vonoprazan fumarate content is 0.01% (W / V, g / 100mL), and the sodium chloride content is 0.9% (W / V, g / 100mL).

[0054] The present invention directly dissolves vonoprazan or its salt in a relatively large volume of water (greater than or equal to 50 mL) to prepare a liquid, such as a large infusion solution, which only needs to add an osmotic pressure regulator and control the pH range of the liquid by hydrochloric acid and / or sodium hydroxide, and does not need to add auxiliary materials such as substituted β-cyclodextrin and ethylenediaminetetraacetic acid, thereby improving the safety of the preparation; and provides a new medication option for patients who cannot tolerate substituted β-cyclodextrin (such as patients with renal insufficiency).

[0055] The advantages of large-volume infusion preparations over tablets in clinical use are that they do not require oral administration, have a rapid onset of action, are suitable for patients with dysphagia and patients with acute gastritis and gastric ulcers, and can be used directly, avoiding contamination and safety risks introduced by operational errors during reconstitution.

[0056] In a second aspect, the present invention provides a method for preparing the above-mentioned composition, comprising the following steps: first preparing an aqueous solution of vonoprazan or its salt, then adding an osmotic pressure regulator thereto, dissolving, sterilizing and filtering, then filling, sealing, and sterilizing at 121°C for 15min to 30min.

[0057] In some embodiments, a method for preparing the above-mentioned composition comprises the following steps: first prepare an aqueous solution of vonoprazan fumarate, then add sodium chloride thereto, dissolve it, sterilize and filter it, and then fill it into a soft infusion bag, seal it with a polypropylene interface of a plastic infusion container, and sterilize it at 121°C for 15min to 30min. In some embodiments, 80% of the total amount of water for injection is weighed according to the production batch dosage, vonoprazan fumarate is added and stirred, sodium chloride is added after it is completely dissolved, and the pH is adjusted to 3.0-5.5 after the sodium chloride is completely dissolved, and the volume is constant (the liquid preparation temperature is controlled between 25°C and 75°C during the preparation process); after sterilization and filtration, it is filled into an infusion soft bag / infusion glass bottle and other infusion containers, and sterilized by wet heat sterilization after sealing, and the sterilization condition is sterilized at 121°C for 15min to prepare the above-mentioned composition.

[0058] The composition provided by the present invention meets the requirements for preparing an injection, and can be sterilized by terminal sterilization, which is thorough and improves the safety of the injection. The vonoprazan fumarate injection provided by the present invention is a new dosage form, which can meet the clinical needs of patients with acute gastritis and gastric ulcers who need rapid onset of action, and can solve the drug administration problem of patients with dysphagia, with high safety and good stability; the preparation method provided is simple and easy to implement, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 A graph depicting the mean plasma concentration of vonoprazan versus time following injection of the formulation of Example 11 of the present invention in beagle dogs. DETAILED DESCRIPTION

[0060] To enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further elaborate on the present invention in detail.

[0061] All 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.

[0062] Example 1: Stability investigation of vonoprazan fumarate solutions (without osmotic pressure regulator) at different concentrations

[0063] Table 1: Prescription table

[0064]

[0065] Process: Weigh vonoprazan fumarate according to the prescription, add water for injection and stir to dissolve. After dissolution, adjust the pH to the target value and make up the volume; after filling into the infusion container, seal it and sterilize it by moist heat sterilization.

[0066] Table 2 Stability of the solution before and after sterilization

[0067] prescription After sterilization Osmotic pressure Prescription 1 Total miscellaneous: 0.15 8mOsm / kg Prescription 2 Total impurities: 0.12 4mOsm / kg Prescription 3 Total Miscellaneous: <LOQ 2mOsm / kg Prescription 4 ND 1mOsm / kg

[0068] Remarks: 1. When the impurity level does not exceed 0.1%, it is indicated by "<LOQ". 2. "ND" indicates not detected.

[0069] Prepare the liquid according to Formulas 1 to 4. After sterilization, the impurity levels of the products of each formula are indistinguishable and the impurity levels are all acceptable. However, the osmotic pressure test results show hypotonicity, and pain is likely to occur during injection.

[0070] Example 2: Stability investigation of vonoprazan fumarate solutions at different concentrations

[0071] Table 3: Prescription table

[0072]

[0073] Process: Weigh vonoprazan fumarate according to the prescription, add water for injection and stir to dissolve. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value and make up the volume; after filling into the infusion container, seal it and sterilize it by moist heat sterilization.

[0074] Table 4 Stability of the solution before and after sterilization according to the prescription

[0075] prescription After sterilization Osmotic pressure Prescription 5 Total Miscellaneous: <LOQ 288mOsm / kg Prescription 6 Total Miscellaneous: <LOQ 295 mOsm / kg Prescription 7 Total impurities: 0.12 287mOsm / kg Prescription 8 Total impurities: 0.15 284mOsm / kg Prescription 9 Total impurities: 0.1 312mOsm / kg

[0076] Remarks: 1. When the impurity level does not exceed 0.1%, it is indicated by "<LOQ".

[0077] After adding sodium chloride, the impurity level of the product after sterilization remains unchanged (compared with Example 1), and the product quality is stable. Therefore, adding sodium chloride has no effect on the product stability. Moreover, the measured osmotic pressures after adding sodium chloride are all within the physiological osmotic pressure range of the human body, meeting the usage requirements of the injection.

[0078] Example 3: Investigation of the effect of different types of osmotic pressure regulators on product stability

[0079] Table 5: Prescription table

[0080]

[0081] Process: Weigh vorinostat fumarate according to the prescription, add water for injection and stir to dissolve. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value and make up the volume. After filling into the infusion container, seal it and sterilize it by moist heat sterilization. The investigation results are shown in Table 6.

[0082] Table 6

[0083] prescription After sterilization Osmotic pressure Prescription 5 Total Miscellaneous: <LOQ 288mOsm / kg Prescription 6 Total Miscellaneous: <LOQ 295 mOsm / kg Prescription 7 Total impurities: 0.12 287mOsm / kg Prescription 10 Total Miscellaneous: 1.65 290 mOsm / kg Prescription 11 Total miscellaneous: 0.92 293mOsm / kg Prescription 12 Total miscellaneous: 0.65 291mOsm / kg

[0084] Remarks: 1. When the impurity level does not exceed 0.1%, it is indicated by "<LOQ".

[0085] Both glucose and sodium chloride can be used as osmotic pressure regulators to maintain the osmotic pressure of the preparation within the normal physiological range of the human body. However, the impurity level of the prescription with added glucose is much higher than that of the sodium chloride prescription after sterilization. The impurity level of the prescription with added glucose as an isotonic regulator is too high to be acceptable.

[0086] Example 4: Investigation of the effect of different dosages of sodium chloride on osmotic pressure

[0087] Table 7: Prescription table

[0088]

[0089] Process: Weigh vorinostat fumarate according to the prescription, add water for injection and stir to dissolve. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value and make up the volume. After filling into the infusion container, seal it and sterilize it by moist heat sterilization. The investigation results are shown in Table 8.

[0090] Table 8

[0091] prescription Prescription 7 Prescription 13 Prescription 14 Prescription 15 Prescription 16 Osmotic pressure 300mOsm / kg 235 mOsm / kg 208mOsm / kg 167mOsm / kg 329mOsm / kg

[0092] According to the above results, the dosage of sodium chloride in a single prescription is 0.5 - 1.0 g, and the measured osmotic pressure is 167 - 329 mOsm / kg. The tolerable osmotic pressure range for intravenous injection is 200 - 500 mOsm / kg. Therefore, the dosage of sodium chloride in a single prescription between 0.6 - 1.0 g is acceptable.

[0093] Example 5: The stability of vonoprazan fumarate solutions with different pH values was investigated using Prescription 7.

[0094] Table 9: Prescription Table

[0095] name Prescription 7-1 Prescription 7-2 Prescription 7-3 Prescription 7-4 Vonoprazan fumarate 26.72mg 26.72mg 26.72mg 26.72mg Sodium chloride 0.9g 0.9mg 0.9mg 0.9mg Sodium hydroxide Adjust pH to 3.99 Adjust pH to 6.06 Adjust pH to 8.11 Adjust pH to 9.14 Water for injection qs100ml qs100ml qs100ml qs100ml

[0096] Process: Weigh vonoprazan fumarate according to the prescription, add water for injection and stir to dissolve it. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value respectively and make up the volume; after filling into the infusion container, seal it and sterilize it by moist heat sterilization. The stability results after sterilization are shown in Table 10.

[0097] Table 10

[0098] name Prescription 7-1 Prescription 7-2 Prescription 7-3 Prescription 7-4 Total Miscellaneous <LOQ 0.81％ 1.74％ 5.14％

[0099] Note: 1. When the impurity level does not exceed 0.1%, it is indicated by "<LOQ".

[0100] The results show that the vonoprazan fumarate solution has the best stability at about pH 4.0.

[0101] Example 6: Investigation on the stability of vonoprazan fumarate solutions with different pH values

[0102] Table 11: Prescription Table

[0103] name Prescription 7-5 Prescription 7-6 Prescription 7-7 Prescription 7-8 Prescription 7-9 Vonoprazan fumarate 26.72mg 26.72mg 26.72mg 26.72mg 26.72mg Sodium chloride 0.9g 0.9g 0.9g 0.9g 0.9g Sodium hydroxide Adjust pH to 3.5 Adjust pH to 4.0 Adjust pH to 4.5 Adjust pH to 5.0 Adjust pH to 5.5 Water for injection qs100ml qs100ml qs100ml qs100ml qs100ml

[0104] Process: Weigh vonoprazan fumarate according to the prescription, add water for injection and stir to dissolve it. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value respectively and make up the volume; after filling into the infusion container, seal it and sterilize it by moist heat sterilization. The stability results after sterilization are shown in Table 12.

[0105] Table 12

[0106] name Prescription 7-5 Prescription 7-6 Prescription 7-7 Prescription 7-8 Prescription 7-9 Total Miscellaneous <LOQ <LOQ 0.12％ 0.41％ 0.59％

[0107] Note: 1. When the impurity level does not exceed 0.1%, it is indicated by "<LOQ".

[0108] The results show that the vonoprazan fumarate solution has good stability after sterilization within the pH range of 3.5 - 4.5.

[0109] Example 7: Investigate the influence of the solution preparation temperature on the product stability according to Prescription 7

[0110] Table 13: Prescription Table

[0111]

[0112]

[0113] Process: Weigh voriconazole fumarate according to the prescription, add water for injection and stir to dissolve it. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value and make up the volume (control the solution preparation temperature at 25°C, 50°C, and 75°C respectively during the solution preparation process); after filling into the infusion container, seal it and sterilize it by moist heat sterilization method.

[0114] Table 14: Solution preparation temperature adopted during the solution preparation process and the corresponding results

[0115] Liquid preparation temperature 25℃ 50℃ 75℃ Active ingredient dissolution time 30min 7min 2min Total Miscellaneous Total impurities: < LOQ Total impurities: < LOQ Total impurities: < LOQ

[0116] Remarks: 1. When the impurity level does not exceed 0.1%, it is indicated by "<LOQ".

[0117] According to the above results, increasing the solution preparation temperature during the solution preparation process can effectively reduce the dissolution time of the active ingredient, and increasing the solution preparation temperature has no impact on the product quality. Therefore, the solution preparation temperature can be controlled between 25°C and 75°C.

[0118] Example 8: Investigation on different sterilization times of voriconazole fumarate preparations

[0119] Table 15: Prescription Table

[0120] name Dosage Vonoprazan fumarate 26.72mg Sodium chloride 0.9g Sodium hydroxide Moderate Water for injection qs100ml

[0121] Process: Weigh voriconazole fumarate according to the prescription, add water for injection and stir to dissolve it. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value and make up the volume; after filling into the infusion container, seal it and sterilize it by moist heat sterilization method. The sterilization conditions are 121°C, 15 min; 121°C, 20 min; or 121°C, 30 min respectively.

[0122] Table 16: Sterilization conditions and the corresponding results

[0123] Sterilization method A B C Sterilization conditions 121℃,15min 121℃,20min 121℃,30min Total Miscellaneous Total impurities: 0.11% Total impurities: 0.12% Total impurities: 0.11%

[0124] According to the above results, using moist heat sterilization with sterilization conditions of 121°C for 15 min to 30 min, the product quality is stable.

[0125] Example 9: Investigation on different packaging forms of voriconazole fumarate preparations

[0126] Table 17: Prescription Table

[0127] name Dosage Vonoprazan fumarate 26.72mg Sodium chloride 0.9g Sodium hydroxide Moderate Water for injection qs100ml

[0128] Process: Weigh vorapaxar fumarate according to the prescription, add water for injection and stir to dissolve. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to the target value and make up the volume. After filling into different types of infusion containers, seal them and sterilize them by moist heat sterilization method.

[0129] Table 18 Different Packages and Corresponding Results

[0130]

[0131] Remark: 1. When the impurity level does not exceed 0.1%, it is indicated by "<LOQ".

[0132] The above investigation results show that there is no difference in the total impurity level after sterilization when using medium-borosilicate glass infusion bottles and five-layer co-extruded infusion bags as the inner packages of the product. Therefore, both of these two inner package forms, namely medium-borosilicate glass infusion bottles and flexible infusion bags, are applicable.

[0133] Example 10: Stability Investigation of Vorapaxar Fumarate Injection

[0134] Table 19: Prescription Table

[0135] name Dosage Vonoprazan fumarate 26.72mg Sodium chloride 0.9g Sodium hydroxide Moderate Water for injection qs100ml

[0136] Process: Weigh vorapaxar fumarate according to the prescription, add water for injection and stir to dissolve. After complete dissolution, add the weighed sodium chloride. After the sodium chloride is dissolved, adjust the pH to 4.30 with sodium hydroxide and make up the volume. After filling into the infusion container, seal it and sterilize it by moist heat sterilization method.

[0137] Table 20 Stability Investigation Results under Accelerated Conditions (40°C, 75% RH)

[0138]

[0139] The results show that the vorapaxar fumarate injection described in the present invention remains clear, transparent and colorless after being placed under accelerated conditions for 6 months, and there are no obvious changes in pH, content and related substances, indicating good stability.

[0140] Example 11: Pharmacokinetic Study of Vorapaxar Fumarate Injection in Rats

[0141] Table 21: Prescription Table

[0142]

[0143]

[0144] Preparation process: Weigh vonoprazan fumarate according to the prescription, add water for injection and stir to dissolve, add weighed sodium chloride after complete dissolution, adjust pH to 4.10 with sodium hydroxide after sodium chloride is dissolved, and make up the volume. Fill in the infusion container and seal it, and sterilize it by wet heat sterilization.

[0145] The sample of Example 11 was selected for methodological verification and beagle dog PK experiment. The experiment is shown in Table 22.

[0146] Table 22

[0147]

[0148] The LC / MS / MS system used for analysis included a Shimadzu LC30A series vacuum degassing oven, a binary syringe pump, a well plate autosampler, a column thermostat, and a QTRAP5500 triple quadrupole mass spectrometer with an electrospray ionization (ESI) source. Quantitative analysis was performed in the MRM mode, and the parameters for the MRM transitions are shown in Table 23.

[0149] :Table 23: Vonoprazan mass spectrometry conditions

[0150]

[0151] The analysis was performed using a Waters Xbridge C18, 2.1×50 mm, 5 μM column, and 15 μL of sample was injected. Analysis conditions: The mobile phase was 2 mM ammonium formate + 0.1% formic acid (A) and methanol + 2 mM ammonium formate + 0.1% formic acid (B). The flow rate was 0.3 mL / min. The mobile phase gradient is shown in Table 24.

[0152] Table 24: Vonoprazan Liquid Phase Method

[0153]

[0154]

[0155] The present invention evaluated the pharmacokinetic study of the sample of Example 11 in beagle dogs. The drug was administered by continuous infusion. After the animals were given the vonoprazan fumarate solution preparation, about 0.2 mL of blood was collected from the medial cephalic vein of the forelimb at 0 h before administration and 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 12 and 24 h after administration. The plasma was separated and frozen for testing. The mixture was centrifuged at 12,000 rpm for 2 minutes. The plasma was collected and stored at -70°C until the above-mentioned LC / MS / MS analysis was performed. Table 25 lists the pharmacokinetic data of the sample of Example 11 in beagle dogs. The compounds of the present invention have good pharmacokinetic properties. The peak time of plasma in the continuous infusion group is the end time of infusion. There are no obvious adverse reactions during the administration process. The average drug-time curve of the preparation of Example 11 of the present invention in beagle dogs is shown in Figure 25. Figure 1 .

[0156] Table 25: Pharmacokinetic data of compounds in beagle dogs

[0157]

[0158] The results showed that the vonoprazan fumarate injection prepared in Example 11 took effect quickly after intravenous drip into the beagle dog, and the peak time was 0.5 hours.

[0159] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

[0160] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "some implementation methods", "some implementation schemes", "examples", "specific examples", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, unless they are contradictory.

[0161] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A composition consisting of the following components: (1) an active ingredient, vonoprazan fumarate, wherein the amount of the active ingredient is in the range of 0.01%-0.04% (W / V) based on the ratio of the weight of vonoprazan to the total volume of the injection; (2) an osmotic pressure regulator, sodium chloride, wherein the amount of the osmotic pressure regulator is in the range of 0.7%-0.9% (W / V) based on the ratio of the weight of the osmotic pressure regulator to the total volume of the injection; (3) sodium hydroxide; (4) water for injection; the composition is a ready-to-use liquid injection; and the pH of the composition is 4.0-4.

5.

2. A method for preparing the composition as claimed in claim 1, comprising the following steps: According to the production batch dosage, weigh 80% of the total amount of water for injection, add vonoprazan fumarate and stir, add sodium chloride after complete dissolution, adjust the pH to 4.0-4.5 after the sodium chloride is completely dissolved, make up the volume, and control the preparation temperature between 25℃~75℃ during the preparation process; fill in infusion soft bags or infusion glass bottles after sterilization and filtration, and sterilize by wet heat sterilization after sealing. The sterilization conditions are sterilization at 121℃ for 15min.

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