CN113350271B - Proton pump inhibitor composition and preparation method thereof - Google Patents
Proton pump inhibitor composition and preparation method thereof Download PDFInfo
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Abstract
本发明涉及一种质子泵抑制剂的组合物及其制备方法。所述组合物包含质子泵抑制剂和渗透压调节剂，所述组合物无需复溶、可直接使用、稳定性好、安全性好。同时，本发明还提供了制备上述质子泵抑制剂组合物的方法，该方法简单经济，适用于工业化生产。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
The invention relates to a composition of a proton pump inhibitor and a preparation method thereof, in particular to a safe and stable composition of a proton pump inhibitor and a preparation method thereof, and belongs to the technical field of pharmacy.
Background
The code TAK-438 has been used for the generation (Vonoprazan fumarate) of fumaric acid Fu Nuola, which is a novel proton pump inhibitor developed by the Wuta-tsu company in japan, and has quick-acting, powerful and durable gastric acid secretion inhibition effect, and in the last step of gastric acid secretion of parietal cells, the gastric acid secretion is stopped by inhibiting the binding of K + to H +-K+ -ATPase (proton pump), so that the acid inhibition effect is achieved. Vonola fumarate was first marketed in Japan in 2014 under the trade name Takecab.
Vonolamine fumarate has the chemical name 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methyl methylamine fumarate monosalt, and has the structural formula:
The current marketed formulation of vonolamine fumarate is a tablet, and no other formulation has been disclosed. The tablet belongs to an oral preparation, has poor compliance when being taken by dysphagia patients, children, the elderly and the like, and can not meet the clinical requirement of quick-acting on patients with acute gastritis and gastric ulcer which need quick-acting, so that a novel fumaraca drug dosage form, such as an injection, is developed, and has important significance for providing treatment options for more patients with the requirement of taking medicines and difficult to take the tablet or achieve the curative effect.
The vonolla fumarate has poor water solubility, is a substance slightly soluble in water, and is difficult to meet the requirement of injection on the medicine solubility.
CN201510350087 describes a freeze-dried powder injection preparation comprising Fu Nuola-gen fumarate and an acidic freeze-drying protective agent. CN201610051170 describes a small water injection liquid preparation and freeze-dried powder injection, including vonolamine and its salt, pH regulator, metal ion complexing agent and inorganic salt. CN201610714831 describes a small water injection liquid preparation comprising Fu Nuola raw fumaric acid, substituted beta-cyclodextrin and pH regulator. In order to increase the solubility of the active ingredient, namely, the voronoi fumarate, the preparation prescription is added with various auxiliary materials to increase the stability of the solution, or the solution needs to be re-dissolved in clinical use, so that the safety risk of medication is increased.
Therefore, it would be advantageous to provide an injection that can be used directly without reconstitution and has good stability, and that can improve the safety and compliance of administration.
Disclosure of Invention
Summary of The Invention
In a first aspect the invention provides a composition comprising voronoi or a salt thereof, the composition comprising an osmolality adjusting agent.
The second aspect of the invention provides an injection prepared from the composition in the first aspect, which is safe and effective, has good storage stability, brings new medication options for special people who are not suitable for oral administration, and meets the clinical requirements of patients with acute gastritis and gastric ulcer for quick response.
The third aspect of the invention provides a preparation method of the injection according to the second aspect, which is simple and feasible, can be sterilized by a terminal sterilization method, has good stability and high safety, and is suitable for industrial production.
Definition of terms
The terms "comprising" or "including" are used in an open-ended fashion, i.e., including the teachings described herein, but not excluding additional aspects.
Specific parameters of the terminal sterilization method are moist heat sterilization at 121 ℃ for 12min to 30min.
In the context of the present invention, all numbers disclosed herein are approximate, whether or not the word "about" or "about" is used. The numerical value of each number may vary by less than 10% or reasonably as considered by those skilled in the art, such as 1%, 2%, 3%, 4% or 5%.
In the present invention, min represents minutes, h represents hours, mg represents milligrams, g represents grams, mL represents milliliters, W represents weight, V represents volume, and mOsm/kg represents milliosmoles/kg.
The amount of 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, i.e., W/V, g/100mL, for example, 0.6% sodium chloride means that 100mL of the solution contains 0.6g sodium chloride.
Detailed Description
The invention aims to provide an injection which can be directly used without re-dissolution and has good stability.
Based on the defects of the prior art, the invention directly dissolves the vonolamine or the salt thereof in water through intensive investigation and research, does not need to add other auxiliary materials outside the pH range of the liquid obtained by adding the osmotic pressure regulator and controlling, has good stability of the obtained solution, meets the solubility requirement of the prepared injection, and has high bioavailability, quick response, good safety and good medication compliance for special people. On the other hand, in the process of preparing the Fu Nuola raw composition into injection, the solution stability is strong, and the sterilization can be completed by adopting a terminal sterilization method.
In a first aspect of the invention there is provided a composition comprising as active ingredient vonolamine or a salt thereof, said composition comprising an osmolality adjusting agent. In some embodiments, the active ingredient of the composition is voronoi fumarate. When the composition is prepared into injection, the osmotic pressure regulator is added into the composition, so that the use requirement of the injection is met, and the risks of injection pain, hemolysis and the like caused by hypotonic or hypertonic are avoided.
The composition of the invention can be prepared into liquid preparations, and the liquid preparations can be but are not limited to spray, suspension, solution and injection. In some embodiments, the liquid formulation is an injection. In some embodiments, the liquid formulation is a ready-to-use liquid injection. In some embodiments, the liquid formulation is a voronoi fumarate infusion.
In some embodiments, the composition is a ready-to-use liquid injection and the active ingredient is voronoi fumarate.
In some embodiments, the osmolality adjusting agent comprises sodium chloride.
In some embodiments, the osmolality adjusting agent is used in an amount ranging from 0.6% to 1.0% (W/V, g/100 mL) in terms of the weight of the osmolality adjusting agent to the total volume of the injection. In some embodiments, the osmolality adjusting agent is in the range of 0.7% to 0.9%, in some embodiments, the osmolality adjusting agent is in the range of 0.6% to 0.7%, in some embodiments, the osmolality adjusting agent is in the range of 0.6% to 0.9%, in some embodiments, the osmolality adjusting agent is in the range of 0.7% to 1.0%, in some embodiments, the osmolality adjusting agent is in the range of 0.9% to 1.0%. In some embodiments, the osmolality adjusting agent is used in an amount of 0.6%,0.7%,0.9%, or 1.0%.
In some embodiments, the osmolality adjusting agent is sodium chloride, which is used in an amount ranging from 0.6% to 1.0% (W/V, g/100 mL), or from 0.7% to 0.9% by weight of the osmolality adjusting agent to the total volume of the injection. In some embodiments, sodium chloride is used in an amount of 0.6%,0.7%,0.9%, or 1.0%.
The pH of the composition of the present invention may be 3.0 to 5.5. In some embodiments, the composition pH is from 3.5 to 4.5, in some embodiments, from 3.5 to 4.0, in some embodiments, from 3.0 to 4.0, in some embodiments, from 4.0 to 5.0, and in some embodiments, from 4.0 to 4.5. In some embodiments, the pH of the composition is 3.5, in some embodiments, the pH of the composition is 4.0, in some embodiments, the pH of the composition is 4.5, and in some embodiments, the pH of the composition is 5.0.
In some embodiments, the injection pH is preferably 3.8-4.5. The pH of the injection is 3.8-4.2, and the stability is good. In some embodiments, the injection pH is 4.3, and in some embodiments, the injection pH is 4.1.
When the composition is prepared into injection, the dosage of the active ingredients ranges from 0.0025% to 0.4% (W/V, g/100 mL) according to the weight of Fu Nuola raw free alkali 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 0.1%. 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%.
The composition of the invention comprises 5mg-20mg of the active ingredient in single dose by weight of the vonolamine free base. In some embodiments, the single dose of active ingredient is from 10mg to 20mg, and in some embodiments, the single dose of active ingredient is from 5mg to 10mg. In some embodiments, the single dose of active ingredient is 5mg, in some embodiments, the single dose of active ingredient is 10mg, in some embodiments, the single dose of active ingredient is 15mg, and in some embodiments, the single dose of active ingredient is 20mg.
In some embodiments, the osmotic pressure regulator in the composition is sodium chloride, and the dosage of sodium chloride in 100mL of the composition is 0.6 g-1.0 g.
In some embodiments, the composition comprises:
1) Fu Nuola times fumaric acid is produced, and the dosage range is 0.005% -0.1% (W/V, g/100 mL);
2) Sodium chloride, the dosage range is 0.6% -1.0% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate injection comprising:
1) Fu Nuola times fumaric acid is produced, and the dosage range is 0.005% -0.1% (W/V, g/100 mL);
2) Sodium chloride, the dosage range is 0.6% -1.0% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate injection comprising:
1) Fu Nuola times fumaric acid is produced, and the dosage range is 0.01% -0.1% (W/V, g/100 mL);
2) Sodium chloride, in an amount ranging from 0.7% to 0.9% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate infusion solution comprising:
1) Fu Nuola times the amount of fumaric acid (0.01% (W/V, g/100 mL);
2) Sodium chloride in an amount of 0.9% (W/V, g/100 mL);
3) Water for injection.
In some embodiments, the composition is a voronoi fumarate injection comprising Fu Nuola g of fumaric acid, sodium chloride and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is in the range of 0.0025% -0.4% (W/V, g/100 mL) and the sodium chloride content is in the range of 0.6% -1.0% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate injection comprising Fu Nuola g of fumaric acid, sodium chloride and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is in the range of 0.005% -0.1% (W/V, g/100 mL) and the sodium chloride content is in the range of 0.6% -1.0% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate injection comprising Fu Nuola g of fumaric acid, sodium chloride and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is in the range of 0.01% -0.1% (W/V, g/100 mL) and the sodium chloride content is in the range of 0.7% -0.9% (W/V, g/100 mL).
In some embodiments, the composition is a large infusion of voronoi fumarate containing voronoi fumarate, sodium chloride, and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is 0.01% (W/V, g/100 mL) and the sodium chloride content is 0.9% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate injection consisting of Fu Nuola g of fumaric acid, sodium chloride and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is in the range of 0.0025% -0.4% (W/V, g/100 mL) and the sodium chloride content is in the range of 0.6% -1.0% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate injection consisting of Fu Nuola g of fumaric acid, sodium chloride and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is in the range of 0.005% -0.1% (W/V, g/100 mL), and the sodium chloride content is in the range of 0.6% -1.0% (W/V, g/100 mL).
In some embodiments, the composition is a voronoi fumarate injection consisting of Fu Nuola g of fumaric acid, sodium chloride and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is in the range of 0.01% -0.1% (W/V, g/100 mL), and the sodium chloride content is in the range of 0.7% -0.9% (W/V, g/100 mL).
In some embodiments, the composition is a large infusion of voronoi fumarate, consisting of Fu Nuola g of fumaric acid, sodium chloride and water, and having a pH in the range of 3.5-5.5, wherein the voronoi fumarate content is 0.01% (W/V, g/100 mL) and the sodium chloride content is 0.9% (W/V, g/100 mL).
According to the invention, the voronoi or the salt thereof is directly dissolved in a larger volume of water (more than or equal to 50 mL) to prepare liquid, such as large transfusion, only an osmotic pressure regulator is needed, the pH range of the liquid is controlled through hydrochloric acid or/and sodium hydroxide, auxiliary materials such as substituted beta-cyclodextrin, ethylenediamine tetraacetic acid and the like are not needed, the safety of the preparation can be improved, and a new medication option is provided for patients which cannot tolerate substituted beta-cyclodextrin (such as patients with renal insufficiency).
Compared with tablets, the large transfusion preparation has the advantages of no need of oral administration during clinical use, quick response, suitability for dysphagia patients and patients suffering from acute gastritis and gastric ulcer, direct use and avoidance of pollution risks and safety risks caused by misoperation during reconstitution.
The second aspect of the invention provides a preparation method of the composition, which comprises the following steps of firstly preparing an aqueous solution of voronoi or salt thereof, then adding an osmotic pressure regulator into the aqueous solution, dissolving, sterilizing, filtering, filling, sealing in a melting way, and sterilizing at 121 ℃ for 15-30 min.
In some embodiments, the preparation method of the composition comprises the following steps of firstly preparing an aqueous solution of voronoi fumarate, then adding sodium chloride into the aqueous solution, dissolving, sterilizing and filtering the aqueous solution, filling the aqueous solution into an infusion soft bag, sealing the infusion soft bag by using a polypropylene interface of a plastic infusion container, and sterilizing the infusion soft bag for 15-30 min at the temperature of 121 ℃. In some embodiments, weighing 80% of the total amount of water for injection according to the production batch, adding voronoi fumarate, stirring, adding sodium chloride after complete dissolution, adjusting pH to 3.0-5.5 after complete dissolution of sodium chloride, fixing volume (controlling the temperature of the prepared solution to be 25-75 ℃ in the preparation process), sterilizing, filtering, filling into transfusion containers such as transfusion soft bags/transfusion glass bottles, sealing, sterilizing by adopting a damp heat sterilization mode, and sterilizing for 15min under the sterilization condition of 121 ℃ to prepare the composition.
The composition provided by the invention meets the requirements of preparing injection, can be sterilized by adopting a terminal sterilization method, is thorough in sterilization and improves the safety of the injection. The fumaric acid Fu Nuola raw injection provided by the invention is a new dosage form, can meet the clinical requirements of patients with acute gastritis and gastric ulcer on quick response, can solve the administration problem of patients with dysphagia, has high safety and good stability, and the provided preparation method is simple and easy to implement and is suitable for industrial production.
Drawings
Figure 1 depicts a graph of mean plasma concentration of vonolamine versus time following injection of the formulation of example 11 of the present invention in beagle dogs.
Detailed Description
In order to better understand the technical solution of the present invention, the following non-limiting examples are further disclosed for further details of the present invention.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
EXAMPLE 1 investigation of the stability of raw solutions of fumaric acid Fu Nuola (without osmolarity regulator) at different concentrations
TABLE 1 prescription form
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adjusting the pH value to a target value after dissolving, fixing the volume, filling the solution into an infusion container, sealing the container, and sterilizing by adopting a damp-heat sterilization mode.
TABLE 2 stability of solutions before and after sterilization
| Prescription of prescription | After sterilization | Osmotic pressure |
| Prescription 1 | Total impurities 0.15 | 8mOsm/kg |
| Prescription 2 | Total impurities 0.12 | 4mOsm/kg |
| Prescription 3 | Total impurities (< LOQ) | 2mOsm/kg |
| Prescription 4 | ND | 1mOsm/kg |
Remarks 1, when the impurity level is not more than 0.1%, it is expressed as "< LOQ". 2. "ND" means not detected.
The liquid preparation is carried out according to the prescriptions 1-4, the impurity level of each prescription product is not different after sterilization, and the impurity level is acceptable. However, the osmotic pressure test results in hypotonic, and pain is easily generated during injection.
EXAMPLE 2 investigation of the stability of raw solutions of fumaric acid Fu Nuola at different concentrations
TABLE 3 prescription form
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, adjusting the pH value to a target value after dissolving the sodium chloride, fixing the volume, filling the solution into an infusion container, sealing, and sterilizing by adopting a damp-heat sterilization mode.
TABLE 4 examination of stability of solutions before and after sterilization according to the prescription
| Prescription of prescription | After sterilization | Osmotic pressure |
| Prescription 5 | Total impurities (< LOQ) | 288mOsm/kg |
| Prescription 6 | Total impurities (< LOQ) | 295mOsm/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 |
Remarks 1, when the impurity level is not more than 0.1%, it is expressed as "< LOQ".
After adding sodium chloride, the impurity level of the sterilized product is not changed (compared with the example 1), the product quality is stable, and therefore, the adding of sodium chloride has no influence on the product stability. And the osmotic pressure measured after sodium chloride is added is within the physiological osmotic pressure range of the human body. Meets the use requirement of injection.
Example 3 investigation of product stability by different types of osmolarity adjusting Agents
TABLE 5 prescription form
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, adjusting the pH value to a target value after dissolving the sodium chloride, fixing the volume, filling the solution into an infusion container, sealing, and sterilizing by adopting a damp-heat sterilization mode. The results are shown in Table 6.
TABLE 6
| Prescription of prescription | After sterilization | Osmotic pressure |
| Prescription 5 | Total impurities (< LOQ) | 288mOsm/kg |
| Prescription 6 | Total impurities (< LOQ) | 295mOsm/kg |
| Prescription 7 | Total impurities 0.12 | 287mOsm/kg |
| Prescription 10 | 1.65 Of total impurities | 290mOsm/kg |
| Prescription 11 | Total impurities of 0.92 | 293mOsm/kg |
| Prescription 12 | Total impurities of 0.65 | 291mOsm/kg |
Remarks 1, when the impurity level is not more than 0.1%, it is expressed as "< LOQ".
Glucose and sodium chloride can be used as osmotic pressure regulator to maintain osmotic pressure of the preparation within normal physiological range of human body, but the impurity level of the preparation added with glucose after sterilization is far higher than that of the sodium chloride preparation, and the impurity level of the preparation added with glucose as an isotonic regulator is too high to be acceptable.
Example 4 investigation of the Effect of different amounts of sodium chloride on osmotic pressure
TABLE 7 prescription form
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, adjusting the pH value to a target value after dissolving the sodium chloride, fixing the volume, filling the solution into an infusion container, sealing, and sterilizing by adopting a damp-heat sterilization mode. The results are shown in Table 8.
TABLE 8
| Prescription of prescription | Prescription 7 | Prescription 13 | Prescription 14 | Prescription 15 | Prescription 16 |
| Osmotic pressure | 300mOsm/kg | 235mOsm/kg | 208mOsm/kg | 167mOsm/kg | 329mOsm/kg |
According to the results, the dosage of sodium chloride in the unit prescription is 0.5-1.0 g, and the osmotic pressure is 167-399 mOsm/kg. The range of the osmotic pressure which can be tolerated by intravenous injection is 200-500 mOsm/kg. Therefore, the dosage of sodium chloride in the unit prescription is acceptable in the range of 0.6-1.0 g.
Example 5 investigation of the stability of raw fumaric acid Fu Nuola solutions at different pH Using formulation 7
TABLE 9 prescription form
| Name of the name | Prescription 7-1 | Prescription 7-2 | Prescription 7-3 | Prescription 7-4 |
| Fu Nuola raw fumaric acid | 26.72mg | 26.72mg | 26.72mg | 26.72mg |
| Sodium chloride | 0.9g | 0.9mg | 0.9mg | 0.9mg |
| Sodium hydroxide | Adjusting pH to 3.99 | Regulating pH to 6.06 | Adjusting pH to 8.11 | Adjusting pH to 9.14 |
| Water for injection | q.s.100ml | q.s.100ml | q.s.100ml | q.s.100ml |
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, respectively adjusting pH to target values after dissolving the sodium chloride, fixing the volume, filling the solution into an infusion container, sealing, and sterilizing by adopting a damp-heat sterilization mode. The stability results after sterilization are shown in Table 10.
Table 10
| Name of the name | Prescription 7-1 | Prescription 7-2 | Prescription 7-3 | Prescription 7-4 |
| Total impurities | <LOQ | 0.81% | 1.74% | 5.14% |
Remarks 1, when the impurity level is not more than 0.1%, it is expressed as "< LOQ".
The results showed that the raw fumaric acid Fu Nuola solution had the best stability at a pH of about 4.0.
EXAMPLE 6 investigation of the stability of raw solutions of fumaric acid Fu Nuola at different pH' s
TABLE 11 prescription form
| Name of the name | Prescriptions 7-5 | Prescriptions 7-6 | Prescriptions 7-7 | Prescriptions 7-8 | Prescriptions 7-9 |
| Fu Nuola raw fumaric acid | 26.72mg | 26.72mg | 26.72mg | 26.72mg | 26.72mg |
| Sodium chloride | 0.9g | 0.9g | 0.9g | 0.9g | 0.9g |
| Sodium hydroxide | Adjusting pH to 3.5 | Adjusting pH to 4.0 | Adjusting pH to 4.5 | Adjusting pH to 5.0 | Adjusting pH to 5.5 |
| Water for injection | q.s.100ml | q.s.100ml | q.s.100ml | q.s.100ml | q.s.100ml |
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, respectively adjusting pH to target values after dissolving the sodium chloride, fixing the volume, filling the solution into an infusion container, sealing, and sterilizing by adopting a damp-heat sterilization mode. The stability results after sterilization are shown in Table 12.
Table 12
| Name of the name | Prescriptions 7-5 | Prescriptions 7-6 | Prescriptions 7-7 | Prescriptions 7-8 | Prescriptions 7-9 |
| Total impurities | <LOQ | <LOQ | 0.12% | 0.41% | 0.59% |
Remarks 1, when the impurity level is not more than 0.1%, it is expressed as "< LOQ".
The result shows that the pH range of the raw solution of fumaric acid Fu Nuola is 3.5-4.5, and the solution has good stability after sterilization.
Example 7 investigation of the Effect of formulation temperature on product stability according to formulation 7
TABLE 13 prescription form
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, adjusting the pH value to a target value after dissolving the sodium chloride, fixing the volume (controlling the liquid preparation temperature to be 25 ℃, 50 ℃ and 75 ℃ respectively in the liquid preparation process), filling the mixture into an infusion container, sealing the container, and sterilizing by adopting a damp-heat sterilization mode.
TABLE 14 preparation temperatures and corresponding results used in the preparation of liquids
| Temperature of liquid preparation | 25°C | 50°C | 75°C |
| Dissolution time of active ingredient | 30min | 7min | 2min |
| Total impurities | Total impurities (< LOQ) | Total impurities (< LOQ) | Total impurities (< LOQ) |
Remarks 1, when the impurity level is not more than 0.1%, it is expressed as "< LOQ".
According to the results, the dissolution time of active ingredients can be effectively reduced by increasing the liquid preparation temperature in the liquid preparation process, and the product quality is not affected by increasing the liquid preparation temperature, so that the liquid preparation temperature can be controlled to be 25-75 ℃.
EXAMPLE 8 examination of different sterilization times of raw preparation of fumaric acid Fu Nuola
TABLE 15 prescription form
| Name of the name | Dosage of |
| Fu Nuola raw fumaric acid | 26.72mg |
| Sodium chloride | 0.9g |
| Sodium hydroxide | Proper amount of |
| Water for injection | q.s.100ml |
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, adjusting the pH to a target value after dissolving the sodium chloride, fixing the volume, filling the solution into an infusion container, sealing the solution, and sterilizing in a damp-heat sterilization mode under the sterilization conditions of 121 ℃ and 15min, 121 ℃ and 20min or 121 ℃ and 30min respectively.
TABLE 16 Sterilization conditions and corresponding results
| Sterilization mode | A | B | C |
| Sterilization conditions | 121°C,15min | 121°C,20min | 121°C,30min |
| Total impurities | Total impurities 0.11% | Total impurities 0.12% | Total impurities 0.11% |
According to the results, the wet heat sterilization is adopted, the sterilization condition is 121 ℃ and 15-30 min, and the product quality is stable.
EXAMPLE 9 examination of different packaging forms of the Fu Nuola raw fumarate formulations
TABLE 17 prescription form
| Name of the name | Dosage of |
| Fu Nuola raw fumaric acid | 26.72mg |
| Sodium chloride | 0.9g |
| Sodium hydroxide | Proper amount of |
| Water for injection | q.s.100ml |
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after dissolving completely, adjusting the pH value to a target value after dissolving the sodium chloride, fixing the volume, filling the solution into different types of infusion containers, sealing, and sterilizing by adopting a damp-heat sterilization mode.
Table 18 different packages and corresponding results
Remarks 1, when the impurity level is not more than 0.1%, it is expressed as "< LOQ".
The above examination results show that the medium borosilicate glass infusion bottle and the five-layer co-extrusion infusion bag are used as the inner packages of the products, and the total impurity level after sterilization is not different, so that the medium borosilicate glass infusion bottle and the soft infusion bag are suitable for the two inner packages.
EXAMPLE 10 investigation of stability of the Fu Nuola raw Fumaric acid injection
TABLE 19 prescription form
| Name of the name | Dosage of |
| Fu Nuola raw fumaric acid | 26.72mg |
| Sodium chloride | 0.9g |
| Sodium hydroxide | Proper amount of |
| Water for injection | q.s.100ml |
The preparation method comprises the steps of weighing the voronoi fumarate according to a prescription, adding water for injection, stirring and dissolving, adding weighed sodium chloride after the solution is completed, adjusting the pH to 4.30 by adopting sodium hydroxide after the sodium chloride is dissolved, and fixing the volume. Filling into transfusion container, sealing, and sterilizing by wet heat sterilization.
Table 20 results of stability investigation under acceleration conditions (40 ℃ C., 75% RH)
The result shows that the fumaric acid Fu Nuola raw injection provided by the invention is still hot to be in a clear transparent colorless state after being placed for 6 months under an acceleration condition, has no obvious change in pH, content and related substances, and has good stability.
EXAMPLE 11 pharmacokinetic study of Fu Nuola raw Fumaric acid injection in rats
TABLE 21 prescription form
The preparation process includes weighing Funula raw fumarate, adding water for injection, stirring to dissolve, adding sodium chloride, regulating pH to 4.10 with sodium hydroxide, and constant volume. Filling into transfusion container, sealing, and sterilizing by wet heat sterilization.
The samples of example 11 were selected for methodological validation and beagle PK experiments, see table 22.
Table 22
The LC/MS/MS system for analysis comprises a Shimadzu LC30A series vacuum degassing furnace, a binary injection pump, an orifice plate automatic sampler, a column oven and a QTRAP5500 tertiary quadrupole mass spectrometer of an Electrified Spray Ionization (ESI) source. Quantitative analysis was performed in MRM mode, and parameters of MRM conversion are shown in Table 23.
TABLE 23 Vonoprazan Mass Spectrometry conditions
Analysis using a Waters Xbridge C18, 2.1X10 mm, 5. Mu.M column, 15. Mu.L of sample was injected. The conditions for the analysis were 2mM ammonium formate+0.1% formic acid (A) and methanol+2 mM ammonium formate+0.1% formic acid (B) in the mobile phase. The flow rate was 0.3mL/min. The mobile phase gradient is shown in table 24.
TABLE 24 Vonoprazan liquid phase Process
The invention evaluates the pharmacokinetic study of the sample of example 11 in beagle dogs. The preparation is administered by continuous infusion, 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 12 and 24h before and after administration, respectively, 0.2mL of cephalic venous blood inside forelimbs is taken, and the blood plasma is separated and frozen for testing. And centrifuged at 12,000 rpm for 2 minutes. Plasma was collected and stored at-70 ℃ until LC/MS analysis as described above was performed. Table 25 lists the pharmacokinetic data for the samples of example 11 in beagle dogs. The compound of the invention has good pharmacokinetic property, the peak time of the plasma of the continuous infusion group is the end time of the infusion, no obvious adverse reaction exists in the administration process, and the curve of the preparation of the invention example 11 in average drug administration in beagle dogs is shown in figure 1.
TABLE 25 pharmacokinetic data of compounds in beagle dogs
The results show that the fumaric acid Fu Nuola raw injection prepared in example 11 takes effect rapidly after intravenous drip into beagle dogs, and the peak time is 0.5 hour.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
In the description of the present specification, the descriptions of the terms "one embodiment," "some embodiments," "some implementations," "some embodiments," "examples," "particular examples," or "some examples," etc., mean that a particular 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, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
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