Calcitriol injection and preparation method thereof

Abstract

According to the calcitriol injection and the preparation method, in the method, the oxygen content of a liquid preparation container, the oxygen content of injection water and the oxygen content in the filtering process are strictly controlled, and calcitriol is prevented from being degraded in the presence of oxygen; dissolution of calcitriol, mixing with water for injection and filtration are carried out under the condition that the illumination intensity is lower than 200Lux, so that the influence of illumination on calcitriol is avoided; meanwhile, by controlling the mixing temperature of the preparation raw materials and adjusting the pH value of the liquid medicine, the influence of the pH value and the temperature on calcitriol can be effectively avoided, the drug stability of calcitriol is improved, and a high-temperature sterilization process is tolerated.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and relates to a calcitriol injection and a preparation method thereof. Background Art

[0002] Calcitriol is a colorless crystalline compound that exists naturally in the human body. It is an endogenous substance that is mainly used to treat hypocalcemia and / or secondary hyperparathyroidism in patients with chronic renal dialysis. Calcitriol is insoluble in water but soluble in organic solvents. It is sensitive to light, heat, oxygen, metal ions, and pH value and has poor chemical stability. Therefore, stable quality calcitriol injection is a key factor in ensuring drug safety and effectiveness.

[0003] The raw materials for the preparation of the calcitriol injection used in existing production include polysorbate 20, sodium chloride, sodium ascorbate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate, disodium edetate, nitrogen, and water for injection. In preparation, excessive feeding is required to make up for the defect of reduced content caused by drug degradation within the validity period. However, the degradation of the drug will inevitably increase the impurity content, which is unfavorable to the health of the user, so excessive feeding is not a preferred solution. In addition, disodium edetate can complex the calcium ions in the blood after entering the blood as a metal ion complexing agent, reducing free calcium ions in the blood, which is unfavorable for the health of the user.

[0004] In addition, existing patents CN111437251A, CN108030767B and CN103142470B respectively disclose a calcitriol injection and a preparation method thereof. However, in the patent of publication number CN111437251A, the conventional process of injection is adopted for production, and the solubility problem of calcitriol can only be solved by adding a certain proportion of anhydrous ethanol, but the chemically stable calcitriol injection cannot be obtained. In the patent of publication number CN108030767B, activated carbon needs to be added in the production process for adsorption treatment, but activated carbon will introduce new impurities, resulting in reduced stability of calcitriol injection, which belongs to the technology gradually eliminated in drug production. In the patent of publication number CN103142470B, meglumine, polyethylene glycol 400 and polyethylene glycol 6000 are added to the raw materials for preparation as stabilizers, but calcitriol injection is an injection preparation, and the macromolecular organic solvent polyethylene glycol 400 will bring hemolytic and irritation risks. Therefore, the calcitriol injection disclosed in the above patent still has deficiencies in ensuring drug safety and quality control, and these deficiencies cannot be remedied by simply changing the prescription composition. Summary of the invention

[0005] The purpose of the present invention is to provide a calcitriol injection and a preparation method thereof, so as to solve the problem of poor stability of the existing calcitriol injection and improve the safety of the drug.

[0006] To achieve the above object, the present invention adopts the following technical solutions: The present application provides a method for preparing calcitriol injection, the method comprising: S01: Continuously introduce nitrogen into the liquid preparation container to make the oxygen content in the liquid preparation container less than 5%.

[0007] Since calcitriol is sensitive to oxygen, it is easily degraded in the presence of oxygen, which affects the drug stability of calcitriol. Therefore, before preparing the calcitriol injection, nitrogen is continuously introduced into the liquid preparation container to replace the air in the liquid preparation container, thereby making the oxygen content in the liquid preparation container lower than 5%, thereby achieving the purpose of reducing the oxygen content. Preferably, the oxygen content in the liquid preparation container is lower than 3%. More preferably, the oxygen content in the liquid preparation container is lower than 1%.

[0008] In the present application, the distance between the nitrogen inlet and the bottom of the liquid preparation container is less than 20 cm. After the injection water and other reagents are injected, the nitrogen inlet is located below the liquid surface.

[0009] S02: Adding water for injection at 0-40° C. with a dissolved oxygen content of less than 2 mg / L, sodium citrate, sodium dihydrogen phosphate hydrate, sodium chloride and sodium hydroxide into the liquid preparation container to form a mixed solution.

[0010] Since the water for injection in actual production is usually kept warm and circulated at above 70°C to prevent the growth of microorganisms, in this application, uncooled water for injection can also be added to the liquid preparation container, cooled to 0-40°C under the condition of continuous nitrogen protection, and then sodium citrate, sodium dihydrogen phosphate hydrate, sodium chloride and sodium hydroxide are added. The sodium dihydrogen phosphate hydrate in this application can also be replaced by an equimolar amount of anhydrous sodium dihydrogen phosphate.

[0011] Preferably, the distance between the nitrogen inlet and the bottom of the liquid preparation container is less than 10 cm.

[0012] Preferably, the temperature of the water for injection is 0-30°C and the dissolved oxygen content is less than 1 mg / L. More preferably, the temperature of the water for injection is 10-30°C and the dissolved oxygen content is less than 0.5 mg / L.

[0013] S03: Under the condition that the light intensity is lower than 200 Lux, butylated hydroxytoluene and calcitriol are added to polysorbate, stirred to dissolve, and then added to the mixed solution, stirred to dissolve, to form a drug solution.

[0014] Under the condition of light intensity less than 200 Lux, butylated hydroxytoluene is dissolved in polysorbate, and then calcitriol is added and stirred to dissolve. The nitrogen inlet is changed to be located more than 10 cm above the liquid surface, that is, above the liquid surface, and nitrogen is continuously introduced. The mixed and dissolved calcitriol, butylated hydroxytoluene and polysorbate are added to the mixed solution, stirred to dissolve, and a drug solution is formed.

[0015] When the pH value of the drug solution is less than 6.5, adjust the pH value of the drug solution to 6.5-8.0 by adding sodium hydroxide, and add water for injection to the full amount.

[0016] More preferably, the light intensity is lower than 100 Lux; more preferably, the light intensity is lower than 50 Lux.

[0017] Preferably, the nitrogen inlet is located more than 20 cm above the liquid surface.

[0018] S04: The drug solution is filtered and filled into a brown glass ampoule, which is filled with nitrogen to ensure that the residual oxygen content in the headspace is less than 3.0%.

[0019] The raw materials for the preparation of calcitriol injection contain the surfactant polysorbate. When the drug solution is circulated and filtered, a large number of bubbles will be generated, causing the risk of contamination of the calcitriol injection. Therefore, when the drug solution is filtered, the flow direction of the drug solution is unidirectional, that is, it cannot circulate.

[0020] Based on this, in order to filter out impurities and microorganisms in calcitriol injection, the liquid medicine is filtered in two stages using filters with a filtration accuracy of 0.45 μm and / or 0.22 μm. Specifically, the liquid medicine is filtered through filters with a filtration accuracy of 0.45 μm and 0.22 μm in turn, or the liquid medicine is filtered through filters with a filtration accuracy of 0.22 μm and 0.22 μm in turn.

[0021] The filter in the present application adopts a pleated membrane filter element and is made of an absolute membrane, because the deformation of the relative membrane during the filtration process may cause insoluble matter or microorganisms greater than the nominal accuracy to pass through the filter membrane, causing filtration failure, while the absolute membrane does not have this risk.

[0022] The drug solution involved in the present invention has an extremely low concentration. The adsorption of drugs by the filter element will cause the drug solution content to decrease, and some components in the filter element may migrate back into the drug solution and cause pollution to the drug solution. Studies have found that polyethersulfone (PES), as a general filter for filtering chemical drugs, is not suitable for this product, resulting in a significant decrease in drug content and a decrease in drug solution stability. The above two risks can be avoided by selecting specific membrane materials, that is, the raw materials for the preparation of the absolute membrane include but are not limited to hydrophilic polytetrafluoroethylene (PTFE) and polyvinylidene fluoride (PVDF). Preferably, the raw materials for the preparation of the absolute membrane are selected from hydrophilic polytetrafluoroethylene (PTFE) and polyvinylidene fluoride (PVDF); most preferably, the raw material for the preparation of the absolute membrane is hydrophilic polytetrafluoroethylene (PTFE).

[0023] Before the liquid is filtered, the air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen so that the oxygen content in the pipeline is less than 5%. Preferably, the oxygen content in the pipeline is less than 3%, which improves the stability of calcitriol during the filtration process. In addition, during the filtration process, nitrogen is introduced into the liquid preparation container so that the inside of the liquid preparation container is maintained at a slight positive pressure of 0-0.01MPa. Preferably, the pressure is 0-0.005MPa.

[0024] After filtering, the liquid medicine is filled into a brown glass ampoule and filled with nitrogen to ensure that the residual oxygen content in the headspace is less than 3.0%. Preferably, the residual oxygen content in the headspace is less than 2.0%; more preferably, the residual oxygen content in the headspace is less than 1.0%.

[0025] S05: After the brown glass ampoule is sealed, it is sterilized at 121-123° C. for 12-20 min to obtain calcitriol injection.

[0026] When the residual oxygen content in the headspace of the brown glass ampoule is less than 3.0%, seal it. Place it in a sterilizer and sterilize it at 121-123°C for 12-20 minutes using moist heat sterilization with steam or water as the medium to obtain calcitriol injection. The cumulative F0 value after sterilization is 12-25.

[0027] Preferably, the sterilization temperature is 121-123°C, the sterilization time is 12-20 min, and the cumulative F0 value is 12-20. More preferably, the sterilization temperature is 121-122°C, the sterilization time is 12-15 min, and the cumulative F0 value is 13-18.

[0028] In addition, the present application also provides a calcitriol injection, which is prepared according to the above preparation method.

[0029] In the present application, the specifications of calcitriol injection are usually 1 ml: 0.5 μg, 1 ml: 1 μg and 1 ml: 2 μg. Based on general industry knowledge, calcitriol injection of other specifications can also be achieved by using the technology provided by the present invention.

[0030] When the specification of calcitriol injection is 1ml:0.5μg, 1000ml of calcitriol injection contains 0.5mg of calcitriol, 0.03g of butylated hydroxytoluene, 2.0g of polysorbate, 3.0g of sodium citrate, 9.2g of sodium dihydrogen phosphate monohydrate, 1.5g of sodium chloride, 1.8g of sodium hydroxide, and the rest is water for injection. Among them, butylated hydroxytoluene is an antioxidant, polysorbate is a solubilizer, sodium citrate and sodium dihydrogen phosphate monohydrate are buffers, sodium chloride is an osmotic pressure regulator, sodium hydroxide is a pH regulator, and water for injection is a solvent.

[0031] The present invention has the following beneficial effects: (1) In this application, the oxygen content in the liquid preparation container, water for injection, and filtration process is strictly controlled to avoid the degradation of calcitriol in the presence of oxygen and to improve the drug stability of calcitriol.

[0032] (2) The dissolution, mixing with water for injection, and filtration of calcitriol are all carried out under conditions where the light intensity is less than 200 Lux, thus avoiding the effect of light on calcitriol and improving the drug stability of calcitriol.

[0033] (3) By controlling the mixing temperature of the raw materials and adjusting the pH value of the drug solution, the effects of pH value and temperature on calcitriol can be effectively avoided, thereby improving the drug stability of calcitriol.

[0034] (4) There is no need to add the metal ion chelating agent disodium edetate (called disodium edetate in the Chinese Pharmacopoeia), thus avoiding the effect of disodium edetate on human blood calcium.

[0035] (5) The injection solution can withstand an over-killing sterilization process, that is, sterilization at 121°C for 12 minutes or more. This condition is considered an over-killing process in the industry. In other words, under this condition, it is usually not necessary to consider the content and type of microorganisms in the drug solution. A sterile product can be obtained after sterilization, which is very important for ensuring safety.

[0036] (6) Avoid excessive dosing, reduce the impurity content in the solution, and improve safety. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further explained and illustrated by means of specific embodiments below.

[0038] Example 1 The embodiment of the present application provides a calcitriol injection with a specification of 1 ml: 0.5 μg. The raw materials for preparing 1000 ml of the injection include: calcitriol 0.5 mg, butylated hydroxytoluene 0.03 g, polysorbate 2.0 g, sodium citrate 3.0 g, sodium dihydrogen phosphate monohydrate 9.2 g, sodium chloride 1.5 g, sodium hydroxide 1.8 g, and the rest is water for injection.

[0039] The preparation method of the calcitriol injection comprises: S101: Before preparing the calcitriol injection, nitrogen is continuously introduced into the preparation container through a nitrogen inlet located 10 cm above the bottom of the preparation container to reduce the oxygen content in the preparation container to less than 1%.

[0040] S102: Continuously introduce nitrogen into the liquid preparation container, add water for injection at a temperature of 85°C into the liquid preparation container, cool to 25°C, add sodium citrate, sodium dihydrogen phosphate monohydrate, sodium chloride and sodium hydroxide, stir and dissolve to form a mixed solution, wherein the dissolved oxygen content of the water for injection is less than 0.5 mg / L.

[0041] S103: Under the condition of a light intensity of 45 Lux, butylated hydroxytoluene is dissolved in polysorbate, and then calcitriol is added and stirred to dissolve. The nitrogen inlet is changed to a position 10 cm away from the liquid surface, and the mixed and dissolved calcitriol, butylated hydroxytoluene and polysorbate are added to the mixed solution, stirred to dissolve, and a drug solution is formed.

[0042] S104: The air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen to reduce the oxygen content in the pipeline to less than 5%. Sodium hydroxide is used to adjust the pH value of the liquid to 7.5, and water for injection is added to the full amount. The liquid is filtered in two stages using polyvinylidene fluoride filters with a filtration accuracy of 0.22μm and 0.22μm. During the filtration process, nitrogen is introduced into the liquid preparation container to maintain a slight positive pressure of 0.005MPa inside the liquid preparation container.

[0043] S105: After filtering the liquid medicine, fill it into a brown glass ampoule, fill it with nitrogen, ensure that the residual oxygen content in the headspace is less than 1.0%, and seal it. Place it in a sterilizer and sterilize it in a water bath at 121°C for 12 minutes to obtain calcitriol injection.

[0044] Example 2 The present application example provides a calcitriol injection with a specification of 1 ml: 0.5 μg. The raw materials for preparing 1000 ml of the injection are the same as those in Example 1.

[0045] The preparation method of the calcitriol injection comprises: S201: Before preparing the calcitriol injection, nitrogen is continuously introduced into the preparation container through a nitrogen inlet located 20 cm above the bottom of the preparation container to reduce the oxygen content in the preparation container to less than 5%.

[0046] S202: Continuously introduce nitrogen into the liquid preparation container, and add water for injection at a temperature of 40° C. and a dissolved oxygen content of less than 2 mg / L into the liquid preparation container, and then add sodium citrate, sodium dihydrogen phosphate monohydrate, sodium chloride and sodium hydroxide, stir and dissolve to form a mixed solution.

[0047] S203: Under the condition of a light intensity of 100 Lux, butylated hydroxytoluene is dissolved in polysorbate, and then calcitriol is added and stirred to dissolve. The nitrogen inlet is changed to a position 10 cm away from the liquid surface, and the mixed and dissolved calcitriol, butylated hydroxytoluene and polysorbate are added to the mixed solution, stirred to dissolve, and a drug solution is formed.

[0048] S204: The air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen to reduce the oxygen content in the pipeline to less than 5%. The pH of the liquid is adjusted to 8.0 with sodium hydroxide, and water for injection is added to the full amount. The liquid is filtered with a polytetrafluoroethylene filter with a filtration accuracy of 0.45μm. During the filtration process, nitrogen is introduced into the liquid preparation container to maintain a slight positive pressure of 0.01MPa inside the liquid preparation container.

[0049] S205: After filtering the liquid medicine, fill it into a brown glass ampoule, fill it with nitrogen, ensure that the residual oxygen content in the headspace is less than 3.0%, and seal it. Place it in a sterilizing cabinet and steam sterilize it at 121°C for 20 minutes to obtain calcitriol injection.

[0050] Example 3 The present application example provides a calcitriol injection with a specification of 1 ml: 0.5 μg. The raw materials for preparing 1000 ml of the injection are the same as those in Example 1.

[0051] The preparation method of the calcitriol injection comprises: S301: Before preparing the calcitriol injection, nitrogen is continuously introduced into the preparation container through a nitrogen inlet located 10 cm above the bottom of the preparation container to reduce the oxygen content in the preparation container to less than 2%.

[0052] S302: Continuously introduce nitrogen into the liquid preparation container, add water for injection at a temperature of 20° C. and a dissolved oxygen content of less than 1 mg / L into the liquid preparation container, then add sodium citrate, sodium dihydrogen phosphate monohydrate, sodium chloride and sodium hydroxide, stir and dissolve to form a mixed solution.

[0053] S303: Under the condition of light intensity lower than 80 Lux, butylated hydroxytoluene is dissolved in polysorbate, and then calcitriol is added and stirred to dissolve. The nitrogen inlet is changed to 15 cm from the liquid surface, and the mixed and dissolved calcitriol, butylated hydroxytoluene and polysorbate are added to the mixed solution, stirred to dissolve, and a drug solution is formed.

[0054] S304: The air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen to reduce the oxygen content in the pipeline to less than 5%. Sodium hydroxide is used to adjust the pH value of the liquid to 6.8, and water for injection is added to the full amount. The liquid is filtered in two stages using polyvinylidene fluoride filters with a filtration accuracy of 0.45μm and 0.45μm. During the filtration process, nitrogen is introduced into the liquid preparation container to maintain a slight positive pressure of 0.008MPa inside the liquid preparation container.

[0055] S305: After filtering the liquid medicine, fill it into a brown glass ampoule, fill it with nitrogen, ensure that the residual oxygen content in the headspace is less than 1.0%, and seal it. Place it in a sterilizing cabinet and sterilize it in a water bath at 121°C for 12-20 minutes to obtain calcitriol injection.

[0056] Example 4 The embodiment of the present application provides a calcitriol injection with a specification of 1 ml: 1 μg. The raw materials for preparing 1000 ml of the injection include: calcitriol 1 mg, butylated hydroxytoluene 0.03 g, polysorbate 2.0 g, sodium citrate 3.0 g, sodium dihydrogen phosphate monohydrate 9.2 g, sodium chloride 1.5 g, sodium hydroxide 1.8 g, and the rest is water for injection.

[0057] The preparation method of the calcitriol injection comprises: S401: Before preparing the calcitriol injection, nitrogen is continuously introduced into the preparation container through a nitrogen inlet located 15 cm above the bottom of the preparation container to reduce the oxygen content in the preparation container to less than 2%.

[0058] S402: Continuously introduce nitrogen into the liquid preparation container, add water for injection at a temperature of 85°C into the liquid preparation container, cool to 25°C, add sodium citrate, sodium dihydrogen phosphate monohydrate, sodium chloride and sodium hydroxide, stir and dissolve to form a mixed solution, wherein the dissolved oxygen content of the water for injection is less than 0.5 mg / L.

[0059] S403: Under the condition of light intensity of 50 Lux, butylated hydroxytoluene is dissolved in polysorbate, and then calcitriol is added and stirred to dissolve. The nitrogen inlet is changed to 25 cm from the liquid surface, and the mixed and dissolved calcitriol, butylated hydroxytoluene and polysorbate are added to the mixed solution, stirred to dissolve, and a drug solution is formed.

[0060] S404: The air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen to reduce the oxygen content in the pipeline to less than 5%. Sodium hydroxide is used to adjust the pH value of the liquid to 7.5, and water for injection is added to the full amount. The liquid is filtered in two stages using polyvinylidene fluoride filters with a filtration accuracy of 0.45μm and 0.22μm. During the filtration process, nitrogen is introduced into the liquid preparation container to maintain a slight positive pressure of 0.004MPa inside the liquid preparation container.

[0061] S405: After filtering the liquid medicine, fill it into a brown glass ampoule, fill it with nitrogen, ensure that the residual oxygen content in the headspace is less than 1.0%, and seal it. Place it in a sterilizer and sterilize it in a water bath at 121°C for 12 minutes to obtain calcitriol injection.

[0062] Example 5 The embodiment of the present application provides a calcitriol injection with a specification of 1 ml: 2 μg. The raw materials for preparing 1000 ml of the injection include: calcitriol 2 mg, butylated hydroxytoluene 0.03 g, polysorbate 2.0 g, sodium citrate 3.0 g, sodium dihydrogen phosphate monohydrate 9.2 g, sodium chloride 1.5 g, sodium hydroxide 1.8 g, and the rest is water for injection.

[0063] The preparation method of the calcitriol injection comprises: S501: Before preparing the calcitriol injection, nitrogen is continuously introduced into the preparation container through a nitrogen inlet located 15 cm above the bottom of the preparation container to reduce the oxygen content in the preparation container to less than 2%.

[0064] S502: Continuously introduce nitrogen into the liquid preparation container, add water for injection at a temperature of 80°C into the liquid preparation container, cool to 25°C, add sodium citrate, sodium dihydrogen phosphate monohydrate, sodium chloride and sodium hydroxide, stir and dissolve to form a mixed solution, wherein the dissolved oxygen content of the water for injection is less than 0.5 mg / L.

[0065] S503: Under the condition of light intensity lower than 40 Lux, butylated hydroxytoluene is dissolved in polysorbate, and then calcitriol is added and stirred to dissolve. The nitrogen inlet is changed to 25 cm from the liquid surface, and the mixed and dissolved calcitriol, butylated hydroxytoluene and polysorbate are added to the mixed solution, stirred to dissolve, and a drug solution is formed.

[0066] S504: The air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen to reduce the oxygen content in the pipeline to less than 5%. Sodium hydroxide is used to adjust the pH value of the liquid to 7.5, and water for injection is added to the full amount. The liquid is filtered in two stages using polyvinylidene fluoride filters with a filtration accuracy of 0.45μm and 0.22μm. During the filtration process, nitrogen is introduced into the liquid preparation container to maintain a slight positive pressure of 0.006MPa inside the liquid preparation container.

[0067] S505: After filtering the liquid medicine, fill it into a brown glass ampoule, fill it with nitrogen, ensure that the residual oxygen content in the headspace is less than 1.0%, and seal it. Place it in a sterilizing cabinet and sterilize it in a water bath at 121°C for 12 minutes to obtain calcitriol injection.

[0068] Example 6 The present application example provides a calcitriol injection with a specification of 1 ml: 2 μg. The raw materials for preparing 1000 ml of injection are the same as those in Example 5.

[0069] The preparation method of the calcitriol injection comprises: S601: Before preparing the calcitriol injection, nitrogen is continuously introduced into the preparation container through a nitrogen inlet located 10 cm above the bottom of the preparation container to reduce the oxygen content in the preparation container to less than 1%.

[0070] S602: Continuously introduce nitrogen into the liquid preparation container, add water for injection at a temperature of 90° C. into the liquid preparation container, cool to 30° C., add sodium citrate, sodium dihydrogen phosphate monohydrate, sodium chloride and sodium hydroxide, stir and dissolve to form a mixed solution.

[0071] S603: Under the condition of light intensity lower than 60 Lux, butylated hydroxytoluene is dissolved in polysorbate, and then calcitriol is added and stirred to dissolve. The nitrogen inlet is changed to 25 cm from the liquid surface, and the mixed and dissolved calcitriol, butylated hydroxytoluene and polysorbate are added to the mixed solution, stirred to dissolve, and a drug solution is formed.

[0072] S604: The air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen to reduce the oxygen content in the pipeline to less than 5%. Sodium hydroxide is used to adjust the pH value of the liquid to 7.3, and water for injection is added to the full amount.

[0073] The liquid was filtered in two stages using polyvinylidene fluoride filters with a filtration accuracy of 0.22 μm and 0.22 μm. During the filtration process, nitrogen was introduced into the liquid preparation container to maintain a slight positive pressure of 0.004 MPa inside the liquid preparation container.

[0074] S605: After filtering the liquid medicine, fill it into a brown glass ampoule, fill it with nitrogen, ensure that the residual oxygen content in the headspace is less than 1.0%, and seal it. Place it in a sterilizer and steam sterilize it at 121°C for 15 minutes to obtain calcitriol injection.

[0075] Comparative Example 1 The comparative example of the present application provides a calcitriol injection. The raw materials for preparing 1000 ml of the injection include: 0.53 mg of calcitriol, 0.03 g of butylated hydroxytoluene, 2.0 g of polysorbate, 3.0 g of sodium citrate, 9.2 g of sodium dihydrogen phosphate monohydrate, 1.5 g of sodium chloride, 1.8 g of sodium hydroxide, and the rest is water for injection.

[0076] The calcitriol injection is prepared by a conventional production method for injections well known to those skilled in the art. The specific preparation method includes: D101: Add water for injection at a temperature of 85°C into the liquid preparation container. After cooling to 25°C, add sodium citrate, sodium dihydrogen phosphate monohydrate, sodium chloride and sodium hydroxide, stir to dissolve and form a mixed solution.

[0077] D102: Dissolve butylated hydroxytoluene in polysorbate, then add calcitriol and stir to dissolve. Add the dissolved calcitriol, butylated hydroxytoluene and polysorbate to the mixed solution, stir to dissolve, and form a drug solution.

[0078] D103: Sodium hydroxide was used to adjust the pH value of the drug solution to 7.5, and water for injection was added to the full amount. The drug solution was filtered in two stages using polyethersulfone filters with filtration accuracy of 0.45μm and 0.22μm.

[0079] D104: When the residual oxygen content in the headspace of the brown glass ampoule is less than 3.0%, seal it, place it in a sterilizer, and sterilize it in a water bath at 121°C for 12 minutes to obtain calcitriol injection.

[0080] The calcitriol injection prepared in Examples 1-6 and the comparative example was subjected to product stability testing. Specifically, on the day of preparation (i.e., day 0), the properties, content, precalcitriol content, and the total amount of other impurities of the calcitriol injection were tested. After 3 months of observation at 40°C, the properties, content, precalcitriol content, and the total amount of other impurities of the calcitriol injection were tested again to obtain Table 1. Among them, precalcitriol is the main impurity of calcitriol injection degradation and is the main indicator of drug stability.

[0081] Table 1: Stability test results of calcitriol injection prepared in Examples 1-6 and Comparative Examples As can be seen from Table 1, compared with the calcitriol injection just prepared, the calcitriol injection prepared in Examples 1-6 is still a colorless clear liquid after being placed at 40°C for 3 months, with a low content change, and the content of precalcitriol does not change much. However, the calcitriol injection prepared in the comparative example is a slightly yellow clear liquid after being placed at 40°C for 3 months, indicating that degradation has occurred; and the content is greatly reduced, the content of precalcitriol is significantly increased, and the content of other impurities is also significantly increased. This shows that the preparation method provided in the present application can greatly improve the stability of calcitriol injection.

[0082] In addition, in the examples of the present application, three batches of calcitriol injection were produced under industrial conditions using the formula and method shown in Example 1, and the three batches of calcitriol injection were subjected to accelerated tests to obtain the results shown in Table 2. The test conditions were 40°C ± 2°C and 75% RH ± 5% RH.

[0083] Table 2: Accelerated test results As can be seen from Table 2, after 6 months of accelerated testing, the pH, content, precalcitriol content and the total amount of other impurities of the calcitriol injection prepared in the embodiment of the present application did not change much, and all maintained good stability, which greatly improved the medication safety of the calcitriol injection.

[0084] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing calcitriol injection, characterized in that: include: Continuously introduce nitrogen into the liquid preparation container to keep the oxygen content in the liquid preparation container below 5%; Adding water for injection at 0-40° C. with a dissolved oxygen content of less than 2 mg / L, sodium citrate, sodium dihydrogen phosphate hydrate, sodium chloride and sodium hydroxide into the liquid preparation container to form a mixed solution; Under the condition that the light intensity is lower than 200 Lux, butylated hydroxytoluene and calcitriol are added to polysorbate, stirred and dissolved, and then added to the mixed solution, stirred and dissolved to form a drug solution; The liquid medicine is filtered in one direction and then filled into brown glass ampoule, which is filled with nitrogen to ensure that the residual oxygen content in the headspace is less than 3.0%; After the brown glass ampoule is sealed, it is sterilized at 121-123° C. for 12-20 min to obtain the calcitriol injection.

2. The method for preparing calcitriol injection according to claim 1, characterized in that: The injection water has a temperature of 10-30° C. and a dissolved oxygen content of less than 0.5 mg / L.

3. The method for preparing calcitriol injection according to claim 1, characterized in that: The oxygen content in the liquid preparation container is less than 1%.

4. The method for preparing calcitriol injection according to claim 1, characterized in that: The light intensity is lower than 50 Lux.

5. The method for preparing calcitriol injection according to claim 1, characterized in that: When the pH value of the liquid medicine is less than 6.5, the pH value of the liquid medicine is adjusted to 6.5-8.0 by adding sodium hydroxide.

6. The method for preparing calcitriol injection according to claim 1, characterized in that: Before the water for injection is added, the distance between the nitrogen inlet and the bottom of the liquid preparation container is less than 20 cm; before the nitrogen is added to the mixed liquid, the nitrogen inlet is located more than 10 cm above the liquid surface.

7. The method for preparing calcitriol injection according to claim 1, characterized in that: The drug solution is filtered through filters with filtration accuracies of 0.45 μm and 0.22 μm in sequence, or the drug solution is filtered through filters with filtration accuracies of 0.22 μm and 0.22 μm in sequence.

8. The method for preparing calcitriol injection according to claim 7, characterized in that: The raw material for preparing the filter element includes one of hydrophilic polytetrafluoroethylene and polyvinylidene fluoride.

9. The method for preparing calcitriol injection according to claim 1, characterized in that: Before filtering, the air in the pipeline between the liquid preparation container and the filter is replaced with nitrogen to reduce the oxygen content in the pipeline to less than 5%.

10. A calcitriol injection, characterized in that: It is prepared according to the preparation method described in any one of claims 1 to 9.

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