Calcitriol composition for treating hypocalcemia of patients suffering from chronic renal dialysis and preparation method of calcitriol composition

Abstract

The invention discloses a calcitriol composition for treating hypocalcemia of patients suffering from chronic renal dialysis and a preparation method of the calcitriol composition. The composition consists of the following components: calcitriol, a solubilizer, an antioxidant, buffer salt, glycerol, a proper amount of a pH regulator and water for injection. The preparation method of the calcitriol injection comprises the following steps: preparing the raw and auxiliary material components in batches, adding calcitriol into a mixture of the solubilizer and the glycerol, stirring and dissolving uniformly, mixing the mixed solution of the three components with the antioxidant and the buffer saline solution, adjusting the pH value by using the pH regulator, fixing the volume, stirring and mixing uniformly, and filtering by using a sterilization filter to obtain the calcitriol injection. And filling into a brown ampoule, filling nitrogen, sealing, and sterilizing. The content of the calcitriol composition is obviously increased, the stability of the composition to light and air is improved, the reproducibility of a preparation process and the stability of a finished product are good, and the preparation method is suitable for batch production.

Description

Technical Field

[0001] The invention relates to a calcitriol composition for treating hypocalcemia in patients with chronic renal dialysis and a preparation method thereof, belonging to the field of pharmaceutical preparations. Background Art

[0002] In the 1970s, vitamin D3 was found to be metabolized to 1α,25(OH)2D3 (calcitriol) in the liver and kidneys and exert its effects. The synthesis method of calcitriol was established by Uskokovic et al. of Hoffmann-La Roche in the United States in 1975, approved in the United States and Switzerland in 1978, and is currently available worldwide.

[0003] In recent years, hemodialysis treatment for patients with chronic renal failure has become common. On the other hand, due to impaired renal function, the activity of 1α-hydroxylase is reduced, resulting in a decrease in blood calcitriol and a significant increase in blood parathyroid hormone (PTH). Later, intravenous calcitriol was confirmed to be useful for the treatment of secondary hyperparathyroidism in dialysis patients and for the treatment of hypocalcemia in chronic renal dialysis patients.

[0004] Calcitriol, also known as 1,25-dihydroxyvitamin D3. Its biosynthesis pathway is that 7-dehydrocholesterol generates vitamin D3 in the skin after ultraviolet irradiation. Vitamin D3 forms 25-hydroxycholecalciferol in the liver through the action of the hydroxylase system, and then is transported to the kidneys through the blood. Hydroxylase in the proximal tubular cells of the kidneys is hydroxylated by 25-hydroxycholecalciferol to calcitriol. Therefore, it plays an important role in regulating blood calcium and blood phosphorus concentrations. It can accelerate the synthesis of calcium-binding proteins and promote the absorption of calcium and phosphorus by the intestines and renal tubules. It is often used to treat clinical diseases such as osteoporosis, renal osteodystrophy, and hypoparathyroidism.

[0005] Although calcitriol products have good efficacy in the clinical treatment of osteoporosis, renal osteodystrophy and hypoparathyroidism, calcitriol, as an unstable compound, has poor solubility in conventional organic solvents for injection, is almost insoluble in water, and is sensitive to light, heat and air. Therefore, the stability of the existing domestically listed calcitriol injection for long-term storage is poor and the shelf life is short. Therefore, there is a need to provide a calcitriol injection with good reproducibility of preparation process, significantly improved content and good stability. Summary of the invention

[0006] In order to solve the above technical problems, the purpose of the present invention is to provide a calcitriol composition for treating hypocalcemia in chronic renal dialysis patients and a preparation method thereof. The calcitriol composition is composed of the following components: calcitriol, a solubilizing agent, an antioxidant, a buffer salt, glycerol, an appropriate amount of a pH regulator, and water for injection. The sample content after preparation is significantly improved, and the stability of the calcitriol composition to light and air is enhanced. The preparation process has good reproducibility and finished product stability, and the preparation method is suitable for mass production.

[0007] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0008] A calcitriol composition for treating hypocalcemia in chronic renal dialysis patients, comprising the following components:

[0009]

[0010] The amount of the pH adjuster used is based on adjusting the pH value of the composition to 7.0-7.8.

[0011] Furthermore, the calcitriol composition for treating hypocalcemia in chronic renal dialysis patients comprises the following components:

[0012]

[0013] The pH regulator is used to adjust the pH value of the injection. The pH regulator is a sodium hydroxide solution / hydrochloric acid solution. The amount of the pH regulator is used to adjust the pH value of the injection to 7.4±0.2.

[0014] The present invention also provides a method for preparing calcitriol injection, comprising the following steps:

[0015] 1) Prepare the raw material and auxiliary material components in batches, weigh 80-90% of the total liquid volume of water for injection, control the water temperature of the water for injection at 10-40°C, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, and sodium citrate, and stir to dissolve;

[0016] 2) Add calcitriol to the mixed solution of polysorbate 80 and glycerol, stir to dissolve and mix evenly, then add the mixed solution of the three into 10-40°C water for injection, stir to dissolve evenly;

[0017] 3) Mix the calcitriol\polysorbate 80\glycerol mixture with the other excipients, stir evenly, adjust the pH to 7.0-7.8 with a pH regulator, and then make up to volume with water for injection;

[0018] 4) Then stirring at a stirring speed of 200 to 300 rpm for 10 to 30 minutes;

[0019] 5) Filter through a sterilizing filter, fill with nitrogen, seal, sterilize, inspect by light and package.

[0020] Wherein, further, the initial addition amount of the water for injection is 85%, and the temperature range is controlled at 25±5°C. Sodium hydroxide / hydrochloric acid is used to adjust the pH to 7.4±0.2. The sterilization filter pore size is 0.22μm, and the material is polytetrafluoroethylene. The sterilization conditions are: sterilization at 121°C for 15 minutes. DETAILED DESCRIPTION

[0021] Example 1: Preparation of calcitriol composition

[0022] prescription:

[0023] Element Dosage Calcitriol 10mg Polysorbate 80 20g Sodium bisulfite 15g Sodium dihydrogen phosphate 150g Sodium Citrate 50g glycerin 50g Sodium hydroxide Moderate hydrochloric acid Moderate Water for injection Add to 10000ml

[0024] Preparation method: weigh about 8.5L of water for injection, control the water temperature of the water for injection to 20-25℃, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, sodium citrate, and glycerol, and stir to dissolve; weigh calcitriol and add it to 20g of polysorbate 80, stir to dissolve and stir evenly, then add the mixture of the two to about 8.5L of water for injection at 20-25℃, stir for 15 minutes to dissolve; adjust the pH to 7.4±0.2 with a pH adjuster, and make up the volume; then stir at a stirring speed of 250rpm for 20min; then filter through a 0.22μm polytetrafluoroethylene sterilizing filter, fill with nitrogen and seal, and sterilize at 121℃ for 15 minutes.

[0025] Example 2: Preparation of calcitriol composition

[0026] prescription:

[0027]

[0028]

[0029] Preparation method: weigh about 8.5L of water for injection, control the water temperature of the water for injection to 20-25℃, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, sodium citrate, and glycerol, and stir to dissolve; weigh calcitriol and add it to 30g of polysorbate 80, stir to dissolve and stir evenly, then add the mixture of the two to about 8.5L of water for injection at 20-25℃, stir for 30 minutes to dissolve; adjust the pH to 7.4±0.2 with a pH adjuster, and make up the volume; then stir at a stirring speed of 250rpm for 20min; then filter through a 0.22μm polytetrafluoroethylene sterilizing filter, fill with nitrogen and seal, and sterilize at 121℃ for 15 minutes.

[0030] Example 3: Preparation of calcitriol composition

[0031] prescription:

[0032] Element Dosage Calcitriol 10mg Polysorbate 80 40g Sodium bisulfite 15g Sodium dihydrogen phosphate 150g Sodium Citrate 50g glycerin 50g Sodium hydroxide Moderate hydrochloric acid Moderate Water for injection Add to 10000ml

[0033] Preparation method: weigh about 8L of water for injection, control the water temperature of the water for injection to 20-25℃, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, sodium citrate, and glycerol, and stir to dissolve; weigh calcitriol and add it to 40g of polysorbate 80, stir to dissolve and stir evenly, then add the mixture of the three to about 8L of water for injection at 20-25℃, stir for 30 minutes to dissolve; adjust the pH to 7.4±0.2 with a pH adjuster, and make up the volume; then stir at a stirring speed of 250rpm for 20min; then filter through a 0.22μm polytetrafluoroethylene sterilizing filter, fill with nitrogen and seal, and sterilize at 121℃ for 15 minutes.

[0034] Example 4: Preparation of calcitriol composition

[0035] prescription:

[0036]

[0037]

[0038] Preparation method: weigh about 8.5L of water for injection, control the water temperature of the water for injection to 20-25℃, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, and sodium citrate, and stir to dissolve; weigh the prescribed amount of glycerol and add it to 30g of polysorbate 80, stir to mix, then add calcitriol to the mixed solution of polysorbate 80 and glycerol, stir to dissolve and stir evenly, then add the mixture of the three to about 8.5L of water for injection at 20-25℃, stir for 15 minutes to dissolve; adjust the pH to 7.4±0.2 with a pH adjuster, and make up the volume; then stir at a stirring speed of 250rpm for 20min; then filter through a 0.22μm polytetrafluoroethylene sterilizing filter, fill with nitrogen and seal, and sterilize at 121℃ for 15 minutes.

[0039] Example 5: Preparation of calcitriol composition

[0040] prescription:

[0041] Element Dosage Calcitriol 10mg Polysorbate 80 30g Sodium bisulfite 15g Sodium dihydrogen phosphate 150g Sodium Citrate 50g glycerin 50g Sodium hydroxide Moderate hydrochloric acid Moderate Water for injection Add to 10000ml

[0042] Preparation method: weigh about 6L of water for injection, control the water temperature of the water for injection to 20-25°C, add the prescribed amount of polysorbate 80, sodium bisulfite, sodium dihydrogen phosphate, sodium citrate, and glycerol, and stir to dissolve; weigh calcitriol and add it to 6L of water for injection, stir to dissolve and stir evenly; add water to about 9L, stir and mix, adjust the pH to 7.4±0.2 with a pH adjuster, and make up to volume; then stir at a stirring speed of 250rpm for 20min; then filter through a 0.22μm polytetrafluoroethylene sterilizing filter, fill with nitrogen and seal, and sterilize at 121°C for 15 minutes.

[0043] Example 6: Preparation of calcitriol composition

[0044] prescription:

[0045] Element Dosage Calcitriol 10mg Polysorbate 80 20g Sodium bisulfite 15g Sodium dihydrogen phosphate 100g Sodium Citrate 20g glycerin 50g Sodium hydroxide Moderate hydrochloric acid Moderate Water for injection Add to 10000ml

[0046] Preparation method: weigh about 9L of water for injection, control the water temperature of the water for injection to 20-25℃, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, and sodium citrate, and stir to dissolve; weigh the prescribed amount of glycerol and add it to 30g of polysorbate 80, stir to mix, then add calcitriol to the mixed solution of polysorbate 80 and glycerol, stir to dissolve and stir evenly, then add the mixture of the three to about 9L of water for injection at 20-25℃, and stir until completely dissolved; adjust the pH to 7.4±0.2 with a pH adjuster, and make up to volume; then stir at a stirring speed of 250rpm for 20min; then filter through a 0.22μm polytetrafluoroethylene sterilizing filter, fill with nitrogen and seal, sterilize at 121℃ for 15 minutes, inspect by light and package.

[0047] Example 7: Preparation of calcitriol composition

[0048] prescription:

[0049]

[0050]

[0051] Preparation method: weigh about 7L of water for injection, control the water temperature of the water for injection to 20-25℃, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, and sodium citrate, and stir to dissolve; weigh the prescribed amount of glycerol and add it to polysorbate 80, stir to mix, then add calcitriol to the mixed solution of polysorbate 80 and glycerol, stir to dissolve and stir evenly, then add the mixture of the three to about 8.5L of water for injection at 20-25℃, and stir until completely dissolved; adjust the pH to 7.4±0.2 with a pH adjuster, and make up to volume; then stir at a stirring speed of 250rpm for 20min; then filter through a 0.22μm polytetrafluoroethylene sterilizing filter, fill with nitrogen and seal, sterilize at 121℃ for 15 minutes, inspect by light and package.

[0052] The beneficial effects of the present invention are described below through test examples.

[0053] Comparison of samples prepared with different solubilizer dosages in Examples 1-3

[0054] Calcitriol is almost insoluble in water. In order to increase its solubility, the effects of different amounts of solubilizer on the preparation were investigated. 0.2%, 0.3%, and 0.4% polysorbate 80 were used to prepare calcitriol compositions.

[0055] The specific operation is as follows: take 10 mg of calcitriol and different amounts of polysorbate 80 (20 g, 30 g, and 40 g respectively), mix and stir for 30 minutes to make a premixed solution, then mix it with the remaining auxiliary materials and aqueous solution, stir to dissolve, and observe the properties; after filtering with a 0.22 μm polytetrafluoroethylene filter membrane, fill with nitrogen, seal, and sterilize at 121°C for 15 minutes, and determine the content of calcitriol and its related substances in the sample.

[0056] The experimental results are shown in Table 1:

[0057] Table 1 Test results of different solubilizer dosages

[0058]

[0059] The experimental results show that 0.2% polysorbate 80 cannot completely dissolve calcitriol, while 0.3% and 0.4% polysorbate 80 can completely dissolve calcitriol with good quality. Polysorbate 80 has hemolytic activity, so 0.3% polysorbate 80 in the prescription is more advantageous.

[0060] Comparison of samples prepared by different preparation processes in Examples 2, 4 and 5

[0061] Calcitriol is almost insoluble in water. Polysorbate 80 is used as a solubilizer, and 0.3% of it can make calcitriol basically dissolved completely. Glycerol can also be used as a cosolvent. In order to make calcitriol dissolve and disperse evenly in the preparation, the effects of different preparation processes on the preparation were investigated.

[0062] The specific operation is as follows: take a portion of 10 mg of calcitriol and mix it with 30 g of polysorbate 80 and stir it for 30 minutes to make a premixed solution, and then mix it with the remaining auxiliary materials mixed aqueous solution; take a portion of 10 mg of calcitriol and mix it with 30 g of polysorbate 80 and 50 g of glycerol for 30 minutes to make a premixed solution, and then mix it with the remaining auxiliary materials mixed aqueous solution; take a portion of 10 mg of calcitriol and stir it in the mixed aqueous solution of polysorbate 80 and the remaining auxiliary materials for 1 hour, and observe the properties; adjust the pH and fix the volume respectively; filter with a 0.22 μm polytetrafluoroethylene filter membrane, fill with nitrogen, seal, and sterilize at 121°C for 15 minutes, and determine the content of calcitriol and its related substances in the sample.

[0063] The experimental results are shown in Table 2:

[0064] Table 2 Test results of different preparation processes

[0065] Example Example 2 Example 4 Example 5 Characteristics Colorless clear liquid Colorless clear liquid Colorless, clear, slightly opalescent liquid content% 99.8 101.0 97.0 Related substances (total impurities%) 0.62 0.60 0.78

[0066] The experimental results show that the stirring dissolution process of calcitriol in polysorbate 80 aqueous solution causes a 3% loss of content and a high level of total impurities; premixing calcitriol in polysorbate 80 can completely dissolve calcitriol, and premixing calcitriol in polysorbate 80 and glycerol can completely dissolve calcitriol. The total impurity levels of the samples prepared by the two preparation processes are basically the same. Calcitriol is sensitive to air, and the viscosity of polysorbate 80 is higher than that of the mixed solution of polysorbate 80 and glycerol, which is not conducive to the introduction of oxygen in the air. Therefore, the dosage of 0.3% polysorbate 80 in the prescription is more advantageous.

[0067] Comparison of samples prepared with different buffer salt dosages in Examples 2, 6 and 7

[0068] The amount of buffer salt in the prescription is related to the buffering capacity, and the effect of different amounts of buffer salt on the preparation was investigated. Different concentrations of sodium dihydrogen phosphate and sodium citrate were used to prepare the calcitriol composition.

[0069] The specific operation is as follows: take 10 mg of calcitriol, mix it with polysorbate 80 and glycerol and stir it for 30 minutes to make a premixed solution, then mix it with the remaining auxiliary materials mixed aqueous solutions with different buffer salt dosages (the total proportion of buffer salt prescription is 1.2%, 2.0%, and 2.8%, respectively), stir to dissolve; after filtering with a 0.22μm polytetrafluoroethylene filter membrane, fill it with nitrogen, seal it, and sterilize it at 121℃ for 15 minutes, and determine the content of calcitriol and its related substances in the sample.

[0070] The experimental results are shown in Table 3:

[0071] Table 3 Accelerated stability results of different buffer salt dosages

[0072]

[0073]

[0074] The experimental results show that when the amount of buffer salt is reduced to 1.2% of the total amount, the buffering capacity of the solution decreases and the stability decreases; the total amount of buffer salt is 2.0% and 2.8%, the solution has strong buffering capacity and good stability; the type and amount of excipients used in the injection should be as small as possible, so the total amount of buffer salt is 2.0%, that is, 1.5% sodium dihydrogen phosphate and 0.5% sodium citrate. In summary, the calcitriol injection composition and its preparation process developed by our company have good reproducibility, good finished product stability, and the preparation method is suitable for industrial mass production.

Claims

1. A calcitriol composition for treating hypocalcemia in chronic renal dialysis patients, comprising a calcitriol composition containing a solubilizer, an antioxidant, a buffer salt, and an osmotic pressure regulator, and a preparation method thereof.

2. The calcitriol composition according to claim 1, wherein the solubilizing agent is a nonionic surfactant, and the nonionic surfactant is selected from polyoxyethylene fatty acid esters, such as polysorbate 80 [polyoxyethylene sorbitan monooleate], polysorbate 60 [polyoxyethylene sorbitan monostearate], polysorbate 40 [polyoxyethylene sorbitan monopalmitate], polysorbate 20 [polyoxyethylene sorbitan monolaurate], polyoxyethylene castor oils, such as polyoxyethylene (35) castor oil.

3. The calcitriol composition according to claim 2, wherein the nonionic surfactant is polysorbate 80 or castor oil.

4. The calcitriol composition according to claim 2, wherein the amount of the nonionic surfactant is 0.1-0.5% (w / v), preferably 0.2-0.4%, and more preferably about 0.3%.

5. The calcitriol composition according to claims 1-4, wherein the antioxidant is sodium bisulfite.

6. The calcitriol composition according to claims 1-5, wherein the buffer salt is selected from a mixture of one or more of phosphate, citrate and acetate.

7. The calcitriol composition according to claim 6, wherein the buffer salt is a combination of sodium dihydrogen phosphate and sodium citrate.

8. A calcitriol composition comprising: The optional buffer salts in the calcitriol composition are commonly used sodium dihydrogen phosphate and sodium citrate, which have strong buffering capacity.

9. A calcitriol composition comprising: The amount of the pH adjuster used is based on adjusting the pH value of the composition to 7.0-7.

8.

10. A method for preparing the calcitriol injection as claimed in claim 1, comprising the following steps: 1) Prepare the raw material and auxiliary material components in batches, weigh 80%-90% of the total liquid volume of water for injection, control the water temperature of the water for injection at 10-40°C, add the prescribed amount of sodium bisulfite, sodium dihydrogen phosphate, and sodium citrate, and stir to dissolve; 2) Add calcitriol to the mixed solution of polysorbate 80 and glycerol, stir to dissolve and mix evenly, then add the mixed solution of the three into 10-40°C water for injection, stir to dissolve evenly; 3) Mix the calcitriol\polysorbate 80\glycerol mixture with the other excipients, stir evenly, adjust the pH to 7.0-7.8 with a pH regulator, and then make up to volume with water for injection; 4) Then stirring at a stirring speed of 200 to 300 rpm for 10 to 30 minutes; 5) Filter through a sterilizing filter, fill with nitrogen, seal, sterilize, inspect by light and package.

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