Vitamin D3 injection pharmaceutical composition and use thereof

Abstract

The present application provides a vitamin D3 liquid composition, including vitamin D3 and polyethylene glycol-15-hydroxystearate, wherein the pH value of the vitamin D3 liquid composition is 7.1-7.6, and the vitamin D3 liquid composition does not contain ethanol, propylene glycol, polyethylene glycol, poloxamer or polyvinyl pyrrolidine. The aqueous solution composition of the present invention is stable and uniform, more suitable for injection than an oil solution, and can be used for the prevention and treatment of vitamin D deficiency.

Description

Field of the Invention

[0001] The present application belongs to the field of pharmaceutical preparations. Specifically, the present application provides a vitamin D3 injection pharmaceutical composition and its use. Background Art

[0002] Vitamin D3 (cholecalciferol) is mainly synthesized by the human body. The human skin contains a type of cholesterol, which becomes vitamin D3 after being exposed to sunlight. Therefore, if a child can fully receive direct sunlight on the skin for more than 4-6 hours, the self-synthesized vitamin D3 can basically meet the needs. However, due to the increase in skin cancer caused by ultraviolet radiation, air pollution, and weather changes in various places, the time people in various countries receive sunlight is decreasing, and many countries have clearly stipulated that the time to receive sunlight should be limited. Therefore, vitamin D is widely lacking worldwide. In addition to existing in a few animal foods, vitamin D3 is mainly formed by 7-dehydrocholesterol in the skin after being exposed to ultraviolet rays, and 7-dehydrocholesterol is generated by the conversion of cholesterol, so some people call it the sun vitamin.

[0003] Vitamin D3 [9,10-secocholesterol-5,7,10(19)-triene-3β-ol] is one of the important vitamins essential for human health, normal growth and reproduction of livestock and poultry. It is clinically used to treat rickets, osteoporosis in the elderly and hypothyroidism.

[0004] Vitamin D3 is lipophilic, i.e., only slightly or negligibly soluble in water. The poor water solubility of vitamin D3 leads to major difficulties in administration by injection, especially when a sterile and easily manageable homogeneous aqueous solution is required. Therefore, the manufacture of vitamin D3 solutions involves many problems that arise from the sensitivity of vitamin D3 to chemical and physical influences. For example, vitamin D3 in solution is sensitive to chemical degradation, which limits the shelf life of the solution and may produce undesirable degradation products.

[0005] Generally, the degree of vitamin D3 deficiency can be measured by the concentration of calcifediol in the blood. When the concentration of calcifediol in the blood is lower than 25nmol / l, it is considered as deficiency. When the concentration is in the range of 50-74nmol / l and in the range of 75-250nmol / l, it is classified as sufficient.

[0006] Vitamin D3, used to supplement vitamin D deficiency, can effectively increase the concentration of calcifediol in the blood. It is clinically available in the form of oral preparations or injections (especially intramuscular injections).

[0007] Commercially available vitamin D3 intramuscular injections (e.g., Jiangsu Wuzhong vitamin D3 injection, Zhejiang Xianju vitamin D3 injection, VYDEE, CHOLREADY, ARACHITOL, D-GLIT, MERIT-D, ORAJECT-D, INDOMAC, J-VITA, D3-VICOTRAT, DEVAROL S, etc.) usually contain 100,000 to 300,000 IU of vitamin D3. Intramuscular injections are particularly useful for non-elderly patients, patients with vitamin D deficiency and impaired glucose tolerance, patients with decreased digestive function, patients who have undergone gastrectomy or biliary tract resection, and other patients who are not easy to take oral medication. The vitamin D3 injection currently used in clinical commercialization is a yellow clear oily liquid, which is only suitable for intramuscular injection. This type of injection has a large pain reaction during injection, is highly irritating, is prone to allergies, and is prone to cause drug accumulation in local muscle tissues, causing lumps and pain, etc., which is very inconvenient for patients, especially long-term users, and brings inconvenience to clinical use, which seriously limits clinical application. Because vitamin D3 and its metabolites are very lipophilic, they are slowly metabolized in the body and have a long half-life. They can still be detected in the blood even after several months of taking them. They are very sensitive to heat, light, oxidation and ensuring stability.

[0008] Therefore, there has long been a need to provide an oil-free, stable, uniform aqueous solution of vitamin D3 suitable for oral or parenteral administration. Summary of the invention

[0009] In order to improve the bioavailability and solubility of vitamin D3 and improve the drug stability of the preparation, the present invention, based on the solubilization research of vitamin D3 drug, has studied the combination of many kinds of surfactants, surfactant adjuvants, solubilizers and oily components, and found that the use of polyethylene glycol-15-hydroxystearate can make the drug more stable in the solution, better soluble, limit the appearance of degradation products during the storage period, and reduce the harm of hemolysis or other side effects caused by intravenous injection.

[0010] On the one hand, the present application provides a liquid vitamin D3 composition, comprising vitamin D3 and polyethylene glycol-15-hydroxystearate, wherein the liquid vitamin D3 composition does not contain ethanol, propylene glycol, polyethylene glycol, poloxamer or polyvinyl pyrrolidine.

[0011] The vitamin D3 in the composition is present in a solubilized form and is dissolved by micellization or complexation.

[0012] Furthermore, the vitamin D3 liquid composition is an aqueous solution.

[0013] Furthermore, the vitamin D3 liquid composition contains 150-250 mg / mL of polyethylene glycol-15-hydroxystearate, and preferably contains 200 mg / mL of polyethylene glycol-15-hydroxystearate.

[0014] Furthermore, the vitamin D3 liquid composition also contains sodium chloride, preferably sodium chloride that can provide an osmotic pressure isotonic with blood or body fluids.

[0015] Furthermore, the vitamin D3 liquid composition also contains a preservative.

[0016] Furthermore, the vitamin D3 liquid composition contains 1-15 mg / mL of vitamin D3; preferably contains 2.5-15 mg / mL of vitamin D3.

[0017] Furthermore, the liquid composition is an oral solution or an injection solution.

[0018] The injection includes, but is not limited to, injection for intramuscular injection, intravenous injection, and intravenous drip.

[0019] Furthermore, the vitamin D3 liquid composition also contains a pH adjuster, preferably sodium dihydrogen phosphate and sodium citrate.

[0020] Furthermore, the pH value of the vitamin D3 liquid composition is 6.8-7.8, preferably 7.1-7.6, and further preferably 7.2-7.5.

[0021] Furthermore, the vitamin D3 liquid composition consists of vitamin D3, polyethylene glycol-15-hydroxystearate, sodium chloride, and a pH adjuster.

[0022] The pH adjuster in the present application can use various pH adjusters suitable for oral administration or injection, and can use various hydrate forms. Those skilled in the art can calculate the required amount of various hydrates based on reference books and molecular weights.

[0023] On the other hand, the present application provides a method for preparing a vitamin D3 liquid composition, the method comprising the following steps:

[0024] Under nitrogen protection, the prescribed amount of polyethylene glycol-15-hydroxystearate is heated to a temperature of 40-60°C, and vitamin D3 is added to the heated polyethylene glycol-15-hydroxystearate to dissolve and obtain a vitamin D3 solution; the prescribed amount of sodium chloride and a pH adjuster are added to 80-95% of the prescribed amount of water for injection at 60-80°C to obtain an aqueous solution; the cooled vitamin D3 solution is added to the aqueous solution under a nitrogen atmosphere, and the remaining water for injection is added.

[0025] Furthermore, the method further comprises sterilization and perfusion steps; preferably, filtration sterilization is used.

[0026] Furthermore, the pH adjuster is preferably sodium dihydrogen phosphate hydrate and sodium citrate hydrate.

[0027] On the other hand, the present application provides the use of the above-mentioned vitamin D3 liquid composition in the preparation of a drug for preventing or treating vitamin D deficiency.

[0028] On the other hand, the present application also provides a method for treating vitamin D deficiency, which comprises the step of administering the above-mentioned vitamin D3 liquid composition to a subject suffering from vitamin D deficiency.

[0029] Furthermore, the subject is a human or an animal, preferably a human.

[0030] Further, the single administration dose of the administered vitamin D3 liquid composition is 2.5 mg-60 mg of vitamin D3.

[0031] The administrator can determine the dosage, frequency and time of administration according to factors such as the subject's gender, condition, weight, age and related treatment specifications.

[0032] Furthermore, the administration is oral or injection, preferably injection.

[0033] Furthermore, the vitamin D deficiency is chronic hypocalcemia, hypophosphatemia, rickets, osteomalacia with chronic renal insufficiency, familial hypophosphatemia, hypoparathyroidism, postoperative tetany, and idiopathic tetany.

[0034] The hypoparathyroidism includes postoperative, idiopathic or pseudohypoparathyroidism; postoperative tetany and idiopathic tetany include acute, chronic and latent postoperative tetany and idiopathic tetany.

[0035] Polyethylene glycol-15-hydroxystearate (monograph name, European Pharmacopoeia), trade name HS15, a nonionic injection solution solvent, consists of mono- and diesters of 12-hydroxystearic acid and polyethylene glycol (15 mol of ethylene oxide and 1 mol of 12-hydroxystearic acid) and about 30% of free polyethylene glycol (hydrophilic part). Polyethylene glycol-15-hydroxystearate is soluble in water, ethanol and 2-propanol to form a transparent solution; at high temperatures, the solubility in water decreases. Polyethylene glycol-15-hydroxystearate has high chemical stability. However, after prolonged heating, it may physically separate into liquid and solid phases. This can be reversed by subsequent homogenization. Aqueous solutions of polyethylene glycol-15-hydroxystearate can be autoclaved at 121°C. The pH may drop slightly during this process, and phase separation may even occur. The latter can be reversed by shaking the hot solution. Aqueous solutions of polyethylene glycol-15-hydroxystearate can be stabilized by adding preservatives commonly used in pharmaceuticals. Polyethylene glycol-15-hydroxystearate also has good solubility, autoclave resistance, and good stability in aqueous solutions, as well as a good toxicity profile, such as low hemolytic activity. Polyethylene glycol-15-hydroxystearate is approved for parenteral administration.

[0036] The object of the present invention is to overcome the limited solubility of vitamin D3 and to develop pharmaceutical preparations, especially for intravenous administration, comprising as active ingredient lipophilic vitamin D3, which overcome the limitations of many known methods, especially those using organic solvents and oily matrices. It is also an object of the present invention to provide improved vitamin D3 preparations which are chemically and physically stable under long-term storage and suitable for parenteral administration, especially intravenous administration, and also oral administration. The preparations should be diluted with aqueous infusion solutions at physiological pH.

[0037] The inventors have made great efforts to solve these problems. Therefore, in one aspect of the present invention, a pharmaceutical composition in the form of vitamin D3 injection or infusion is provided, comprising vitamin D3 as an active ingredient, non-ionic polyethylene glycol-15-hydroxystearate as a solubilizer, sodium chloride as an isotonicity regulator and an inert atmosphere at pH 7.1 to 7.6, but with the proviso that the use of a cosolvent composed of ethanol, propylene glycol, polyethylene glycol, poloxamer or polyvinyl pyrrolidine is excluded.

[0038] The present invention overcomes the problem of poor solubility of vitamin D3 by adding a third compound or a mixture of compounds to increase the solubility of vitamin D3 in water, wherein vitamin D3 is present in a solubilized form, and vitamin D3 is dissolved by micellization or complexation to form an aqueous solution. In addition, the amount of non-ionic solubilizer polyethylene glycol-15-hydroxystearate is particularly preferably 150 mg to 250 mg / ml. In general, the diluted, stable, sterile, non-pyrogenic aqueous solution contains 1 to 15 mg / ml of vitamin D3, and by using a biocompatible buffer, preferably the buffer is a combination of sodium dihydrogen phosphate hydrate and sodium citrate hydrate, sodium dihydrogen phosphate and sodium citrate to maintain the solution at a pH of 7.1 to 7.6, preferably a pH of 7.2 to 7.5, and the solution is isotonic with sodium chloride. Using an appropriate buffer system to carefully control the pH of the solution is essential for the practice of the present invention. The present invention does not use effective antioxidants and chelating agents, but only uses an inert atmosphere of nitrogen to resist oxidation.

[0039] In a preferred embodiment of the present invention, a stable, aqueous, diluted sterile vitamin D3 solution for parenteral administration such as intramuscular injection, intravenous injection, intravenous drip or oral administration is provided in a unit dose of 1 ml, 2 ml, 3 ml, 4 ml, 5 ml amber brown glass or plastic ampoules, the top space of which is filled with an inert atmosphere (such as nitrogen).

[0040] In order to prepare the solution of the present invention, the following steps are adopted: under nitrogen protection, polyethylene glycol-15-hydroxystearate is adjusted to a temperature of 40-60°C in a container equipped with a stirrer, vitamin D3 is added to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stirred and dissolved at a temperature of 40-60°C to form a solution until the mixture is uniform and cooled to room temperature, while the solution is cooled, 90% of the prescribed amount of water for injection at about 70°C is cooled under nitrogen protection, appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate are added to the cooling water, and the pH value is checked; the cooled solution is gently mixed under a nitrogen atmosphere and added to the aqueous solution prepared above, and a sufficient amount of water for injection is added to the final volume, and then the solution is aseptically filtered under a nitrogen atmosphere, and filled into each glass or plastic ampoule, and before sealing, the filtered nitrogen is introduced into the top space of each ampoule.

[0041] The present invention also relates to a pharmaceutical composition in the form of vitamin D3 injection or infusion, which is used for the prevention and treatment of vitamin D deficiency, for the treatment of chronic hypocalcemia, hypophosphatemia, rickets and osteomalacia associated with chronic renal insufficiency, familial hypophosphatemia and hypoparathyroidism (postoperative, idiopathic or pseudohypoparathyroidism), and for the treatment of acute, chronic and potential postoperative tetany and idiopathic tetany. DETAILED DESCRIPTION

[0042] In order to achieve the purpose of the present invention, the present invention has gone through multiple research stages such as establishment of a solubilizing agent dissolution system, impurity control test, low-temperature crystallization test, stability test, irritation test, hemolytic test, and in vivo pharmaceutical behavior evaluation, and has been completed by achieving multiple phased goals. The following is a further detailed description of the present invention using specific embodiments in conjunction with the implementation stage of the present invention, but the present invention is not limited to the scope of the described embodiments.

[0043] Test Example 1: Establishment of an effective solubilizer dissolution system

[0044] Since API has poor solubility in water, in order to ensure the development of subsequent formulation process parameters, we screened and studied the excipients in the prescription, with the aim of selecting suitable solvents / solvent enhancers to increase the solubility of API and enable the API to be completely dissolved in the prescription.

[0045] Select commonly used additives / solvents in injections, such as polyethylene glycol-15-hydroxystearate, Tween 80, lecithin, poloxamer 188, ethanol, propylene glycol, polyethylene glycol 400 and hydroxypropyl beta-cyclodextrin. Add each excipient in the usual amount. According to the proposed prescription composition, weigh each excipient into a suitable container, add water to the full amount of the prescription, stir to dissolve it all, then add the prescribed amount of vitamin D3, stir to dissolve. During the experiment, observe the dissolution phenomenon of vitamin D3 and the properties of the drug solution. The prescription composition is shown in Table 1, and the test results are shown in Table 2.

[0046] Table 1 Prescription composition

[0047]

[0048] Table 2 Screening results of the dosage of each auxiliary material

[0049]

[0050] Conclusion: The above experimental phenomena and results show that among the above excipients, polyethylene glycol-15-hydroxystearate has a significant solubilizing effect, and lecithin also has a relatively significant solubilizing effect, but the precipitation of the API in the later stage may indicate that its prescription concentration is low. According to the test results, polyethylene glycol-15-hydroxystearate is preferred as the solubilizing agent / solubilizing agent in the prescription of this product, and the reasonable dosage is further screened.

[0051] Test Example 2: Investigation and Optimization of Dosage of Polyethylene Glycol-15-Hydroxystearate

[0052] According to the screening results of excipient types, different dosages of polyethylene glycol-15-hydroxystearate were designed on the basis of prescription 1 for sample preparation, and the dosage of polyethylene glycol-15-hydroxystearate was optimized. During the experiment, the dissolution time, dissolution phenomenon, properties of the drug solution, pH value and content of each prescription were focused on. The prescription composition and test results are shown in Table 3.

[0053] Table 3 Results of the investigation on the dosage of polyethylene glycol-15-hydroxystearate

[0054]

[0055]

[0056] The dosage of polyethylene glycol-15-hydroxystearate in the above prescription ranges from 10% to 50%. From the test results, when the dosage of polyethylene glycol-15-hydroxystearate is ≤10%, the API cannot be completely dissolved. When the dosage of polyethylene glycol-15-hydroxystearate is ≥20%, the API is completely dissolved, and the dissolution time decreases due to the increase in concentration and the pH value increases. According to the results of this test, the dosage of polyethylene glycol-15-hydroxystearate is further optimized, and the dosage of polyethylene glycol-15-hydroxystearate is reduced to between 15% and 25%, and the prescription is prepared. The optimized results are shown in Table 4.

[0057] Table 4 Optimization results of dosage of polyethylene glycol-15-hydroxystearate

[0058]

[0059] Analysis of results: The test results show that when the dosage ratio of polyethylene glycol-15-hydroxystearate reaches 15% (i.e. 150 mg / ml), the API can be completely dissolved, but the dissolution time is longer and the pH value is slightly lower than the 20% prescription dosage. When the dosage reaches 25% (i.e. 250 mg / ml), there is no significant difference in API dissolution time from 20%, and the pH value has no obvious change. The content determination results are basically consistent with the API dosage.

[0060] According to the results of the screening and optimization of the dosage of polyethylene glycol-15-hydroxystearate, the dosage range of polyethylene glycol-15-hydroxystearate in the prescription of this product is between 150 mg and 250 mg / ml, which can completely dissolve the API. The results show that there is no significant difference in the dissolution time of the API between prescription 10 and prescription 15. Considering the clinical safety of drug use and the operability of the production process, the dosage of polyethylene glycol-15-hydroxystearate in prescription 10 is preferred as the prescription dosage.

[0061] Test Example 3: Study on pH value of drug solution

[0062] Preliminary screening of pH range of drug solution

[0063] In order to investigate the stability of the drug solution within a certain pH range, the pH range of the drug solution was screened. A batch of drug solutions was prepared with prescription 10 as the basic prescription. The pH values ​​of the drug solutions were adjusted to 3.0, 4.0, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, and 8.5 using 0.1 mol / L hydrochloric acid solution and sodium hydroxide solution, respectively. After completion, the drug solution was placed at room temperature for 24 hours and samples were taken at 0, 1, 2, 3, 6, and 24 hours to observe the properties, clarity and color, visible foreign matter, pH, content, and related substances of the drug solution. During the pH adjustment process, it was found that when the pH value of the drug solution was lower than 5, the properties of the drug solution changed and it had optical rotation. After continuing to add the acid regulator, the drug solution had flocculent precipitation, indicating that too low a pH value would affect the solubility of the drug. When the pH value of the drug solution exceeded 8, the color of the drug solution changed and became slightly light yellow. Therefore, the pH range of this test is planned to be between 5.0 and 8.0. The test results are shown in Table 5.

[0064] Table 5 Preliminary screening results of pH range of drug solution

[0065]

[0066]

[0067]

[0068]

[0069] Analysis of the results showed that when the pH of the drug solution was less than 7, the changes in various indicators of the drug solution were more obvious. When the pH of the drug solution was between 7.0 and 8.0, the various indicators of the drug solution were relatively stable. However, the pH of the drug solution of 8.0 changed after 24 hours compared with 0 hours. Therefore, the pH control range of the drug solution needs to be further narrowed.

[0070] Optimization of pH range of drug solution

[0071] Based on prescription 10, a batch of liquid medicine was prepared, and the liquid medicine was adjusted to about 7.2, 7.4, 7.6 and 7.8 with 0.1 mol / L sodium hydroxide solution. The amount of regulator was recorded during the adjustment process. The adjusted liquid medicine was placed at room temperature for observation for 24 hours and samples were taken at 0, 1, 2, 3, 6 and 24 hours to observe the liquid medicine properties, clarity and color, visible foreign matter, pH, content and related substances. The test results are shown in Table 6.

[0072] Table 6 Results of the test on the optimization of the pH range of the liquid medicine

[0073]

[0074]

[0075]

[0076]

[0077] Test conclusion: The optimization test results show that when the pH range of the liquid medicine is between 7.1 and 7.6, there is no obvious change trend in various indicators, indicating that the pH of the liquid medicine can be kept in this range to stabilize the quality. Based on the above test results, the pH range of the liquid medicine of this product is determined to be 7.1 to 7.6.

[0078] Test Example 4: Investigation of Nitrogen Filling Process

[0079] In order to ensure the stability of product quality, we conducted a study on the stability of nitrogen filling of drug solution. According to the basic prescription composition, a batch of drug solution was prepared, and the drug solution was divided into two parts and placed in a suitable container. One part was not filled with nitrogen and placed at room temperature, and the remaining part was continuously filled with nitrogen. Both samples were observed for 24 hours, and appropriate amounts of samples were taken at 0, 2, 4, 8 and 24 hours to test the properties of the samples, solution clarity and color, pH value, related substances and content. The test results are shown in Table 7 and Table 8.

[0080] Table 7 Nitrogen filling test results (1)

[0081]

[0082] Table 8 Nitrogen filling test results (2)

[0083]

[0084]

[0085] Conclusion: Compared with the nitrogen-filled solution, the non-nitrogen-filled solution has a slight change in solution clarity and color, a slight increase in the total amount of impurities, and no obvious change trend in other indicators, indicating that the stability of the solution after nitrogen filling is more stable than that of the non-nitrogen-filled solution. Therefore, it is determined that this product needs to be nitrogen-filled during production to ensure sample stability.

[0086] Test Example 5: Sterilization Process Investigation

[0087] According to the relevant technical requirements of the "Guidelines for Sterilization and Aseptic Process Research and Validation of Chemical Injections (Trial)", combined with the dosage form characteristics of this product and the physical and chemical properties of the active ingredients, the sterilization process research of this product was carried out. In the selection of sterilization process, we firstly use the sterilization process of F0≥12 for sterilization, and then conduct relevant research on F0≥8 or aseptic filtration process according to the quality change of the sample after sterilization.

[0088] According to the basic prescription process, a batch of samples were prepared, and the sterilization process was investigated. The properties of the samples before and after sterilization, solution clarity and color, visible foreign matter, pH value, content and related substances were tested. The prescription composition and preparation process are shown in Table 9, and the sample test results are shown in Table 10.

[0089] Table 9 Prescription composition and preparation

[0090]

[0091] Table 10 Sterilization process investigation results

[0092]

[0093]

[0094] Conclusion: The foreign matter, pH value, content and related substances in the samples after moist heat sterilization have changed significantly, indicating that the product has poor thermal stability and is not suitable for heat sterilization. The non-sterile samples, i.e. the samples after sterilization filtration, all indicators meet the quality standard requirements, so this product intends to use sterilization filtration technology to ensure that the sterility level of this product meets the requirements.

[0095] Test Example 6 Combination Effect of Other Vitamin D Compounds and Polyethylene Glycol-15-Hydroxystearate

[0096] In order to expand the API of the above preferred preparation, the applicant tried the solubility of various vitamin D substances in a similar polyethylene glycol-15-hydroxystearate aqueous solution system, and the results are as follows:

[0097] Table 10 Dissolution effect of other vitamin D compounds

[0098] Drug Name Initial dissolution Vitamin D2 The solution is too viscous to be injected into the solution. Vitamin D3 Good dissolution Calcitriol Dissolved generally Paricalcitol The solubility is average, and other co-solvents such as ethanol and propylene glycol are required.

[0099] Example 1 Preparation of Vitamin D3 Injection (1 ml: 2.5 mg, 100,000 units)

[0100] Heat 70g of polyethylene glycol-15-hydroxystearate to 50°C to melt, add 2.5g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 2.5mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the head space of each ampoule before sealing.

[0101] Example 2 Preparation of Vitamin D3 Injection (1 ml: 5 mg, 200,000 units)

[0102] Heat 150g of polyethylene glycol-15-hydroxystearate to 50°C to melt, add 5g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 5.0mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the head space of each ampoule before sealing.

[0103] Example 3 Preparation of Vitamin D3 Injection (1 ml: 7.5 mg, 300,000 units)

[0104] Heat 200g of polyethylene glycol-15-hydroxystearate to 50°C to melt, add 7.5g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 7.5mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce filtered nitrogen into the head space of each ampoule before sealing.

[0105] Example 4 Preparation of Vitamin D3 Injection (1 ml: 10 mg, 400,000 units)

[0106] Heat 300g of polyethylene glycol-15-hydroxystearate to 55°C for melting, add 10g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 10mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the top space of each ampoule before sealing.

[0107] Example 5 Preparation of Vitamin D3 Injection (1 ml: 15 mg, 600,000 units)

[0108] Heat 600g of polyethylene glycol-15-hydroxystearate to 50°C for melting, add 15g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 15mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the head space of each ampoule before sealing.

[0109] Example 6 Preparation of Vitamin D3 Injection (1 ml: 2.5 mg, 100,000 units)

[0110] Heat 90g of polyethylene glycol-15-hydroxystearate to 55°C to melt, add 2.5g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 2.5mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the head space of each ampoule before sealing.

[0111] Example 7 Preparation of Vitamin D3 Injection (1 ml: 5 mg, 200,000 units)

[0112] Heat 180g of polyethylene glycol-15-hydroxystearate to 50°C to melt, add 5g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 5.0mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the top space of each ampoule before sealing.

[0113] Example 8 Preparation of Vitamin D3 Injection (1 ml: 7.5 mg, 300,000 units)

[0114] Heat 250g of polyethylene glycol-15-hydroxystearate to 50°C to melt, add 7.5g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 7.5mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce filtered nitrogen into the head space of each ampoule before sealing.

[0115] Example 9 Preparation of Vitamin D3 Injection (1 ml: 10 mg, 400,000 units)

[0116] Heat 400g of polyethylene glycol-15-hydroxystearate to 50°C for melting, add 10g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 10mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the head space of each ampoule before sealing.

[0117] Example 10 Preparation of Vitamin D3 Injection (1 ml: 15 mg, 600,000 units)

[0118] Heat 650g of polyethylene glycol-15-hydroxystearate to 50°C for melting, add 15g of vitamin D3 to the adjusted polyethylene glycol-15-hydroxystearate to fully dissolve, stir and dissolve at 50-55°C to form a solution until the mixture is uniform and cool to room temperature. When the solution is cooled, cool the injection water of about 70°C with a prescription amount of 90% under nitrogen protection, add appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate to the cooling water, and check the pH value to 7.3-7.5; gently mix the cooled solution under nitrogen atmosphere and add it to the aqueous solution prepared above, and add enough injection water to the final volume to obtain an active ingredient concentration of 15mg / ml. Then filter the solution aseptically under nitrogen atmosphere, use 1ml brown glass ampoules, fill each bottle with 1ml of solution, and introduce the filtered nitrogen into the head space of each ampoule before sealing.

[0119] Certain embodiments of the present invention are described herein, including the best mode known to the inventor for carrying out the present invention. Of course, after reading the foregoing description, the changes in the embodiments described are obvious to those of ordinary skill in the art. The inventor hopes that those skilled in the art will use these changes appropriately, and the inventor hopes that the present invention will be implemented in a manner that is not specifically described herein. Therefore, the present invention includes all modifications and equivalent variations of the subject matter cited in the claims attached to the present invention as allowed by applicable law. In addition, unless otherwise specified or clearly conflicting with the context, the present invention will include all possible variations of any combination of the above elements. Finally, it should be understood that the embodiments of the present invention disclosed herein are exemplary illustrations of the principles of the present invention. Other modifications that can be used are within the scope of the present invention. Therefore, by way of example, but in a non-restrictive manner, the optional configuration of the present invention can be utilized according to the teachings herein. Therefore, the present invention is not limited to the content clearly shown and described.

Claims

1. A vitamin D3 liquid composition, characterized in that: The vitamin D3 liquid composition is an aqueous solution; the vitamin D3 liquid composition includes vitamin D3 and polyethylene glycol-15-hydroxystearate; the vitamin D3 liquid composition only uses polyethylene glycol-15-hydroxystearate as a solubilizer; the vitamin D3 liquid composition does not contain ethanol, propylene glycol, polyethylene glycol, poloxamer and polyvinyl pyrrolidone; The vitamin D3 liquid composition comprises 1-15 mg / mL of vitamin D3; The vitamin D3 liquid composition comprises 150-250 mg / mL of polyethylene glycol-15-hydroxystearate; The pH value of the vitamin D3 liquid composition is 7.0-7.

4.

2. The liquid vitamin D3 composition according to claim 1, comprising 200 mg / mL of polyethylene glycol-15-hydroxystearate.

3. The liquid vitamin D3 composition according to claim 1, further comprising sodium chloride.

4. The liquid vitamin D3 composition according to claim 3, comprising sodium chloride that can provide an osmotic pressure isotonic with blood or body fluids.

5. The liquid vitamin D3 composition according to claim 1, comprising 2.5-15 mg / mL of vitamin D3.

6. The vitamin D3 liquid composition according to claim 1, which is an oral solution or an injection solution.

7. The liquid vitamin D3 composition according to any one of claims 1 to 6, further comprising a pH adjuster.

8. The vitamin D3 liquid composition according to claim 7, wherein the pH adjuster is sodium dihydrogen phosphate and sodium citrate.

9. The vitamin D3 liquid composition according to claim 7, wherein the pH adjuster is sodium dihydrogen phosphate hydrate and sodium citrate hydrate.

10. The vitamin D3 liquid composition according to claim 1, wherein the pH value of the vitamin D3 liquid composition is 7.2-7.

4.

11. A method for preparing a liquid vitamin D3 composition according to any one of claims 7 to 9, comprising the following steps: Under nitrogen protection, the prescribed amount of polyethylene glycol-15-hydroxystearate is heated until it melts, and vitamin D3 is added to the heated polyethylene glycol-15-hydroxystearate to dissolve and obtain a vitamin D3 solution; the prescribed amount of sodium chloride and a pH adjuster are added to 80-95% of the prescribed amount of water for injection at 60-80°C to obtain an aqueous solution; the cooled vitamin D3 solution is added to the aqueous solution under a nitrogen atmosphere, and the remaining water for injection is added.

12. The preparation method according to claim 11, further comprising sterilization and perfusion steps. The preparation method according to claim 12 , wherein the sterilization is filtration sterilization.

14. Use of the vitamin D3 liquid composition according to any one of claims 1 to 10 in the preparation of a medicament for preventing or treating vitamin D deficiency.

15. The use according to claim 14, wherein the vitamin D deficiency is chronic hypocalcemia, hypophosphatemia, rickets, osteomalacia associated with chronic renal insufficiency, hypoparathyroidism, postoperative tetany or idiopathic tetany.

16. The use according to claim 15, wherein the hypophosphatemia is familial hypophosphatemia.

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