Vitamin d3 injection liquid drug composition and use thereof

Abstract

The present application provides a vitamin D3 liquid composition, which comprises vitamin D3 and polyethylene glycol-15-hydroxystearate. The pH value of the vitamin D3 liquid composition is 7.1-7.6. The vitamin D3 liquid composition does not comprise ethanol, propylene glycol, polyethylene glycol, poloxamer, or polyvinylpyrrolidone. The aqueous solution composition of the present invention is stable and uniform, is more suitable for injection than oil solutions, and can be used for preventing and treating vitamin D deficiency.

Description

Vitamin D3 injection drug composition and use thereof Field of the invention:

[0001] The present application belongs to the field of medicaments, and specifically, the present application provides a vitamin D3 injection drug composition and use thereof. BACKGROUND

[0002] Vitamin D3 (cholecalciferol) is mainly synthesized by the human body, and the skin of the human body contains a kind of cholesterols, which becomes vitamin D3 after being irradiated by sunlight. Therefore, if children can fully receive sunlight for more than 4-6 hours, the self-synthesized vitamin D3 can basically meet the needs. However, due to the problems such as the increase of skin cancer caused by ultraviolet radiation, air pollution, and weather changes in different regions, the time for people in various countries to receive sunlight is decreasing, and many countries have explicitly stipulated to limit the time for receiving sunlight, so the phenomenon of widespread vitamin D deficiency exists in the whole world. Vitamin D3 exists mainly in a small number of animal foods, and is formed by 7-dehydrocholesterol in the skin after being irradiated by ultraviolet rays, and 7-dehydrocholesterol is generated by the transformation of cholesterols, so it is called sun vitamin.

[0003] Vitamin D3 [9,10-secocholesta-5,7,10(19)-triene-3beta-ol] is one of the important vitamins necessary for the normal growth and reproduction of human health, livestock and poultry, and is clinically used for the treatment of rickets, osteoporosis in the elderly, and hypothyroidism, etc.

[0004] Vitamin D3 is lipophilic, i.e. only a small amount or negligible water-soluble. The poor water-solubility of vitamin D3 leads to significant difficulties in injection administration, especially when a sterile and easily manageable homogeneous aqueous solution is required. Therefore, the production of vitamin D3 solution involves many problems caused by 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 can produce adverse degradation products.

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

[0006] Vitamin D3 is used to supplement the deficiency of vitamin D, which can effectively increase the concentration of calcidiol in the blood, and is clinically used as an oral preparation or an injection (especially a muscle injection).

[0007] Commercially available vitamin D3 muscle injection (for example, 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 contains 100,000 to 300,000 IU of vitamin D3. Muscle injection is particularly useful for non-elderly patients, patients with vitamin D deficiency and impaired glucose tolerance, patients with reduced digestive function, patients who have undergone gastrectomy or cholecystectomy, and other patients who are not easy to take orally. The currently clinically used vitamin D3 injection is a yellow clear oily liquid, which is only suitable for intramuscular injection. The injection has a large pain response, is highly irritating, is prone to allergies, and can easily cause drug accumulation in local muscle tissue, causing lump pain, which is very inconvenient for patients, especially long-term users, and brings inconvenience to clinical use, which seriously limits clinical use. Vitamin D3 and its metabolites have very strong lipophilicity, slow metabolism in the body, long half-life, and can be detected in the blood even after taking for several months, and are very important for heat, light, oxidation and stability.

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

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

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

[0011] The vitamin D3 in the composition exists in a solubilized form, which is dissolved by micellization or complexation.

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

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

[0014] Further, the vitamin D3 liquid composition further comprises sodium chloride, preferably sodium chloride to provide an osmotic pressure equivalent to that of blood or body fluids.

[0015] Further, the vitamin D3 liquid composition further comprises a preservative.

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

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

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

[0019] Further, the vitamin D3 liquid composition further comprises a pH adjuster, preferably sodium phosphate monobasic and sodium citrate.

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

[0021] Further, 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 or injection, and various hydrate forms can be used, and the required amount of various hydrates can be calculated by a person skilled in the art according to a reference book and molecular weight.

[0023] In another aspect, the present application provides a method for preparing a vitamin D3 liquid composition, the method comprising the following steps:

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

[0025] Further, the method further comprises a sterilization and filling step; preferably using filtration for sterilization.

[0026] Further, the pH adjusting agent is preferably sodium phosphate monobasic monohydrate and sodium citrate dihydrate.

[0027] In another aspect, the present application provides use of the above-mentioned vitamin D3 liquid composition in the preparation of a medicament for preventing or treating vitamin D deficiency.

[0028] In another aspect, 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] Further, 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 administration dose, frequency and time can be determined by the administrator according to the gender, condition, weight, age and other factors of the subject, and relevant treatment standards.

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

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

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

[0035] Polyethylene glycol-15-hydroxystearate (monograph name, European Pharmacopoeia), trade name is HS15 is a non-ionic injection solution solvent consisting of mono- and di-esters of 12-hydroxystearic acid and polyethylene glycol (15 moles of ethylene oxide and 1 mole of 12-hydroxystearic acid) and about 30% of free polyethylene glycol (hydrophilic fraction). Polyethylene glycol-15-hydroxystearate dissolves in water, ethanol and 2-propanol to form a clear solution; solubility in water decreases at high temperatures. Polyethylene glycol-15-hydroxystearate has a high chemical stability. However, after prolonged heating it can physically separate into a liquid and a solid phase. This can be reversed by subsequent homogenization. Aqueous solutions of polyethylene glycol-15-hydroxystearate can be autoclaved at 121 °C. During this process the pH value can decrease slightly and even phase separation can occur. The latter can be reversed by shaking the hot solution. Aqueous solutions of polyethylene glycol-15-hydroxystearate can be stabilized by the addition of preservatives commonly used in pharmaceuticals. Polyethylene glycol-15-hydroxystearate also has a good solubilizing capacity, autoclave resistance and good stability in aqueous solution, as well as a good toxicity profile, e.g. 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 a pharmaceutical preparation, in particular for intravenous administration, comprising a lipophilic vitamin D3 as active ingredient, which overcomes the limitations of many known methods, in particular the limitations of methods using organic solvents and oily bases. The object of the present invention is also to provide an improved vitamin D3 preparation which has chemical and physical stability under long-term storage and which is suitable for parenteral administration, in particular for intravenous administration, and can also be administered orally. The preparation should be diluted with an aqueous infusion solution at physiological pH.

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

[0038] The present invention overcomes the problem of poor solubility of vitamin D3 by adding a third compound or mixture of compounds to increase the solubility of vitamin D3 in water, wherein the vitamin D3 is present in solubilized form, while the vitamin D3 is solubilized by micellization or complexation to form an aqueous solution. Furthermore, the amount of non-ionic solubilizer polyethylene glycol-15-hydroxystearate is particularly preferred to be 150 mg to 250 mg per ml. Generally, the diluted, stable, sterile, non-pyrogenic aqueous solution contains 1 to 15 mg of vitamin D3 per ml, and by using a biocompatible buffer, preferably a combination of sodium phosphate monobasic hydrate and sodium citrate hydrate, the sodium phosphate monobasic and sodium citrate maintain the solution at a pH of 7.1 to 7.6, preferably 7.2 to 7.5, and the solution is isotonic by using sodium chloride. The careful control of the pH of the solution using the appropriate buffer system is essential to the practice of the present invention. The present invention does not use an effective antioxidant and chelating agent, but only uses an inert atmosphere of nitrogen gas against oxidation,

[0039] In a preferred embodiment of the present invention, the stable, aqueous, diluted, sterile solution of vitamin D3 for parenteral administration, such as intramuscular injection, intravenous injection, intravenous infusion or oral administration is provided in unit doses of 1 ml, 2 ml, 3 ml, 4 ml, 5 ml in a glass or plastic ampoule of amber brown color, the headspace of which is filled with an inert atmosphere, such as nitrogen gas.

[0040] To prepare the solution of the present invention, the following steps are used: under nitrogen protection, polyethylene glycol-15-hydroxystearate is adjusted to a temperature of 40 to 60 °C in a container equipped with a stirrer, vitamin D3 is added to the adjusted polyethylene glycol-15-hydroxystearate to dissolve completely, the solution is stirred at a temperature of 40 to 60 °C until the mixture is homogeneous and cooled to room temperature, while the solution is cooling, the prescribed amount of 90% of about 70 °C water for injection is cooled under nitrogen protection, the appropriate amount of sodium chloride, sodium phosphate monobasic hydrate and sodium citrate hydrate is added to the cooled water, and the pH is checked; the cooled solution is added to the above prepared aqueous solution under gentle mixing under a nitrogen atmosphere, and enough water for injection is added to the final volume, then the solution is sterile filtered under a nitrogen atmosphere, filled into each glass or plastic ampoule, and before sealing, filtered nitrogen is introduced into the headspace of each ampoule.

[0041] The present invention also relates to a pharmaceutical composition in the form of an injection or infusion solution of vitamin D3 for the prophylaxis 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 pseudoparathyroidism), as well as for the treatment of acute, chronic and latent postoperative tetany and idiopathic tetany. Detailed Implementation

[0042] To achieve the objectives of this invention, it has undergone several research stages, including the establishment of a solubilizing and dissolving system, impurity control experiments, low-temperature crystallization experiments, stability experiments, irritation experiments, hemolytic experiments, and in vivo pharmaceutical behavior evaluation. The invention was completed by achieving multiple stage objectives. The following detailed description of the invention is based on specific embodiments in conjunction with the implementation stages of the invention, but this does not limit the invention to the scope of the embodiments described.

[0043] Experimental Example 1: Establishment of an Effective Solubilizing and Dissolving System

[0044] Because APIs have poor solubility in water, in order to ensure the development of subsequent formulation process parameters, we conduct screening studies on excipients in the formulation. The aim is to screen out suitable solubilizers / co-solvents to increase the solubility of APIs and make them completely dissolved in the formulation.

[0045] Commonly used solubilizers / co-solvents in injections were selected, such as polyethylene glycol-15-hydroxystearate, Tween 80, lecithin, poloxamer 188, ethanol, propylene glycol, polyethylene glycol 400, and hydroxypropyl betacyclodextrin. Each excipient was added in the usual amount. According to the proposed formulation, each excipient was weighed into a suitable container, water was added to the total amount of the formulation, and the mixture was stirred until completely dissolved. Then, the prescribed amount of vitamin D3 was added and stirred until dissolved. During the experiment, the dissolution of vitamin D3 and the properties of the drug solution were observed. The formulation composition is shown in Table 1, and the experimental results are shown in Table 2.

[0046] Table 1 Prescription Composition

[0047] Table 2. Screening Results of Amount of Each Auxiliary Material

[0048] Conclusion: The above experimental phenomena and results indicate that among the excipients, polyethylene glycol-15-hydroxystearate (PEG-15-hydroxystearate) has a significant solubilizing / co-solubilizing effect, and lecithin also has a relatively significant solubilizing / co-solubilizing effect. However, the precipitation of the active pharmaceutical ingredient (API) in the later stages may indicate that its formulation concentration is too low. Based on the experimental results, PEG-15-hydroxystearate is selected as the preferred solubilizer / co-solubilizer in this product formulation, and a reasonable dosage will be further screened.

[0049] Experimental Example 2: Investigation and Optimization of the Dosage of Polyethylene Glycol-15-Hydroxystearate

[0050] According to the screening result of the adjuvant category, the different prescription amount of polyethylene glycol-15-hydroxystearate was designed on the basis of prescription 1 to prepare the sample, the amount of polyethylene glycol-15-hydroxystearate was optimized, and the dissolution time, dissolution phenomenon, drug liquid properties, pH value and content of each prescription were focused on during the test. The prescription composition and test results are shown in Table 3.

[0051] Table 3: Investigation results of the amount of polyethylene glycol-15-hydroxystearate

[0052] The amount of polyethylene glycol-15-hydroxystearate in the above prescription is in the range of 10% to 50%. From the test results, when the amount of polyethylene glycol-15-hydroxystearate is ≤10%, the API cannot be completely dissolved, when the amount of polyethylene glycol-15-hydroxystearate is ≥20%, the API is completely dissolved, and the dissolution time decreases with the increase of the concentration, and the pH value increases. According to the test results, the amount of polyethylene glycol-15-hydroxystearate is further optimized to 15% to 25%, and the prescription is prepared. The optimized results are shown in Table 4.

[0053] Table 4: Optimization results of the amount of polyethylene glycol-15-hydroxystearate

[0054] The results analysis shows that when the amount 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 that of the 20% prescription amount. When the amount reaches 25% (i.e. 250 mg / ml), the API dissolution time has no significant difference with that of 20%, and the pH value has no obvious change. The content determination results are basically consistent with the API feed amount.

[0055] According to the screening and optimization results of the amount of polyethylene glycol-15-hydroxystearate, the amount of polyethylene glycol-15-hydroxystearate in the prescription is in the range of 150 mg to 250 mg / ml, which can completely dissolve the API. From the results, there is no significant difference in the API dissolution time between prescription 10 and prescription 15. Considering the safety of clinical medication and the operability of production process, the amount of polyethylene glycol-15-hydroxystearate in prescription 10 is selected as the prescription amount.

[0056] Test example 3: pH value of drug liquid

[0057] Preliminary screening of the pH value range of drug liquid

[0058] To investigate the stability of the drug solution in a certain pH range, the pH range of the drug solution was screened. A batch of drug solution was prepared based on the prescription 10, and the pH value of the drug solution was 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 adjustment, 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 drug solution properties, clarity and color, visible foreign matter, pH, content, and related substances. During the pH adjustment process, it was found that when the pH value of the drug solution was less than 5, the properties of the drug solution changed, and the drug solution had flocculation after adding more acidic adjuster, indicating that too low 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 to a slight yellow. Therefore, the pH range of this test was determined to be between 5.0 and 8.0, and the test results are shown in Table 5.

[0059] Table 5 Preliminary screening results of drug solution pH range

[0060] The results analysis showed that when the pH of the drug solution was less than 7, the changes of 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, but the drug solution at pH 8.0 changed after 24 hours compared with 0 hours, so the pH control range of the drug solution needed to be further narrowed.

[0061] Optimization of drug solution pH range

[0062] Based on prescription 10, a batch of drug solution was prepared, and the drug solution was adjusted to about 7.2, 7.4, 7.6, and 7.8 using 0.1 mol / L sodium hydroxide solution. The amount of adjuster was recorded during the adjustment process, and the adjusted 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 drug solution properties, clarity and color, visible foreign matter, pH, content, and related substances. The test results are shown in Table 6.

[0063] Table 6 Optimization test results of drug solution pH range

[0064] Test conclusion: The optimization test results showed that when the pH range of the drug solution was between 7.1 and 7.6, there was no obvious change trend in various indicators, indicating that maintaining the pH of the drug solution in this range could stabilize the quality. According to the above test results, the pH range of the drug solution of this product was determined to be 7.1-7.6.

[0065] Test Example 4: Nitrogen Filling Process Investigation

[0066] To ensure the stability of product quality, we carried out the stability study of liquid filling with nitrogen. According to the basic prescription composition, a batch of liquid was prepared, and the liquid was divided into two parts, one of which was not filled with nitrogen and placed at room temperature, and the remaining one was continuously filled with nitrogen. Both samples were investigated for 24 hours, and samples were taken at 0, 2, 4, 8 and 24 hours, respectively, to detect the properties, solution clarity and color, pH value, related substances and content of the samples. The test results are shown in Tables 7 and 8.

[0067] Table 7 Nitrogen Filling Test Investigation Results (1)

[0068] Table 8 Nitrogen Filling Test Investigation Results (2)

[0069] Conclusion: Compared with the nitrogen-filled liquid, the non-nitrogen-filled liquid had slight changes in solution clarity and color, slight increase in total impurities, and no significant changes in other indicators, indicating that the stability of the nitrogen-filled liquid was more stable than the non-nitrogen-filled liquid. Therefore, it is determined that the product needs to be filled with nitrogen in production to ensure sample stability.

[0070] Test Example 5: Sterilization Process Investigation

[0071] According to the relevant technical requirements in the "Guidelines for Sterilization and Aseptic Process Research and Validation of Chemical Drug Injection (Trial)", combined with the characteristics of the dosage form and the physicochemical properties of the active ingredients, the sterilization process research of the product was carried out. In the selection of sterilization process, we first selected F0≥12 sterilization process for sterilization, and then carried out related research on F0≥8 or sterile filtration process according to the quality changes of the sample after sterilization.

[0072] According to the basic prescription process, a batch of samples was prepared for sterilization process investigation, and the properties, solution clarity and color, visible foreign matter, pH value, content and related substances of the samples before and after sterilization were detected. The prescription composition and preparation process are shown in Table 9, and the sample test results are shown in Table 10.

[0073] Table 9 Prescription Composition and Preparation

[0074] Table 10 Sterilization Process Investigation Results

[0075] Conclusion: The foreign matter, pH value, content and related substances of the sample after moist heat sterilization changed significantly, indicating that the product has poor heat stability and is not suitable for heating sterilization process. The unsterilized sample, i.e. the sample after sterile filtration, meets the requirements of the quality standards, so the product is intended to use sterile filtration process to ensure that the sterile level meets the requirements.

[0076] Test Example 6 Combination effect of other vitamin D compounds with polyethylene glycol-15-hydroxystearate

[0077] To expand the API of the above preferred preparation, the applicant tried the solubility of various vitamin D substances in the polyethylene glycol-15-hydroxystearate aqueous solution system, and the results are as follows:

[0078] Table 10 Solubility effect of other vitamin D compounds

[0079] Example 1 Preparation of vitamin D3 injection (1 ml: 2.5 mg, 100,000 units)

[0080] 70 g of polyethylene glycol-15-hydroxystearate was heated to adjust the temperature to 50°C, 2.5 g of vitamin D3 was added to the adjusted polyethylene glycol-15-hydroxystearate and dissolved thoroughly, and the mixture was stirred and dissolved at a temperature of 50-55°C to form a solution, and then cooled to room temperature. When the solution was cooled, 90% of the prescribed amount of water for injection at about 70°C was cooled under nitrogen protection, and an appropriate amount of sodium chloride, sodium dihydrogen phosphate hydrate and sodium citrate hydrate was added to the cooled water, and the pH value was checked to be 7.3-7.5; the cooled solution was gently mixed and added to the above prepared aqueous solution under a nitrogen atmosphere, and enough water for injection was added to the final volume to obtain an active ingredient concentration of 2.5 mg / ml. Then the solution was sterile filtered under a nitrogen atmosphere, and 1 ml of brown glass ampoule was filled with 1 ml of solution, and before sealing, filtered nitrogen was introduced into the headspace of each ampoule to obtain the product.

[0081] Example 2 Preparation of vitamin D3 injection (1 ml: 5 mg, 200,000 units)

[0082] Example 1 Preparation of Vitamin D3 Injection (1 ml : 2.5 mg, 10 million units)

[0083] Example 3 Preparation of Vitamin D3 Injection (1 ml : 7.5 mg, 300 thousand units)

[0084] Example 3 Preparation of Vitamin D3 Injection (1 ml : 7.5 mg, 300 thousand units)

[0085] Example 4 Preparation of Vitamin D3 Injection (1 ml : 10 mg, 400 thousand units)

[0086] 300g of polyethylene glycol-15-hydroxystearate was melted by heating to 55°C. 10g of vitamin D3 was added to the melted polyethylene glycol-15-hydroxystearate and dissolved completely. The mixture was stirred at 50-55°C until homogeneous and then cooled to room temperature. While the solution was cooling, approximately 90% of the prescribed amount of water for injection at 70°C was cooled under nitrogen protection. Appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate, and sodium citrate hydrate were added to the cooling water, and the pH was checked to 7.3-7.5. The cooled solution was gently mixed and added to the prepared aqueous solution under a nitrogen atmosphere, and sufficient water for injection was added to the final volume to obtain an active ingredient concentration of 10mg / ml. The solution was then aseptically filtered under a nitrogen atmosphere and 1ml of the solution was filled into 1ml amber glass ampoules. Before sealing, the filtered nitrogen gas was introduced into the top space of each ampoule.

[0087] Example 5: Preparation of Vitamin D3 Injection (1 ml: 15 mg, 600,000 units)

[0088] 600g of polyethylene glycol-15-hydroxystearate was melted by heating to 50°C. 15g of vitamin D3 was added to the melted polyethylene glycol-15-hydroxystearate and dissolved completely. The solution was stirred at 50-55°C until homogeneous and then cooled to room temperature. While the solution was cooling, approximately 90% of the prescribed amount of water for injection at 70°C was cooled under nitrogen protection. Appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate, and sodium citrate hydrate were added to the cooling water, and the pH was checked to 7.3-7.5. The cooled solution was gently mixed and added to the prepared aqueous solution under a nitrogen atmosphere, and sufficient water for injection was added to the final volume to obtain an active ingredient concentration of 15mg / ml. The solution was then aseptically filtered under a nitrogen atmosphere and 1ml of the solution was filled into 1ml amber glass ampoules. Before sealing, the filtered nitrogen gas was introduced into the top space of each ampoule.

[0089] Example 6: Preparation of Vitamin D3 Injection (1 ml: 2.5 mg, 100,000 units)

[0090] Example 1 Preparation of Vitamin D3 Injection (1 ml : 2.5 mg, 100,000 units)

[0091] Example 7 Preparation of Vitamin D3 Injection (1 ml : 5 mg, 200,000 units)

[0092] Example 7 Preparation of Vitamin D3 Injection (1 ml : 5 mg, 200,000 units)

[0093] Example 8 Preparation of Vitamin D3 Injection (1 ml : 7.5 mg, 300,000 units)

[0094] 250g of polyethylene glycol-15-hydroxystearate was melted by heating to 50°C. 7.5g of vitamin D3 was added to the melted polyethylene glycol-15-hydroxystearate and dissolved completely. The solution was stirred at 50-55°C until homogeneous and then cooled to room temperature. While the solution was cooling, approximately 90% of the prescribed amount of water for injection at 70°C was cooled under nitrogen protection. Appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate, and sodium citrate hydrate were added to the cooling water, and the pH was checked to 7.3-7.5. The cooled solution was gently mixed and added to the prepared aqueous solution under a nitrogen atmosphere, and sufficient water for injection was added to the final volume to obtain an active ingredient concentration of 7.5mg / ml. The solution was then aseptically filtered under a nitrogen atmosphere and 1ml of the solution was filled into 1ml amber glass ampoules. Before sealing, the filtered nitrogen gas was introduced into the top space of each ampoule.

[0095] Example 9: Preparation of Vitamin D3 Injection (1 ml: 10 mg, 400,000 units)

[0096] 400g of polyethylene glycol-15-hydroxystearate was melted by heating to 50°C. 10g of vitamin D3 was added to the melted polyethylene glycol-15-hydroxystearate and dissolved completely. The mixture was stirred at 50-55°C until homogeneous and then cooled to room temperature. While the solution was cooling, approximately 90% of the prescribed amount of water for injection at 70°C was cooled under nitrogen protection. Appropriate amounts of sodium chloride, sodium dihydrogen phosphate hydrate, and sodium citrate hydrate were added to the cooling water, and the pH was checked to 7.3-7.5. The cooled solution was gently mixed and added to the prepared aqueous solution under a nitrogen atmosphere, and sufficient water for injection was added to the final volume to obtain an active ingredient concentration of 10mg / ml. The solution was then aseptically filtered under a nitrogen atmosphere and 1ml of the solution was filled into 1ml amber glass ampoules. Before sealing, the filtered nitrogen gas was introduced into the top space of each ampoule.

[0097] Example 10: Preparation of Vitamin D3 Injection (1 ml: 15 mg, 600,000 units)

[0098] 650 g of polyethylene glycol-15-hydroxystearate is melted by heating to a temperature of 50°C, 15 g of vitamin D3 is added to the adjusted polyethylene glycol-15-hydroxystearate and dissolved by stirring at a temperature of 50-55°C to form a solution until the mixture is uniform and cooled to room temperature. While the solution is cooling, a prescribed amount of 90% of water for injection at about 70°C is cooled under nitrogen, and an appropriate amount of sodium chloride, sodium phosphate monobasic hydrate and sodium citrate hydrate is added to the cooled water, and the pH is checked to be 7.3-7.5. The cooled solution is added to the above-prepared aqueous solution under a nitrogen atmosphere with gentle mixing, and an appropriate amount of water for injection is added to the final volume to obtain a concentration of 15 mg / ml of the active ingredient. Then the solution is sterile-filtered under a nitrogen atmosphere, and 1 ml of the solution is filled into each brown glass ampoule, and filtered nitrogen is introduced into the headspace of each ampoule before sealing to obtain the final product.

[0099] Certain embodiments of the present application are described herein, including the best mode known to the inventors for carrying out the application. Of course, modifications to the described embodiments will be readily apparent to those of ordinary skill in the art, having the benefit of this disclosure. The inventors expect skilled persons to employ such modifications in employing the application in its fullest scope. The inventors intend the application to embrace all such modifications and alterations as fall within the scope of the appended claims, permitted by applicable law. Additionally, unless otherwise specified, the application is intended to cover all combinations of the above-described elements, in any order and amount. Finally, it is to be understood that the application disclosed herein is merely exemplary of the principles of the application. Other modifications can be employed which fall within the scope of the application. Accordingly, the present application is not limited to that precisely as shown and described.

Claims

1. A vitamin D3 liquid composition, characterized in that, The vitamin D3 liquid composition comprises vitamin D3 and macrogol-15-hydroxystearate, and does not comprise ethanol, propylene glycol, polyethylene glycol, poloxamer or polyvinylpyrrolidone.

2. The vitamin D3 liquid composition according to claim 1, which is an aqueous solution.

3. The vitamin D3 liquid composition according to claim 1 or 2, which comprises 150-250 mg / mL of macrogol-15-hydroxystearate, preferably 200 mg / mL of macrogol-15-hydroxystearate.

4. The vitamin D3 liquid composition according to any one of claims 1-3, which further comprises sodium chloride, preferably sodium chloride that provides an osmotic pressure that is isotonic with blood or body fluids.

5. The vitamin D3 liquid composition according to any one of claims 1-4, which comprises 1-15 mg / mL of vitamin D3; preferably 2.5-15 mg / mL of vitamin D3.

6. The vitamin D3 liquid composition according to any one of claims 1-5, which is an oral solution or an injection solution.

7. The vitamin D3 liquid composition according to any one of claims 1-6, which further comprises a pH adjuster, preferably sodium phosphate monobasic and sodium citrate; and has a pH of 6.8-7.8, preferably a pH of 7.1-7.6, and more preferably a pH of 7.2-7.

5.

8. A method for preparing the vitamin D3 liquid composition according to any one of claims 1-7, which comprises the following steps: heating a prescribed amount of macrogol-15-hydroxystearate to melt under nitrogen protection, dissolving vitamin D3 in the heated macrogol-15-hydroxystearate to obtain a vitamin D3 solution; adding a prescribed amount of sodium chloride and a pH adjuster to a prescribed amount of 80-95% of 60-80°C water for injection to obtain an aqueous solution; adding the cooled vitamin D3 solution to the aqueous solution under nitrogen atmosphere, and adding the remaining water for injection, and further comprising sterilization and filling steps; preferably using filtration for sterilization, and further preferably the pH adjuster is sodium phosphate monobasic hydrate and sodium citrate hydrate.

9. Use of the vitamin D3 liquid composition according to any one of claims 1-7 in the preparation of a medicament for preventing or treating vitamin D deficiency, preferably the vitamin D deficiency is chronic hypocalcemia, hypophosphatemia, rickets, osteomalacia with chronic renal insufficiency, familial hypophosphatemia, hypoparathyroidism, postoperative tetany, idiopathic tetany.

10. A method of treating vitamin D deficiency, characterized in that, The method comprises the step of administering the above vitamin D3 liquid composition to a subject suffering from vitamin D deficiency.

11. The method according to claim 10, wherein the subject is a human or an animal, preferably a human.

12. The method according to claim 10 or 11, wherein the single administration dose of the vitamin D3 liquid composition administered is between 2.5 mg and 60 mg of vitamin D3.

13. The method according to any one of claims 10 to 12, wherein the administration is oral or injection administration, preferably injection administration.

14. The method according to any one of claims 10 to 13, wherein the vitamin D deficiency is chronic hypocalcemia, hypophosphatemia, rickets, osteomalacia with chronic renal insufficiency, familial hypophosphatemia, hypoparathyroidism, postoperative tetany, idiopathic tetany.

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