A highly stable vitamin D3 granule and its preparation method

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a highly stable vitamin D3 granule and its preparation method. The preparation method of vitamin D3 granules provided by this invention includes: (1) mixing vitamin D3 and an oil phase solvent to obtain an oil phase; (2) mixing an emulsifier, a film-forming agent, a thickener, and water to obtain an aqueous phase; (3) mixing the oil phase and the aqueous phase, shearing, and homogenizing to obtain a vitamin D3 emulsion; and (4) spray drying to obtain vitamin D3 granules. The viscosity of the vitamin D3 emulsion is 350-400.9 mPa·s. In the spray drying, the feed rate of the vitamin D3 emulsion is 160-180 mL / h. This preparation method is simple, low in cost, and easy to industrialize. The obtained vitamin D3 granules have uniform particle size, good content uniformity, and controllable specifications.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a highly stable vitamin D3 granule and its preparation method. Background Technology

[0002] Vitamin D3, also known as cholecalciferol, is formed in the human body from 7-dehydrocholesterol under ultraviolet radiation and is the most bioavailable active form of the vitamin D family. As an essential fat-soluble vitamin, vitamin D3 is present in relatively small amounts in natural foods and is primarily synthesized by the body under natural light. However, in recent years, changes in lifestyle have led to insufficient ultraviolet radiation exposure, resulting in a growing problem of vitamin D3 deficiency. Vitamin D3 is chemically unstable and easily degrades upon exposure to light, heat, and oxygen. Furthermore, the amount required by the human body is extremely low, necessitating very small amounts in formulations. Therefore, the development of vitamin D3 drug formulations faces technical challenges related to poor stability and uneven content. Currently, only one company has approved the marketing of vitamin D3 intermediate granules in China, with licensing fees reaching $700,000 to $1 million, severely limiting the development of this type of product in the country. In addition, the intermediate granules have a relatively large particle size, making them prone to stratification and uneven mixing when directly mixed with other excipients. Furthermore, pulverizing the intermediate granules would damage their structure and reduce their stability.

[0003] In recent years, there has been a continuous stream of domestic imitations of vitamin D3 intermediate granules, but most of these productions utilize large-scale equipment, resulting in high costs. Furthermore, the technology is immature, leading to poor improvements in vitamin D3 stability. Existing technologies provide preparation processes and apparatus for vitamin D3 microcapsule powder, but these involve long equipment routes and significant particle adhesion. Existing technologies also provide spray drying devices for vitamin microcapsules, which have high equipment requirements, significant energy consumption, and are not conducive to large-scale production. Moreover, existing methods for preparing vitamin D3 intermediate granules use mannitol as a carrier and fluidized bed spray drying. The high amount of mannitol carrier results in low drug content in the final granules, large dosage volumes, inconvenience for patients, and a higher risk of adverse reactions. The high static electricity of the mannitol carrier makes it prone to adhesion to the granulation walls, resulting in incomplete vitamin D3 intermediate granule structure and poor stability. Fluidized bed-prepared granules are loose and easily broken during granulation, leading to uneven particle size distribution. Ultimately, the resulting vitamin D3 intermediate granules have a short shelf life and poor stability. Summary of the Invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the defects of the existing technology, such as complex preparation process, short shelf life and poor stability of vitamin D3 granules, so as to provide a highly stable vitamin D3 granule and its preparation method.

[0005] To this end, the present invention provides the following technical solution.

[0006] This invention provides a method for preparing vitamin D3 granules, comprising:

[0007] (1) Mix vitamin D3 with an oil phase solvent to obtain an oil phase; (2) Mix emulsifier, film-forming agent, thickener and water to obtain an aqueous phase; (3) Mix the oil phase and aqueous phase, shear and homogenize to obtain a vitamin D3 emulsion; (4) Spray dry the vitamin D3 emulsion to obtain vitamin D3 granules.

[0008] The viscosity of the vitamin D3 emulsion is 350-400.9 mPa·s; in the spray drying process, the feed rate of the vitamin D3 emulsion is 160-180 mL / h.

[0009] The emulsifier includes at least one of gum arabic and gelatin; the oil phase solvent includes at least one of soybean oil, partially hydrogenated vegetable oil, and fully hydrogenated vegetable oil; the thickener includes at least one of sucrose and seaweed polysaccharide; and the film-forming agent includes maltodextrin.

[0010] The weight ratio of the emulsifier to the oil phase solvent is (10-25):(5-7.5);

[0011] The shearing time is 8-12 minutes, the shearing speed is 16000-19000 rpm, the homogenization is performed 8-12 times, and the homogenization pressure is 800-1000 bar.

[0012] In one optional embodiment, the inlet air temperature in the spray drying is 120-180°C.

[0013] In one alternative embodiment, step (1) further includes the addition of an antioxidant;

[0014] Preferably, the antioxidant includes at least one of propyl gallate, tert-butylhydroquinone, butylated hydroxytoluene, and DL-α-tocopherol;

[0015] More preferably, the antioxidant is DL-α-tocopherol.

[0016] In one optional embodiment, the weight ratio of vitamin D3, antioxidant, and oil phase solvent is (0.05-0.25):(0.2-0.6):(5-7.5);

[0017] In one optional embodiment, in step (2), the weight ratio of the emulsifier, film-forming agent, thickener and water is (10-25):(10-40):(10-50):(45-150);

[0018] In one alternative embodiment, the emulsifier is gum arabic;

[0019] In one alternative embodiment, the thickener is sucrose;

[0020] In one optional embodiment, the oil phase solvent is soybean oil;

[0021] In one optional embodiment, the spray drying process further includes the addition of a flow aid;

[0022] Preferably, the weight ratio of the emulsifier to the flow aid is (10-25):(0.25-5);

[0023] Preferably, the flow aid comprises silicon dioxide.

[0024] In one alternative implementation, the mixing step (1) is performed under light-protected conditions;

[0025] In one optional implementation, in step (1), the temperature of the mixing step is controlled to be 60-80°C;

[0026] In one optional implementation, in step (2), the temperature of the mixing step is controlled to be 60-80°C.

[0027] The present invention also provides a vitamin D3 granule prepared by the above preparation method.

[0028] The present invention also provides a formulation containing vitamin D3 granules, the formulation comprising vitamin D3 granules prepared by the above preparation method; preferably, the dosage form of the formulation is selected from tablets, capsules or granules.

[0029] The technical solution of this invention has the following advantages:

[0030] 1. The method for preparing vitamin D3 granules provided by the present invention includes: (1) mixing vitamin D3 and an oil phase solvent to obtain an oil phase; (2) mixing an emulsifier, a film-forming agent, a thickener, and water to obtain an aqueous phase; (3) mixing the oil phase and the aqueous phase, shearing, and homogenizing to obtain a vitamin D3 emulsion; (4) spray drying the vitamin D3 emulsion to obtain vitamin D3 granules; wherein the viscosity of the vitamin D3 emulsion is 350-400.9 mPa·s; and the feed rate of the vitamin D3 emulsion during spray drying is 160-180 mL / h; wherein the emulsifier... The mixture includes at least one of gum arabic and gelatin; the oil phase solvent includes at least one of soybean oil, partially hydrogenated vegetable oil, and fully hydrogenated vegetable oil; the thickener includes at least one of sucrose and seaweed polysaccharide; the film-forming agent includes maltodextrin; the weight ratio of the emulsifier to the oil phase solvent is (10-25):(5-7.5); the shearing time is 8-12 min, the shearing speed is 16000-19000 rpm; the homogenization is performed 8-12 times, and the homogenization pressure is 800-1000 bar. By employing a specific formulation and process, a stable emulsified vitamin D3 emulsion is obtained. By controlling the emulsion viscosity, the feed rate during spray drying, the shearing time and speed, and the homogenization pressure and number of times, vitamin D3 is thoroughly dried, resulting in vitamin D3 granules with intact structure, long shelf life, and high stability. This preparation method is simple, low-cost, and easy for industrial production; the obtained vitamin D3 granules have uniform particle size, good content uniformity, and controllable specifications.

[0031] 2. The method for preparing vitamin D3 intermediate particles provided by the present invention can significantly improve the high temperature stability, high humidity stability and strong light stability of the obtained vitamin D3 intermediate particles by adding a film-forming agent. Attached Figure Description

[0032] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0033] Figure 1 This is a diagram showing the results of destructive experiment 1 in Experiment Example 3 of this invention;

[0034] Figure 2 This is a diagram showing the results of destructive experiment 2 in Experiment Example 3 of this invention;

[0035] Figure 3 This is a diagram showing the results of destructive experiment 3 in Experiment Example 3 of this invention;

[0036] Figure 4 This is a diagram showing the results of destructive experiment 4 in Experiment Example 3 of this invention;

[0037] Figure 5 This is a diagram showing the results of destructive experiment 5 in Experiment Example 3 of this invention. Detailed Implementation

[0038] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0039] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0040] Experimental Example 1

[0041] This experimental example screens the formulation and process for preparing vitamin D3 emulsion.

[0042] 1. Types and dosages of emulsifiers

[0043] Using the type and amount of emulsifier as variables, the use of gum arabic, modified starch, gelatin, glyceryl monostearate, hydrolyzed gelatin, and tragacanth gum as emulsifiers and their amounts were investigated. The formulation parameters of formulations 1-9 are shown in Table 1. The preparation methods of each formulation are the same.

[0044] Table 1

[0045]

[0046] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0047] The preparation method is as follows: (1) Weigh vitamin D3 and DL-α-tocopherol into soybean oil according to Table 1, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0048] (2) Weigh the emulsifier, maltodextrin and sucrose into pure water according to Table 1, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0049] (3) Mix the oil phase and the water phase, cut and homogenize according to Table 1 to obtain vitamin D3 emulsion.

[0050] After standing at room temperature for 24 hours, the oil separation was observed. When gum arabic or gelatin was selected as the emulsifier to prepare the vitamin D3 emulsion, the physical stability of the vitamin D3 emulsion was better. Considering the lower cost of gum arabic, gum arabic was selected as the emulsifier in this invention. When the amount of gum arabic was 5g, the physical stability of the vitamin D3 emulsion was poor. When the amount of gum arabic was 10-25g, the physical stability of the vitamin D3 emulsion was better. For now, 10g of gum arabic was selected for further investigation.

[0051] 2. Types and amounts of oil phase solvents

[0052] Using the type and amount of oil phase solvent as variables, the use of soybean oil, corn oil, fully hydrogenated vegetable oil, partially hydrogenated vegetable oil, and medium-chain triglycerides as oil phase solvents and their amounts were investigated. The formulation parameters of formulations 10-16 are shown in Table 2, and the preparation methods of each formulation are the same.

[0053] Table 2

[0054]

[0055] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0056] The preparation method is as follows: (1) Weigh vitamin D3 and DL-α-tocopherol into the oil phase solvent according to Table 2, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0057] (2) Weigh out gum arabic, maltodextrin and sucrose according to Table 2 and add them to pure water. Heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0058] (3) Mix the oil phase and the water phase, cut according to Table 2, and homogenize to obtain vitamin D3 emulsion.

[0059] After standing at room temperature for 24 hours, the oil separation was observed. When soybean oil, partially hydrogenated vegetable oil, or fully hydrogenated vegetable oil was selected as the oil phase solvent to prepare the vitamin D3 emulsion, the physical stability of the vitamin D3 emulsion was better. Considering the influence of oxidation value, soybean oil was selected as the oil phase solvent in this invention. When the amount of soybean oil was 10g, the physical stability of the obtained vitamin D3 emulsion was poor. When the amount of soybean oil was 5-7.5g, the physical stability of the obtained vitamin D3 emulsion was better. For now, 5g of soybean oil was selected for further investigation.

[0060] 3. Types and dosages of thickeners

[0061] Using the type and amount of thickener as variables, we investigated the use of mannitol, seaweed polysaccharide, sucrose, carrageenan, and starch as thickeners and their amounts. The formulation parameters of formulations 17-23 are shown in Table 3. The preparation methods of each formulation are the same.

[0062] Table 3

[0063]

[0064]

[0065] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0066] The preparation method is as follows: (1) Weigh vitamin D3 and DL-α-tocopherol into soybean oil according to Table 3, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0067] (2) Weigh out gum arabic, maltodextrin and thickener according to Table 3 into pure water, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase;

[0068] (3) Mix the oil phase and the water phase, cut and homogenize according to Table 3 to obtain vitamin D3 emulsion.

[0069] After being left at room temperature for 24 hours, the oil separation was observed. When sucrose or seaweed polysaccharide was selected as a thickener to prepare vitamin D3 emulsion, the physical stability of vitamin D3 emulsion was better. In this invention, sucrose was selected as the thickener. When the amount of sucrose was 10-50g, the amount of thickener had no significant effect on the physical stability of the prepared vitamin D3 emulsion. Now, 10g of sucrose was selected for further investigation.

[0070] 4. Types and dosages of film-forming agents

[0071] Using the type and amount of film-forming agent as variables, we investigated maltodextrin, shellac, hydroxypropyl-β-cyclodextrin, and carrageenan as film-forming agents and their amounts. The formulation parameters of formulations 24-29 are shown in Table 4. The preparation methods of each formulation are the same.

[0072] Table 4

[0073]

[0074] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0075] The preparation method is as follows: (1) Weigh vitamin D3 and DL-α-tocopherol into soybean oil according to Table 4, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0076] (2) Weigh out gum arabic, film-forming agent and sucrose into pure water according to Table 4, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase;

[0077] (3) Mix the oil phase and the water phase, cut and homogenize according to Table 4 to obtain vitamin D3 emulsion.

[0078] After being left at room temperature for 24 hours, the oil separation was observed. When maltodextrin was selected as the film-forming agent to prepare the vitamin D3 emulsion, the vitamin D3 emulsion showed good physical stability and no oil separation was observed. In this invention, maltodextrin was selected as the film-forming agent. When the amount of maltodextrin was 5-40g, the amount of film-forming agent had no significant effect on the physical stability of the prepared vitamin D3 emulsion. Now, a maltodextrin amount of 10g was selected for further investigation.

[0079] 5. Types and dosages of antioxidants

[0080] Using the type and amount of antioxidants as variables, the formulation parameters of formulations 30-35 are shown in Table 5. The preparation methods of each formulation are the same.

[0081] Table 5

[0082]

[0083] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0084] The preparation method is as follows: (1) Weigh vitamin D3 and antioxidants into soybean oil according to Table 5, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0085] (2) Weigh out gum arabic, maltodextrin and sucrose into pure water according to Table 5, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0086] (3) Mix the oil phase and the water phase, cut and homogenize according to Table 5 to obtain vitamin D3 emulsion.

[0087] After being left at room temperature for 24 hours, the oil leaching was observed. The type of antioxidant had no significant effect on the physical stability of the vitamin D3 emulsion, and no oil leaching was observed. In this invention, DL-α-tocopherol was selected as the film-forming agent. When the dosage of DL-α-tocopherol was 0.2-0.6g, the dosage of DL-α-tocopherol had no significant effect on the physical stability of the prepared vitamin D3 emulsion. Now, a dosage of 0.2g of DL-α-tocopherol was selected for further investigation.

[0088] 6. Investigation on the dosage of aqueous phase

[0089] With the amount of aqueous phase as a variable, the formulation parameters of formulations 36-41 are shown in Table 6, and the preparation methods of each formulation are the same.

[0090] Table 6

[0091]

[0092]

[0093] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0094] The preparation method is as follows: (1) Weigh vitamin D3 and DL-α-tocopherol into soybean oil according to Table 6, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0095] (2) Weigh out gum arabic, maltodextrin and sucrose into pure water according to Table 6, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0096] (3) Mix the oil phase and the water phase, cut and homogenize according to Table 6 to obtain vitamin D3 emulsion.

[0097] After standing at room temperature for 24 hours, the oil leaching situation was observed. When the aqueous phase volume was 45-150 mL, the aqueous phase volume had no significant effect on the physical stability of the vitamin D3 emulsion, and no oil leaching was observed. When the aqueous phase volume was 42.5 mL, the homogenizer was blocked during emulsion preparation, which is not conducive to industrial production. Now, an aqueous phase volume of 150 mL is selected for further investigation.

[0098] 7. Examination of shearing time and shearing speed

[0099] With shearing time and shearing speed as variables, the formulation parameters for processes 1-6 are shown in Table 7, and the preparation methods are the same for each process.

[0100] Table 7

[0101]

[0102]

[0103] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0104] The preparation method is as follows: (1) Weigh vitamin D3 and DL-α-tocopherol into soybean oil according to Table 7, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0105] (2) Weigh out gum arabic, maltodextrin and sucrose into pure water according to Table 7, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0106] (3) Mix the oil phase and the water phase, and shear and homogenize according to process 1-6 in Table 7 to obtain vitamin D3 emulsion.

[0107] After standing at room temperature for 24 hours, the oil separation was observed. The vitamin D3 emulsion exhibited good physical stability when sheared for 10 minutes at a rotation speed of 16,000-19,000 rpm. Considering that excessively high shearing speeds might affect the lifespan of the shearing machine, a shearing speed of 16,000 rpm was selected for further investigation.

[0108] 8. Examination of the pressure and number of homogenization cycles.

[0109] With the homogenization pressure and the number of homogenization cycles as variables, the formulation parameters for processes 7-12 are shown in Table 8, and the preparation methods for each process are the same.

[0110] Table 8

[0111]

[0112] Note: "-" indicates that the emulsion does not have oil floating, "+" indicates that the emulsion has oil floating, and the more "+" signs there are, the more serious the oil floating is.

[0113] The preparation method is as follows: (1) Weigh vitamin D3 and DL-α-tocopherol into soybean oil according to Table 8, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase;

[0114] (2) Weigh out gum arabic, maltodextrin and sucrose into pure water according to Table 8, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0115] (3) Mix the oil phase and the water phase, shear, and homogenize according to process 7-12 in Table 8 to obtain vitamin D3 emulsion.

[0116] After standing at room temperature for 24 hours, the oil separation was observed. Homogenization was performed 10 times, and the physical stability of the vitamin D3 emulsion was good when the homogenization pressure was 800-1000 bar. Considering that excessive homogenization pressure may affect the service life of the homogenizer, a homogenization pressure of 800 bar was selected for further investigation.

[0117] 9. Optimal formulation and process for vitamin D3 emulsion

[0118] In summary, the following preferred formulations and processes for preparing vitamin D3 emulsions are further investigated, and the specific parameters are shown in Table 9.

[0119] Table 9

[0120]

[0121] Examples 1-2 and Comparative Examples 1-2

[0122] Example 1 provides a method for preparing vitamin D3 intermediate granules, comprising the following steps:

[0123] (1) Weigh vitamin D3 and DL-α-tocopherol into soybean oil according to Table 10, protect from light, heat in a water bath at 60°C, and stir until completely dissolved to obtain the oil phase.

[0124] (2) Weigh out gum arabic, maltodextrin and sucrose into pure water according to Table 10, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0125] (3) Mix the oil phase and the water phase, shear at 16000 rpm for 10 min to obtain the colostrum, and homogenize at 800 bar 10 times; control the particle size of the vitamin D3 emulsion to 200 nm to obtain the vitamin D3 emulsion.

[0126] (4) The emulsion is added to the feed inlet of the spray dryer using a peristaltic pump. The spray drying parameters are: inlet air temperature 140℃, and peristaltic liquid velocity 180mL / h. Spraying begins after the temperature reaches the set value, and the material is collected after spraying ends.

[0127] (5) The spray-dried product from step (4) was mixed with 1.5g of silica to obtain vitamin D3 intermediate particles (referred to as sample 3).

[0128] Table 10

[0129]

[0130] Comparative Example 1, Comparative Example 2, and Example 2 each provide a method for preparing vitamin D3 granules. Compared with Example 1, the only difference is that the prescription parameters are different. The vitamin D3 granules are prepared according to the prescription parameters in Samples 1, 2, and 4 in Table 10, respectively.

[0131] Comparative Examples 3-4 and Example 3

[0132] Comparative Example 3 provides a method for preparing vitamin D3 intermediate granules, comprising the following steps:

[0133] (1) Weigh out vitamin D3 and DL-α-tocopherol according to Table 11 and add them to soybean oil. Protect from light and heat in a water bath at 60°C. Stir until completely dissolved to obtain the oil phase.

[0134] (2) Weigh out gum arabic, maltodextrin and sucrose into pure water according to Table 11, heat in a water bath at 60°C and stir until completely dissolved to obtain the aqueous phase.

[0135] (3) Mix the oil phase and the water phase, shear at 16000 rpm for 10 min to obtain the colostrum, and homogenize at 800 bar 10 times; control the particle size of the vitamin D3 emulsion to 200 nm to obtain the vitamin D3 emulsion.

[0136] (4) The emulsion is added to the feed inlet of the spray dryer using a peristaltic pump. The spray drying parameters are: inlet air temperature 140℃, and peristaltic liquid velocity 180mL / h. Spraying begins after the temperature reaches the set value, and the material is collected after spraying ends.

[0137] (5) The spray-dried product from step (4) was mixed with 1.5g of silica to obtain vitamin D3 intermediate particles.

[0138] Table 11

[0139]

[0140] Comparative Example 4 and Example 3 respectively provide a method for preparing vitamin D3 intermediate granules. The only difference between them and Comparative Example 3 is that the prescription parameters are different. The vitamin D3 intermediate granules are prepared according to the prescription parameters in samples 6-7 in Table 11.

[0141] Examples 4-5

[0142] Example 4 provides a method for preparing vitamin D3 intermediate granules. Compared with Example 1, the only difference is that the amount of vitamin D3 added is 0.05g, instead of 0.15g in Example 1. Sample 8 was obtained.

[0143] Example 5 provides a method for preparing vitamin D3 intermediate granules. Compared with Example 1, the only difference is that the amount of vitamin D3 added is 0.25g, instead of 0.15g in Example 1. Sample 9 was obtained.

[0144] Examples 6-7

[0145] Example 6 provides a method for preparing vitamin D3 intermediate granules. Compared with Example 1, the only difference is that the inlet air temperature is 120°C, instead of 140°C in Example 1. Sample 10 was obtained.

[0146] Example 7 provides a method for preparing vitamin D3 intermediate granules. Compared with Example 1, the only difference is that the inlet air temperature is 180°C, instead of 140°C in Example 1. Sample 11 was obtained.

[0147] Example 8 and Comparative Example 5

[0148] Example 8 provides a method for preparing vitamin D3 intermediate particles. Compared with Example 1, the only difference is that the peristaltic flow rate is 160 rpm, instead of 180 rpm in Example 1. Sample 12 was obtained.

[0149] Comparative Example 5 provides a method for preparing vitamin D3 intermediate particles. Compared with Example 1, the only difference is that the peristaltic flow rate is 200 rpm, instead of 180 rpm in Example 1. Sample 13 was obtained.

[0150] Experiment Example 2

[0151] The performance of the vitamin D3 emulsions and vitamin D3 intermediate particles prepared in Examples 1-8 and Comparative Examples 1-5 was tested, as detailed below.

[0152] 1. Viscosity test of vitamin D3 emulsion

[0153] The vitamin D3 emulsions prepared in Examples 1-8 and Comparative Examples 1-5 were tested for viscosity at 25°C using a DV2T rotary viscometer (Bolefei Co., Ltd.). Test conditions: rotor LV-062, rotation speed 30 rpm, multi-point mode (time 2 min, interval between each point 20 s). The results are shown in Table 12.

[0154] Table 12 Results of Emulsion Viscosity (mPa·s) Measurement

[0155]

[0156] As shown in Table 12, there are significant differences in the viscosity of vitamin D3 emulsions of samples 1-13. Among them, samples 3 and 7-13 have higher viscosity, while sample 4 has the highest viscosity.

[0157] 2. Particle size determination of vitamin D3 intermediates

[0158] Samples 1-13 were taken and measured by a laser particle size analyzer. The results are shown in Table 13.

[0159] Table 13. Results of Particle Size (μm) Measurement

[0160]

[0161] Table 13 shows that the particle size of samples 1-4 gradually increases. Within a certain range, the higher the emulsion viscosity, the larger the particle size. Samples 4-7 show that the more film-forming agent added, the larger the particle size. Samples 3 and 8-9 show that the amount of vitamin D3 added has no significant effect on the particle size. Samples 3 and 10-11 show that the higher the inlet air temperature in spray drying, the smaller the particle size. Samples 3 and 12-13 show that the faster the emulsion feed rate in spray drying, the larger the particle size.

[0162] 3. Flowability test of vitamin D3 intermediate particles

[0163] 3.1 Angle of repose test

[0164] Samples 1-13 were taken respectively, and the particle flowability was tested by measuring the angle of repose. The results are shown in Table 14.

[0165] Table 14 Results of Angle of Repose (°)

[0166] sample 1 2 3 4 5 6 7 8 9 10 11 12 13 Angle of repose (°) 31.2 30.3 29.9 32.4 30.6 32.2 31.3 30.2 29.6 31.3 32.6 30.5 31.09

[0167] As shown in Table 14, the angle of repose of samples 1-13 prepared in Examples 1-8 and Comparative Examples 1-5 is less than 35°, indicating that the vitamin D3 granules prepared by the present invention have good flowability.

[0168] 3.2 Compression Test

[0169] Take appropriate amounts of samples 1-13 into a 50mL graduated cylinder and measure the loose volume of the particles. Then place the graduated cylinder containing the drug-containing particles into a rotary shaker and shake it to measure the compacted volume of the particles. Further calculate its compressibility using the formula below. The results are shown in Table 15.

[0170] Compression = 100 × ((V0 - V)) F ) / V0)

[0171] Table 15 Compressibility (%) Results

[0172] sample 1 2 3 4 5 6 7 8 9 10 11 12 13 Compression (%) 11.4 12.3 10.9 11.3 10.6 12.2 11.3 10.5 11.2 10.8 11.4 11.3 12.6

[0173] As shown in Table 15, the compressibility of the vitamin D3 intermediate particles prepared in Examples 1-8 and Comparative Examples 1-5 is less than 15%, indicating that the vitamin D3 intermediate particles prepared by the present invention have good flowability.

[0174] 4. Test for uniformity of vitamin D3 intermediate particle content

[0175] Ten samples from each of samples 1-13 were taken, and the vitamin D3 content in the granules was tested. The average value and RSD were calculated. The results are shown in Table 16.

[0176] Table 16 Results of Particle Content (%) Determination

[0177]

[0178]

[0179] As shown in Table 16, the vitamin D3 intermediate particles prepared by this invention have good uniformity in content.

[0180] Experimental Example 3

[0181] Destructive experiments were conducted on samples 1-13 prepared in Examples 1-8 and Comparative Examples 1-5, as detailed below.

[0182] 1. Destructive Experiment 1

[0183] Appropriate amounts of samples 1-4, commercially available vitamin D3 intermediate granules, and vitamin D3 raw material were taken and placed in an 80℃ forced-air drying oven for a 10-day destructive experiment. After the experiment, the vitamin D3 content in the granules was determined by high-performance liquid chromatography (HPLC). The results are shown in the table below. Figure 1 See Table 17.

[0184] Table 17 Results of Destructive Experiment 1

[0185] sample 0 days (%) 5 days (%) 10 days (%) Commercially available granules 100±0.34 95.92±1.2 93.05±1.04 raw materials 100±0.12 0.97±0.01 0.39±0.001 1 100±1.56 45.67±0.45 32.45±0.89 2 100±1.43 70.32±0.89 60.43±0.99 3 100±1.20 97.32±0.76 96.32±0.54 4 100±0.43 98.46±0.45 95.09±0.60

[0186] Depend on Figure 1 As shown in Table 17, the stability of samples 3 and 4 at 80℃ is not significantly different from that of commercially available drugs; the stability of samples 1-4 gradually increases, indicating that the higher the viscosity of the emulsion, the better the stability; when the emulsion viscosity is 350-400.9 mPa·s, the stability is basically not significantly different from that of commercially available drugs; therefore, the vitamin D3 intermediate particles prepared by samples 3 and 4 of this invention have good physical stability when the viscosity of the vitamin D3 emulsion is controlled at 350-400.9 mPa·s.

[0187] 2. Destructive Experiment 2

[0188] Take appropriate amounts of samples 5-7 and place them openly in an 80℃ forced-air drying oven for a 10-day destructive experiment. After the experiment, the vitamin D3 content in the granules was determined by high-performance liquid chromatography (HPLC), and the results were compared with those of sample 3, commercially available vitamin D3 intermediate granules, and vitamin D3 raw material. The results are shown in the table below. Figure 2 See Table 18.

[0189] Table 18 Results of Destructive Experiment 2

[0190] sample 0 days (%) 5 days (%) 10 days (%) Commercially available granules 100±0.34 95.92±1.2 93.05±1.04 raw materials 100±0.12 0.97±0.01 0.39±0.001 3 100±1.20 97.32±0.76 96.32±0.54 5 100±1.56 75.67±0.45 62.45±0.89 6 100±1.20 80.32±0.76 75.32±1.54 7 100±0.43 99.46±0.45 97.09±0.36

[0191] Depend on Figure 2As shown in Table 18, the stability of sample 5 is worse than that of samples 3 and 6-7, indicating that the stability of vitamin D3 intermediate particles prepared without the addition of film-forming agent is poor; sample 7 has the best stability, indicating that the stability of the prepared vitamin D3 intermediate particles will gradually improve with the increase of the amount of film-forming agent.

[0192] 3. Destructive Experiment 3

[0193] Appropriate amounts of samples 8-9 were taken and placed openly in an 80℃ forced-air drying oven for a 10-day destructive experiment. After the experiment, the vitamin D3 content in the granules was determined by high-performance liquid chromatography (HPLC), and the results were compared with those of sample 3, commercially available vitamin D3 intermediate granules, and vitamin D3 raw material. The results are shown in the table below. Figure 3 See Table 19.

[0194] Table 19 Results of Destructive Experiment 3

[0195]

[0196]

[0197] Depend on Figure 3 As shown in Table 19, the amount of vitamin D3 added has no significant effect on the stability of vitamin D3 intermediate particles.

[0198] 4. Destructive Experiment 4

[0199] Take appropriate amounts of samples 10-11 and place them openly in an 80℃ forced-air drying oven for a 10-day destructive experiment. After the experiment, the vitamin D3 content in the granules was determined by high-performance liquid chromatography (HPLC), and the results were compared with those of sample 3, commercially available vitamin D3 intermediate granules, and vitamin D3 raw materials. The results are shown in the table below. Figure 4 See Table 20.

[0200] Table 20 Results of Destructive Experiment 4

[0201] sample 0 days (%) 5 days (%) 10 days (%) Commercially available granules 100±0.34 95.92±1.2 93.05±1.04 raw materials 100±0.12 0.97±0.01 0.39±0.001 3 100±1.20 97.32±0.76 96.32±0.54 10 100±1.56 96.32±0.89 94.43±0.99 11 100±1.20 96.45±0.67 94.32±1.54

[0202] Depend on Figure 4 As shown in Table 20, within the inlet air temperature range of 120-180℃, changes in inlet air temperature have no significant effect on the stability of vitamin D3 intermediate particles.

[0203] 5. Destructive Experiment 5

[0204] Appropriate amounts of samples 12-13 were taken and placed openly in an 80℃ forced-air drying oven for a 10-day destructive experiment. After the experiment, the vitamin D3 content in the granules was determined by high-performance liquid chromatography (HPLC), and the results were compared with those of sample 3, commercially available vitamin D3 intermediate granules, and vitamin D3 raw material. The results are shown in the table below. Figure 5 See Table 21.

[0205] Table 21 Results of Destructive Experiment 5

[0206] sample 0 days (%) 5 days (%) 10 days (%) Commercially available granules 100±0.34 95.92±1.2 93.05±1.04 raw materials 100±0.12 0.97±0.01 0.39±0.001 3 100±1.20 97.32±0.76 96.32±0.54 12 100±1.56 96.32±0.89 95.43±0.99 13 100±1.20 85.32±0.76 70.32±1.54

[0207] Depend on Figure 5 As shown in Table 21, when the feed rate of the emulsion is within 160-180 mL / h, the change in the feed rate has no significant effect on the stability of vitamin D3 intermediate particles; however, when the feed rate of the emulsion reaches 200 mL / h, the drying efficiency decreases and the stability of vitamin D3 intermediate particles deteriorates.

[0208] Experiment Example 4

[0209] Appropriate amounts of samples 1-13 and vitamin D3 raw materials were taken and placed under high humidity (25±2℃, RH90%±5%) and strong light (4500Lx±500Lx) conditions for 10 days. Samples were taken at 0, 5 and 10 days and the content was determined by high performance liquid chromatography. The results are shown in Table 22.

[0210] Table 22 Results of stability tests under high humidity and strong light conditions

[0211]

[0212]

[0213] Table 22 shows that the high humidity and strong light stability of samples 1 to 4 gradually increased, indicating that the high humidity and strong light stability gradually improved with increasing emulsion viscosity. Sample 5 (without film-forming agent) had the worst high humidity and strong light stability, while the high humidity and strong light stability of samples 3 and 7 gradually improved, indicating that the high humidity and strong light stability significantly improved with increasing film-forming agent dosage. Samples 3 and 8-9 show that the vitamin D3 loading had no significant effect on high humidity and strong light stability. Samples 3 and 10-11 show that within the inlet air temperature range of 120-180℃, changes in inlet air temperature had no significant effect on the high humidity and strong light stability of vitamin D3 intermediate particles. In samples 3 and 12-13, within the emulsion feed rate range of 160-180 mL / h, changes in the emulsion feed rate had no significant effect on the high humidity and strong light stability of vitamin D3 intermediate particles; however, when the emulsion feed rate reached 200 mL / h, the high humidity and strong light stability deteriorated.

[0214] Experimental Example 5

[0215] 1. Accelerated stability assessment

[0216] Take appropriate amounts of samples 3, 7-8 and commercially available vitamin D3 intermediate granules respectively, and conduct accelerated stability tests (40℃±2℃, RH75%±5%). The results are shown in Table 23.

[0217] Table 23 Comparison of accelerated stability of vitamin D3 intermediate particles

[0218]

[0219] As shown in Table 23, the accelerated stability of the vitamin D3 intermediate particles prepared by the method of the present invention is better than that of commercially available vitamin D3 intermediate particles.

[0220] 2. Long-term stability assessment

[0221] Appropriate amounts of samples 3, 7-8, and commercially available vitamin D3 intermediate granules were taken and subjected to long-term stability tests (25℃±2℃, RH60%±5%). The results are shown in Table 24.

[0222] Table 24 Comparison of long-term stability of vitamin D3 intermediate particles

[0223]

[0224] As shown in Table 24, the long-term stability of the vitamin D3 intermediate particles prepared by the method of the present invention is better than that of commercially available vitamin D3 intermediate particles.

[0225] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A process for the preparation of vitamin D3 granules, characterized in that, include: (1) Mix vitamin D3 with an oil phase solvent to obtain an oil phase; (2) Mix emulsifier, film-forming agent, thickener and water to obtain an aqueous phase; (3) Mix the oil phase and the aqueous phase, shear and homogenize to obtain a vitamin D3 emulsion; (4) Spray dry the vitamin D3 emulsion to obtain vitamin D3 granules. The viscosity of the vitamin D3 emulsion is 350-400.9 mPa·s; in the spray drying process, the feed rate of the vitamin D3 emulsion is 160-180 mL / h. The emulsifier is at least one of gum arabic and gelatin; the oil phase solvent is at least one of soybean oil, partially hydrogenated vegetable oil, and fully hydrogenated vegetable oil; the thickener is at least one of sucrose and seaweed polysaccharide; and the film-forming agent is maltodextrin. The weight ratio of the emulsifier to the oil phase solvent is (10-25):(5-7.5). The shearing time is 8-12 minutes, the shearing speed is 16000-19000 rpm, the homogenization is performed 8-12 times, and the homogenization pressure is 800-1000 bar.

2. The preparation method according to claim 1, characterized in that, In the spray drying process, the inlet air temperature is 120-180℃.

3. The preparation method according to claim 1, characterized in that, In step (1), the mixing also includes the addition of an antioxidant.

4. The preparation method according to claim 3, characterized in that, The antioxidants include at least one of propyl gallate, tert-butylhydroquinone, butylated hydroxytoluene, and DL-α-tocopherol.

5. The preparation method according to claim 4, characterized in that, The antioxidant is DL-α-tocopherol.

6. The preparation method according to any one of claims 3-5, characterized in that, The weight ratio of vitamin D3, antioxidant and oil phase solvent is (0.05-0.25):(0.2-0.6):(5-7.5).

7. The preparation method according to claim 1, characterized in that, In step (2), the weight ratio of the emulsifier, film-forming agent, thickener and water is (10-25):(10-40):(10-50):(45-150).

8. The preparation method according to claim 1 or 7, characterized in that, The emulsifier is gum arabic; and / or, The thickener is sucrose; and / or, The oil phase solvent is soybean oil.

9. The preparation method according to claim 1, characterized in that, The spray drying process also includes the addition of a flow aid.

10. The preparation method according to claim 9, characterized in that, The weight ratio of the emulsifier to the flow aid is (10-25):(0.25-5).

11. The preparation method according to claim 9 or 10, characterized in that, The flow aid includes silica.

12. The preparation method according to claim 1, characterized in that, The mixing step in step (1) is carried out under light-protected conditions; and / or, In step (1), the temperature of the mixing step is controlled to be 60-80℃; and / or, In step (2), the temperature of the mixing step is controlled to be 60-80℃.

13. Vitamin D3 granules prepared by the method according to any one of claims 1-12.

14. A formulation containing vitamin D3 granules, characterized in that, The formulation comprises vitamin D3 granules prepared by the preparation method according to any one of claims 1-12.

15. The formulation containing vitamin D3 granules according to claim 14, characterized in that, The dosage form of the preparation is selected from tablets, capsules, or granules.

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