High-stability vitamin D3 granules and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to high-stability vitamin D3 granules and a preparation method thereof. The preparation method of the vitamin D3 granules provided by the invention comprises the following steps: (1) mixing vitamin D3 and an oil-phase solvent to obtain an oil phase; (2) mixing an emulsifier, a film-forming agent, a thickening agent and water to obtain a water phase; (3) mixing, shearing and homogenizing the oil phase and the water phase to obtain a vitamin D3 emulsion, and (4) performing spray drying to obtain vitamin D3 particles; the viscosity of the vitamin D3 emulsion ranges from 350 mPa.s to 400.9 mPa.s; in the spray drying, the feeding speed of the vitamin D3 emulsion is 160 to 180 mL / h; the preparation method is simple and convenient, low in cost and easy for industrial production; the prepared vitamin D3 particles are uniform in particle size, good in content uniformity and controllable in specification.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to high-stability vitamin D3 particles and a preparation method thereof. Background Art

[0002] Vitamin D3, also known as cholecalciferol, is formed in the human body by 7-dehydrocholesterol under ultraviolet irradiation. It is the active form with the highest biological metabolic rate in the vitamin D family. As a fat-soluble vitamin essential to the human body, vitamin D3 is present in low levels in natural foods and is mainly synthesized by the human body under natural light. However, in recent years, due to changes in human lifestyles, insufficient exposure to ultraviolet rays has led to an increasingly serious deficiency of vitamin D3 in the body. Vitamin D3 has the characteristics of unstable chemical properties and is prone to severe degradation when exposed to light, heat, and oxygen. In addition, the amount of vitamin D3 required by the human body is extremely low, and very little drug needs to be added to the preparation. Therefore, there are technical difficulties in the development of vitamin D3 drug preparations, such as poor stability and poor content uniformity. At present, there is only one company that has approved the listing of vitamin D3 intermediate particles in China, and the authorization fee is as high as 700,000 to 1 million US dollars, which seriously restricts the development of this type of product in China; in addition, the intermediate particles are large in size, and direct mixing with other excipients is prone to material stratification and uneven mixing; if the intermediate particles are crushed, the particle structure will be destroyed and its stability will be reduced.

[0003] In recent years, there has been a continuous flow of imitation of vitamin D3 intermediate particles in China, but most of them use large-scale equipment, which is costly; and the technology is immature, and the effect of improving the stability of vitamin D3 is poor. The prior art provides a preparation process and device for vitamin D3 microcapsule powder, the equipment operation route is long, and there is more adhesion between particles; the prior art also provides a spray device for vitamin microcapsules, which has high equipment requirements and large energy loss, which is not conducive to large-scale production; and the preparation method of vitamin D3 intermediate particles provided by the prior art uses mannitol carrier and fluidized bed for spray drying; the amount of mannitol carrier is high, resulting in a low drug content in the final particles, a large administration volume, inconvenience for patients to take, and easy to produce adverse reactions; the mannitol carrier has a large static electricity, and it is easy to stick to the wall during the granulation process, and the structure of the obtained vitamin D3 intermediate particles is incomplete and the stability is poor; the particles prepared by the fluidized bed are fluffy and easy to break during granulation, resulting in uneven particle size distribution of the obtained particles; the vitamin D3 intermediate particles finally obtained 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 prior art such as complex preparation process, short shelf life and poor stability of the obtained vitamin D3 particles, so as to provide a high-stability vitamin D3 particle and a preparation method thereof.

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

[0006] The present invention provides a method for preparing vitamin D3 particles, comprising:

[0007] (1) mixing vitamin D3 and an oil phase solvent to obtain an oil phase; (2) mixing an emulsifier, a film former, 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 particles;

[0008] The viscosity of the vitamin D3 emulsion is 350-400.9 mPa·s; during the spray drying, 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; 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 number of homogenization is 8-12 times, and the homogenization pressure is 800-1000 bar.

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

[0013] In an optional embodiment, in the step (1), the mixing further comprises adding an antioxidant;

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

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

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

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

[0018] In an optional embodiment, the emulsifier is gum arabic;

[0019] In an optional embodiment, the thickener is sucrose;

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

[0021] In an optional embodiment, the spray drying further comprises adding a glidant;

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

[0023] Preferably, the glidant comprises silicon dioxide.

[0024] In an optional embodiment, the mixing step of step (1) is carried out under light-proof conditions;

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

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

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

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

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

[0030] 1. The preparation method of vitamin D3 particles provided by the present invention comprises: (1) mixing vitamin D3 and an oil phase solvent to obtain an oil phase; (2) mixing an emulsifier, a film former, 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 particles; the viscosity of the vitamin D3 emulsion is 350-400.9 mPa·s; during the spray drying, the feed rate of the vitamin D3 emulsion is 160-180 mL / h; the emulsifier The invention comprises at least one of gum arabic and gelatin; the oil phase solvent comprises at least one of soybean oil, partially hydrogenated vegetable oil and fully hydrogenated vegetable oil; the thickener comprises at least one of sucrose and seaweed polysaccharide; the film former comprises 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 number of homogenization is 8-12 times, and the homogenization pressure is 800-1000 bar. The vitamin D3 emulsion with stable emulsion is obtained by adopting a specific formula and a specific process, and the viscosity of the emulsion, the feed speed of the emulsion in spray drying, the shearing time and speed, and the homogenization pressure and times are controlled to make the vitamin D3 fully dry, so as to obtain vitamin D3 particles with complete structure, long shelf life and high stability. The preparation method is simple, low in cost and easy to industrialize; the obtained vitamin D3 particles have uniform particle size, good content uniformity and controllable specifications.

[0031] 2. The method for preparing the 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 vitamin D3 intermediate particles by adding a film-forming agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0033] Figure 1 is a result diagram of destructive experiment 1 in Experimental Example 3 of the present invention;

[0034] Figure 2 is a result diagram of destructive experiment 2 in Experimental Example 3 of the present invention;

[0035] Figure 3 is a result diagram of destructive experiment 3 in Experimental Example 3 of the present invention;

[0036] Figure 4 is a result diagram of destructive experiment 4 in Experimental Example 3 of the present invention;

[0037] Figure 5 This is a result diagram of destructive experiment 5 in Experimental Example 3 of the present invention. DETAILED DESCRIPTION

[0038] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0039] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0040] Experimental Example 1

[0041] This experimental example screened the prescription and process for preparing vitamin D3 emulsion.

[0042] 1. Type and dosage of emulsifier

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

[0044] Table 1

[0045]

[0046] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

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

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

[0049] (3) The oil phase and the water phase are mixed, sheared and homogenized according to Table 1 to obtain a vitamin D3 emulsion.

[0050] The bleached oil was observed after standing at room temperature for 24 hours. When gum arabic or gelatin was selected as an emulsifier to prepare the vitamin D3 emulsion, the vitamin D3 emulsion had better physical stability. Considering that the cost of gum arabic was relatively low, gum arabic was selected as the emulsifier in the present invention. When the amount of gum arabic was 5 g, the physical stability of the prepared vitamin D3 emulsion was poor. When the amount of gum arabic was 10-25 g, the physical stability of the prepared vitamin D3 emulsion was better. The amount of gum arabic was temporarily selected as 10 g for further investigation.

[0051] 2. Type and dosage of oil phase solvent

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

[0053] Table 2

[0054]

[0055] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

[0056] The preparation method is as follows: (1) according to Table 2, vitamin D3 and DL-α-tocopherol are weighed into an oil phase solvent, protected from light, heated in a water bath at 60°C, and stirred until completely dissolved to serve as the oil phase;

[0057] (2) According to Table 2, gum arabic, maltodextrin, and sucrose were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0058] (3) The oil phase and the water phase are mixed, sheared and homogenized according to Table 2 to obtain a vitamin D3 emulsion.

[0059] The oil bleaching condition was observed after standing at room temperature for 24 hours. 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 vitamin D3 emulsion had better physical stability. Considering the influence of the oxidation value, the present invention selected soybean oil as the oil phase solvent. When the amount of soybean oil was 10 g, the physical stability of the prepared vitamin D3 emulsion was poor. When the amount of soybean oil was 5-7.5 g, the physical stability of the prepared vitamin D3 emulsion was better. The amount of soybean oil was temporarily selected as 5 g for further investigation.

[0060] 3. Type and dosage of thickener

[0061] Taking the type and amount of thickener as variables, mannitol, seaweed polysaccharide, sucrose, carrageenan and starch as thickeners and their amounts were investigated. The prescription parameters of prescriptions 17 to 23 are shown in Table 3. The preparation methods of each prescription are the same.

[0062] Table 3

[0063]

[0064]

[0065] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

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

[0067] (2) According to Table 3, gum arabic, maltodextrin, and thickener were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0068] (3) The oil phase and the water phase are mixed, sheared and homogenized according to Table 3 to obtain a vitamin D3 emulsion.

[0069] After standing at room temperature for 24 hours, the floating oil was observed. When sucrose or seaweed polysaccharide was selected as the thickener to prepare the vitamin D3 emulsion, the physical stability of the vitamin D3 emulsion was better. The present invention uses sucrose as the thickener; when the amount of sucrose is 10-50g, the amount of the thickener has no obvious effect on the physical stability of the prepared vitamin D3 emulsion. Now, a sucrose amount of 10g is selected for further investigation.

[0070] 4. Type and dosage of film-forming agent

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

[0072] Table 4

[0073]

[0074] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

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

[0076] (2) According to Table 4, gum arabic, film-forming agent, and sucrose were weighed into pure water, heated in a water bath at 60°C, and stirred until completely dissolved to form the aqueous phase;

[0077] (3) The oil phase and the water phase are mixed, sheared and homogenized according to Table 4 to obtain a vitamin D3 emulsion.

[0078] After standing at room temperature for 24 hours, the floating oil situation was observed. When maltodextrin was selected as a film-forming agent to prepare the vitamin D3 emulsion, the physical stability of the vitamin D3 emulsion was good, and no floating oil was observed in the emulsion. The present invention uses maltodextrin as a film-forming agent. When the amount of maltodextrin is 5-40g, the amount of the film-forming agent has no obvious effect on the physical stability of the prepared vitamin D3 emulsion. Now, a maltodextrin amount of 10g is selected for further investigation.

[0079] 5. Types and dosage of antioxidants

[0080] Taking the type and dosage of antioxidants as variables, DL-α-tocopherol, propyl gallate, tert-butylhydroquinone, and dibutylhydroxytoluene were investigated as antioxidants and their dosages. The prescription parameters of prescriptions 30 to 35 are shown in Table 5. The preparation methods of each prescription are the same.

[0081] Table 5

[0082]

[0083] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

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

[0085] (2) According to Table 5, gum arabic, maltodextrin, and sucrose were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0086] (3) The oil phase and the water phase are mixed, sheared and homogenized according to Table 5 to obtain a vitamin D3 emulsion.

[0087] After being placed at room temperature for 24 hours, the bleaching oil was observed. The type of antioxidant had no obvious effect on the physical stability of the vitamin D3 emulsion, and no bleaching oil was observed. The present invention uses DL-α-tocopherol as a film-forming agent. When the amount of DL-α-tocopherol is 0.2-0.6g, the amount of DL-α-tocopherol has no obvious effect on the physical stability of the prepared vitamin D3 emulsion. Now, the amount of DL-α-tocopherol is selected as 0.2g for further investigation.

[0088] 6. Investigation of water phase dosage

[0089] Taking the amount of water phase as a variable, the formulation parameters of formulation 36 to formulation 41 are shown in Table 6, and the preparation methods of each formulation are the same.

[0090] Table 6

[0091]

[0092]

[0093] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

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

[0095] (2) According to Table 6, gum arabic, maltodextrin, and sucrose were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0096] (3) The oil phase and the water phase are mixed, sheared and homogenized according to Table 6 to obtain a vitamin D3 emulsion.

[0097] After being placed at room temperature for 24 hours, the floating oil was observed. When the amount of water phase was 45-150mL, the amount of water phase had no obvious effect on the physical stability of the vitamin D3 emulsion, and no floating oil was observed. When the amount of water phase was 42.5mL, the homogenizer was blocked during the emulsion preparation, which was not conducive to industrial production. The water phase amount of 150mL is now selected for further investigation.

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

[0099] Taking shearing time and shearing speed as variables, the prescription parameters of process 1 to process 6 are shown in Table 7, and the preparation methods of each process are the same.

[0100] Table 7

[0101]

[0102]

[0103] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

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

[0105] (2) According to Table 7, gum arabic, maltodextrin, and sucrose were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0106] (3) The oil phase and the water phase are mixed, and sheared and homogenized according to processes 1-6 in Table 7 to obtain a vitamin D3 emulsion.

[0107] After being placed at room temperature for 24 hours, the oil bleaching was observed. When the shearing time was 10 minutes and the shearing speed was 16000-19000 rpm, the physical stability of the vitamin D3 emulsion was good. Considering that the shearing speed was too high, it might affect the service life of the shearing machine, so the shearing speed was preferably 16000 rpm for further investigation.

[0108] 8. Investigation of homogenization pressure and homogenization times

[0109] Taking the homogenization pressure and the number of homogenization times as variables, the prescription parameters of process 7 to process 12 are shown in Table 8, and the preparation methods of each process are the same.

[0110] Table 8

[0111]

[0112] Note: “-” means the emulsion has no oil bleaching, “+” means the emulsion has oil bleaching. The more “+” there are, the more serious the oil bleaching is.

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

[0114] (2) According to Table 8, gum arabic, maltodextrin, and sucrose were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0115] (3) The oil phase and the water phase are mixed, sheared, and homogenized according to processes 7-12 in Table 8 to obtain a vitamin D3 emulsion.

[0116] After being placed at room temperature for 24 hours, the floating oil was observed. When the homogenization times were 10 times and the homogenization pressure was 800-1000 bar, the physical stability of the vitamin D3 emulsion was good. Considering that too high a homogenization pressure may affect the service life of the homogenizer, the homogenization pressure was preferably 800 bar for further investigation.

[0117] 9. Optimize the formula and process of vitamin D3 emulsion

[0118] In summary, the present invention preferably selects the following prescription and process for preparing vitamin D3 emulsion for further investigation, and the specific parameters are shown in Table 9.

[0119] Table 9

[0120]

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

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

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

[0124] (2) According to Table 10, gum arabic, maltodextrin, and sucrose were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0125] (3) mixing the oil phase and the water phase, shearing at 16000 rpm for 10 min to obtain colostrum, and homogenizing at 800 bar for 10 times; controlling the particle size of the vitamin D3 emulsion to 200 nm, and obtaining a vitamin D3 emulsion;

[0126] (4) Use a peristaltic pump to add the emulsion to the feed port of the spray dryer. The spray drying parameters are: inlet air temperature 140°C, peristaltic speed 180 mL / h. When the temperature reaches the set value, start spraying, and collect the material after spraying.

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

[0128] Table 10

[0129]

[0130] Comparative Example 1, Comparative Example 2 and Example 2 respectively provide a method for preparing vitamin D3 particles. Compared with Example 1, the only difference is that the prescription parameters are different. Vitamin D3 particles are prepared according to the prescription parameters of 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 particles, comprising the following steps:

[0133] (1) According to Table 11, vitamin D3 and DL-α-tocopherol were weighed into soybean oil, protected from light, heated in a water bath at 60° C., and stirred until completely dissolved to serve as the oil phase;

[0134] (2) According to Table 11, gum arabic, maltodextrin, and sucrose were weighed into pure water, heated in a water bath at 60° C., and stirred until completely dissolved to form the aqueous phase;

[0135] (3) mixing the oil phase and the water phase, shearing at 16000 rpm for 10 min to obtain colostrum, and homogenizing at 800 bar for 10 times; controlling the particle size of the vitamin D3 emulsion to 200 nm, and obtaining a vitamin D3 emulsion;

[0136] (4) Use a peristaltic pump to add the emulsion to the feed port of the spray dryer. The spray drying parameters are: inlet air temperature 140°C, peristaltic speed 180 mL / h. When the temperature reaches the set value, start spraying, and collect the material after spraying.

[0137] (5) The spray-dried product of step (4) is mixed with 1.5 g of silicon dioxide to prepare vitamin D3 intermediate particles.

[0138] Table 11

[0139]

[0140] Comparative Example 4 and Example 3 respectively provide a method for preparing vitamin D3 intermediate particles. Compared with Comparative Example 3, the only difference is that the prescription parameters are different. Vitamin D3 intermediate particles are prepared according to the prescription parameters of samples 6-7 in Table 11.

[0141] Embodiment 4-5

[0142] Example 4 provides a method for preparing vitamin D3 intermediate particles, which is different from Example 1 in that the amount of vitamin D3 added is 0.05 g, instead of 0.15 g of vitamin D3 added in Example 1. Sample 8 is obtained.

[0143] Example 5 provides a method for preparing vitamin D3 intermediate particles, which is different from Example 1 in that the amount of vitamin D3 added is 0.25 g, instead of 0.15 g of vitamin D3 added in Example 1. Sample 9 is obtained.

[0144] Embodiment 6-7

[0145] Example 6 provides a method for preparing vitamin D3 intermediate particles, which is different from Example 1 only in that the inlet air temperature is 120° C. instead of 140° C. in Example 1. Sample 10 is obtained.

[0146] Example 7 provides a method for preparing vitamin D3 intermediate particles, which is different from Example 1 in that the inlet air temperature is 180° C. instead of 140° C. in Example 1. Sample 11 is obtained.

[0147] Example 8 and Comparative Example 5

[0148] Example 8 provides a method for preparing vitamin D3 intermediate particles, which is different from Example 1 in that the peristaltic speed is 160 rpm instead of 180 rpm in Example 1. Sample 12 is obtained.

[0149] Comparative Example 5 provides a method for preparing vitamin D3 intermediate particles, which is different from Example 1 in that the creeping speed is 200 rpm instead of 180 rpm in Example 1. Sample 13 is obtained.

[0150] Experimental Example 2

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

[0152] 1. Vitamin D3 emulsion viscosity test

[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 (Bolefield Co., Ltd.). The test conditions were: rotor LV-062, rotation speed 30 rpm, multi-point mode (time 2 min, interval 20 s between each point). The results are shown in Table 12.

[0154] Table 12 Emulsion viscosity (mPa·s) measurement results

[0155]

[0156] As can be seen from Table 12, there are obvious differences in the viscosity of the vitamin D3 emulsions of samples 1-13, among which samples 3 and 7-13 have higher viscosities; the viscosity of the vitamin D3 emulsion of sample 4 is the highest.

[0157] 2. Vitamin D3 intermediate particle size detection

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

[0159] Table 13 Particle size (μm) measurement results

[0160]

[0161] It can be seen from Table 13 that the particle size of samples 1-4 gradually increases. Within a certain range, the higher the viscosity of the emulsion, the larger the particle size; it can be seen from samples 4-7 that the more film-forming agent is added, the larger the particle size; it can be seen from samples 3, 8-9 that the amount of vitamin D3 added has no obvious effect on the particle size; it can be seen from samples 3, 10-11 that the higher the inlet air temperature in spray drying, the smaller the particle size; it can be seen from samples 3, 12-13 that the faster the feed speed of the emulsion 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 fluidity was tested by measuring the angle of repose. The results are shown in Table 14.

[0165] Table 14 Repose angle (°) Results

[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] It can be seen from Table 14 that the repose angles of samples 1-13 prepared in Examples 1-8 and Comparative Examples 1-5 are all less than 35°, indicating that the vitamin D3 particles prepared in the present invention have good fluidity.

[0168] 3.2 Compression test

[0169] Take appropriate amount of samples 1-13 into 50mL measuring cylinders respectively, and measure the loose volume of particles. Then place the measuring cylinder containing drug-containing particles on a rotary shaker for shaking, measure the compacted volume of particles, and further calculate the compression degree. The calculation formula is as follows, and the results are shown in Table 15.

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

[0171] Table 15 Compression (%) 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] It can be seen from Table 15 that the compression degree 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 in the present invention have good fluidity.

[0174] 4. Vitamin D3 intermediate granule content uniformity test

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

[0176] Table 16 Particle content (%) Determination results

[0177]

[0178]

[0179] It can be seen from Table 16 that the vitamin D3 intermediate particles prepared by the present invention have good content uniformity.

[0180] Experimental Example 3

[0181] Destructive tests were performed on samples 1-13 prepared in Examples 1-8 and Comparative Examples 1-5, as follows.

[0182] 1. Destructive experiment 1

[0183] Take appropriate amounts of samples 1-4, commercially available vitamin D3 intermediate granules and vitamin D3 API, place them in an open air drying oven at 80°C, and conduct a destructive experiment for 10 days. After the experiment, the content of vitamin D3 in the granules was detected by high performance liquid chromatography; the results are shown in Figure 1 and Table 17.

[0184] Table 17 Destructive test 1 results

[0185] sample 0 days (%) 5 days (%) 10 days (%) Commercially available particles 100±0.34 95.92±1.2 93.05±1.04 API 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°C 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; and when the viscosity of the emulsion is 350-400.9 mPa·s, there is basically no significant difference in stability from commercially available drugs; therefore, when the viscosity of the vitamin D3 emulsion is controlled at 350-400.9 mPa·s by samples 3 and 4 of the present invention, the obtained vitamin D3 intermediate particles have good physical stability performance.

[0187] 2. Destructive experiment 2

[0188] Take appropriate amount of samples 5-7 respectively, put them in an open air drying oven at 80℃, and conduct destructive experiment for 10 days. After the experiment, use high performance liquid chromatography to detect the content of vitamin D3 in the granules, and compare the results with those of sample 3, commercially available vitamin D3 intermediate granules and vitamin D3 raw materials; the results are shown in Figure 2 and Table 18.

[0189] Table 18 Destructive test 2 results

[0190] sample 0 days (%) 5 days (%) 10 days (%) Commercially available particles 100±0.34 95.92±1.2 93.05±1.04 API 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 can be seen from Table 18, the stability of sample 5 is worse than that of samples 3 and 6-7, indicating that the stability of the vitamin D3 intermediate particles prepared without adding a film-forming agent is poor; sample 7 has the best stability, indicating that as the amount of film-forming agent increases, the stability of the prepared vitamin D3 intermediate particles will gradually improve.

[0192] 3. Destructive experiment 3

[0193] Take appropriate amount of samples 8-9 respectively, put them in an open air drying oven at 80℃, and conduct a destructive test for 10 days. After the test, use high performance liquid chromatography to detect the content of vitamin D3 in the granules, and compare the results with those of sample 3, commercially available vitamin D3 intermediate granules and vitamin D3 raw materials; the results are shown in Figure 3 and Table 19.

[0194] Table 19 Destructive test 3 results

[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 the vitamin D3 intermediate particles.

[0198] 4. Destructive experiment 4

[0199] Take appropriate amount of samples 10-11 respectively, put them in an open air drying oven at 80℃, and conduct a destructive test for 10 days. After the test, use high performance liquid chromatography to detect the content of vitamin D3 in the granules, and compare the results with those of sample 3, commercially available vitamin D3 intermediate granules and vitamin D3 raw materials; the results are shown in Figure 4 and Table 20.

[0200] Table 20 Destructive test 4 results

[0201] sample 0 days (%) 5 days (%) 10 days (%) Commercially available particles 100±0.34 95.92±1.2 93.05±1.04 API 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°C, changes in the inlet air temperature have no significant effect on the stability of the vitamin D3 intermediate particles.

[0203] 5. Destructive experiment 5

[0204] Take appropriate amount of samples 12-13 respectively, put them in an open air drying oven at 80℃, and conduct a destructive test for 10 days. After the test, use high performance liquid chromatography to detect the content of vitamin D3 in the granules, and compare the results with those of sample 3, commercially available vitamin D3 intermediate granules and vitamin D3 raw materials; the results are shown in Figure 5 and Table 21.

[0205] Table 21 Destructive test 5 results

[0206] sample 0 days (%) 5 days (%) 10 days (%) Commercially available particles 100±0.34 95.92±1.2 93.05±1.04 API 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 can be seen from Table 21, when the emulsion feed rate is within the range of 160-180 mL / h, the change in the emulsion feed rate has no obvious effect on the stability of the vitamin D3 intermediate particles; but when the emulsion feed rate reaches 200 mL / h, the drying efficiency decreases and the stability of the vitamin D3 intermediate particles deteriorates.

[0208] Experimental Example 4

[0209] Take appropriate amounts of samples 1-13 and vitamin D3 raw materials respectively, place them under high humidity (25±2℃, RH90%±5%) and strong light (4500Lx±500Lx) conditions for 10 days, and take samples at 0, 5, and 10 days for content determination by HPLC. The results are shown in Table 22.

[0210] Table 22 Stability test results under high humidity and strong light conditions

[0211]

[0212]

[0213] It can be seen from Table 22 that the high humidity and strong light stability of sample 1 to sample 4 gradually improves, indicating that as the viscosity of the emulsion increases, its high humidity and strong light stability also gradually improves; sample 5 (without adding film-forming agent) has the worst high humidity and strong light stability, while samples 3 and 7 gradually improve in high humidity and strong light stability, indicating that as the amount of film-forming agent increases, the high humidity and strong light stability significantly improves; it can be seen from samples 3, 8-9 that the drug loading of vitamin D3 has no obvious effect on the high humidity and strong light stability; it can be seen from samples 3, 10-11 that within the inlet air temperature range of 120-180°C, the change in inlet air temperature has no obvious effect on the high humidity and strong light stability of the vitamin D3 intermediate particles; in samples 3, 12-13, within the emulsion feed rate of 160-180mL / h, the change in the emulsion feed rate has no obvious effect on the high humidity and strong light stability of the vitamin D3 intermediate particles; but when the emulsion feed rate reaches 200mL / h, the high humidity and strong light stability deteriorates.

[0214] Experimental Example 5

[0215] 1. Accelerated stability test

[0216] Appropriate amounts of samples 3, 7-8, and commercially available vitamin D3 intermediate particles were taken for accelerated stability testing (40°C±2°C, RH75%±5%). The results are shown in Table 23.

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

[0218]

[0219] It can be seen from Table 23 that the accelerated stability of the vitamin D3 intermediate particles prepared by the preparation method of the present invention is better than that of the commercially available vitamin D3 intermediate particles.

[0220] 2. Long-term stability study

[0221] Appropriate amounts of samples 3, 7-8, and commercially available vitamin D3 intermediate particles were taken for long-term stability experiments (25°C±2°C, RH60%±5%). The results are shown in Table 24.

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

[0223]

[0224] It can be seen from Table 24 that the long-term stability of the vitamin D3 intermediate particles prepared by the preparation method of the present invention is better than that of the commercially available vitamin D3 intermediate particles.

[0225] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the scope of protection of the invention.

Claims

1. A method for preparing vitamin D3 particles, characterized in that: include: (1) mixing vitamin D3 and an oil phase solvent to obtain an oil phase; (2) mixing an emulsifier, a film former, 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 particles; The viscosity of the vitamin D3 emulsion is 350-400.9 mPa·s; during the spray drying, the feed rate of the vitamin D3 emulsion is 160-180 mL / h; 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; 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 minutes, the shearing speed is 16000-19000 rpm; the number of homogenization is 8-12 times, and the homogenization pressure is 800-1000 bar.

2. The preparation method according to claim 1, characterized in that: During the spray drying, the air inlet temperature is 120-180°C.

3. The preparation method according to claim 1, characterized in that: In the step (1), the mixing further comprises adding an antioxidant; Preferably, the antioxidant includes at least one of propyl gallate, tert-butylhydroquinone, dibutylhydroxytoluene, and DL-α-tocopherol; More preferably, the antioxidant is DL-α-tocopherol.

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

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

6. The preparation method according to claim 1 or 5, characterized in that: The emulsifier is gum arabic; and / or, The thickener is sucrose; and / or, The oil phase solvent is soybean oil.

7. The preparation method according to claim 1, characterized in that: The spray drying further comprises adding a glidant; Preferably, the weight ratio of the emulsifier to the glidant is (10-25): (0.25-5); Preferably, the glidant comprises silicon dioxide.

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

9. Vitamin D3 particles obtained by the preparation method according to any one of claims 1 to 8.

10. A preparation containing vitamin D3 particles, characterized in that: The preparation comprises vitamin D3 particles prepared by the preparation method according to any one of claims 1 to 8; preferably, the dosage form of the preparation is selected from tablets, capsules or granules.

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