Vitamin D3 inclusion compound, preparation thereof, and preparation method thereof

Abstract

The present invention discloses a vitamin D 3 inclusion compound and a preparation method thereof. The present invention also discloses calcium carbonate D 3 tablets containing the vitamin D 3 inclusion compound and a preparation method thereof. The vitamin D3 inclusion compound of the present invention is calculated by mass percentage and includes: 0.05~0.75% vitamin D3; 80.00~92.25% hydroxypropyl-β-cyclodextrin; 1.00~10.00% antioxidant; 0.00~5.00% anti-adherent; wherein the antioxidant is butylated hydroxytoluene (BHT), vitamin E and sodium ascorbate. The present invention also provides a preparation method of the vitamin D 3 inclusion compound. The vitamin D 3 inclusion compound prepared by the present invention has a high inclusion rate, a high yield, and can be stored stably for a long time. The preparation prepared with the inclusion compound (such as calcium carbonate D 3 tablets) meets pharmaceutical requirements, has good long-term stability, high uniformity, is simple to prepare, and has low cost.

Description

Technical Field

[0001] The present invention relates to the technical field of preparations, and in particular to a vitamin D3 inclusion compound and a preparation method thereof. The present invention also relates to a preparation (such as a calcium carbonate D3 tablet) containing the vitamin D3 inclusion compound and a preparation method thereof. Background Art

[0002] Vitamin D3 plays an important role in promoting calcium absorption, inducing calcium-phosphorus deposition, and preventing rickets. However, vitamin D3 deficiency is widespread among the population, and a large number of people require additional vitamin D3 supplementation. To meet the human body's vitamin D3 supplementation needs, industry researchers have developed calcium carbonate-vitamin D3 compound oral solid preparations (including granules, tablets, and chewable tablets) and alendronate sodium vitamin D3 tablets.

[0003] However, developing vitamin D3 formulations presents numerous technical challenges. These include: Vitamin D3 is sensitive to light, oxygen, and acid, easily degrading under these conditions, resulting in poor stability, reduced content, and increased impurities. Furthermore, the unit dose of vitamin D3 in formulations is extremely low, typically containing only 60–200 IU (1.5–5.0 μg). Therefore, when mixed with a large number of other active ingredients and excipients, uniform mixing is difficult, making it difficult to meet the pharmaceutical standard for uniformity of the formulation, RSD <6. Therefore, pretreatment of vitamin D3 (i.e., preparation of the formulation inclusion complex) is particularly important.

[0004] British Patent GB2037773A discloses a method for preparing an inclusion complex of vitamin D3 and β-cyclodextrin, wherein the reaction molar ratio of vitamin D to cyclodextrin is 1:2-6. However, the inventors have discovered that while this method can fully dissolve vitamin D3 and achieve the required uniform dispersion, the resulting inclusion complex suffers from poor stability during the preparation process and cannot meet the long-term stability requirements for pharmaceutical use.

[0005] Chinese patent CN112716904A discloses a formulation of a calcium carbonate and vitamin D3 composite formulation, designed to reduce the moisture absorption of the vitamin D3 and cyclodextrin inclusion complex, overcome the sticking problem, and reduce the hygroscopicity of the formulation. However, the inventors discovered that this formulation also failed to address the long-term stability and uniformity issues of the inclusion complex and the formulation.

[0006] Although technicians in this field have tried various means to improve the stability and uniformity of vitamin D3, currently only one or two companies' vitamin D3 preparation inclusion compounds meet pharmaceutical requirements, and the prices are high.

[0007] Therefore, the industry needs to provide a vitamin D3 preparation inclusion compound with good long-term stability, high uniformity, simple preparation and low cost, and a preparation method thereof, and at the same time provide a preparation containing vitamin D3 prepared using the preparation inclusion compound. Summary of the Invention

[0008] The present invention aims to overcome at least one of the defects of the above-mentioned prior art, and provide a vitamin D3 inclusion compound with high inclusion rate, high yield, good long-term stability, simple preparation and low cost, and a preparation method thereof, and at the same time provide a vitamin D3 preparation prepared by using the inclusion compound with good stability, high uniformity and low cost.

[0009] The vitamin D3 inclusion compound provided by the present invention comprises, by mass percentage:

[0010] Vitamin D3 0.05-0.75%;

[0011] Hydroxypropyl-β-cyclodextrin 80.00~99.50%;

[0012] Antioxidants 1.00~10.00%;

[0013] Anti-sticking agent 0.00~5.00%.

[0014] The antioxidant is a combination of butylated hydroxytoluene (BHT), vitamin E, and sodium ascorbate; the mass percentages of butylated hydroxytoluene (BHT), vitamin E, and sodium ascorbate are 1-2:2-3:1-3. The vitamin D3 inclusion complex thus prepared has good long-term stability and stable content, and can be stored at room temperature for more than 24 months. Preferably, the mass ratio of the three is 2:3:2, and the vitamin D3 inclusion complex thus prepared can be stored at room temperature for more than 36 months.

[0015] Preferably, the anti-adherent is talcum powder, and the mass percentage of the anti-adherent is 0.5-5.00%. Thus, adhesion to the wall can be avoided during the preparation of the inclusion compound, and the yield is higher.

[0016] More preferably, the vitamin D3 inclusion compound is composed of the following components and mass percentages: vitamin D3 0.25%, hydroxypropyl-β-cyclodextrin 90.75%, butylated hydroxytoluene (BHT) 2%, vitamin E 3%, sodium ascorbate 2%, and talc 2%. The inclusion compound prepared in this way has good long-term stability, stable content, can be stored at room temperature for at least 36 months, has high content uniformity, and high yield.

[0017] The method for preparing the vitamin D3 inclusion compound provided by the present invention comprises the following steps:

[0018] S1: Dissolve vitamin D3 and antioxidant in ethanol to obtain solution 1;

[0019] S2: Add hydroxypropyl-β-cyclodextrin to purified water and then add an anti-adhesive agent to obtain solution 2;

[0020] S3: Mix solution 1 and solution 2 to obtain solution 3;

[0021] S4: spray drying solution 3 using a spray dryer to obtain a vitamin D3 inclusion complex;

[0022] S5: Pass through a 60-mesh sieve.

[0023] Preferably, the ethanol concentration is 60% to 99.5%, more preferably, the ethanol concentration is 99.5%.

[0024] The present invention also provides a preparation comprising the vitamin D3 inclusion compound of the present invention, characterized in that the preparation consists of the following components and mass percentages:

[0025] Vitamin D3 inclusion complex 0.01~1%;

[0026] Active substance A 30~90%;

[0027] Diluent 5~60%;

[0028] Disintegrant 1~10%;

[0029] Adhesive 1~10%;

[0030] Lubricant 0.1~3%.

[0031] The active substance A is calcium salt or sodium alendronate, the diluent is microcrystalline cellulose, the disintegrant is cross-linked polyvinylpyrrolidone, the binder is povidone, and the lubricant is magnesium stearate.

[0032] In some embodiments, the calcium salt is calcium carbonate.

[0033] Preferably, the preparation containing vitamin D3 inclusion complex is calcium carbonate D3 tablets, which are composed of the following components and mass fractions: 0.1% vitamin D3 inclusion complex, 82% calcium carbonate, 10.4% microcrystalline cellulose, 3% cross-linked polyvinylpyrrolidone, 4% povidone, and 0.5% magnesium stearate.

[0034] Preferably, the preparation containing the vitamin D3 inclusion complex is a calcium carbonate D3 chewable tablet, which is composed of the following components and mass fractions: 0.05% vitamin D3 inclusion complex, 62.5% calcium carbonate, 30.45% mannitol, 5% sorbitol, 1% silicon dioxide, 0.5% strawberry flavor, and 0.5% magnesium stearate.

[0035] Preferably, the preparation containing vitamin D3 inclusion complex is calcium carbonate D3 particles, consisting of the following composition and mass fraction: vitamin D3 inclusion complex 0.1%, calcium carbonate 82%, mannitol 5%, sucrose 5.4%, pregelatinized starch 3%, povidone 4%, and sweet orange flavor 0.5%.

[0036] Preferably, the preparation containing the vitamin D3 inclusion complex is alendronate sodium tablet, which is composed of the following components and mass fractions: 23% vitamin D3 inclusion complex, 7% alendronate sodium, 30% microcrystalline cellulose, 30% lactose, 5% pregelatinized starch, 4% croscarmellose sodium, 0.5% colloidal silicon dioxide, and 0.5% magnesium stearate. Preferably, the preparation containing the vitamin D3 inclusion complex is a calcium carbonate D3 tablet, which includes: 0.1% vitamin D3 inclusion complex, 82% calcium carbonate, 10.4% microcrystalline cellulose, 3% crospovidone, 4% povidone, and 0.5% magnesium stearate.

[0037] Preferably, the preparation containing the vitamin D3 inclusion complex is a pharmaceutical preparation. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and do not limit the scope of protection of the present invention.

[0039] Example 1

[0040] Prepare a vitamin D3 inclusion complex according to the proportions in Table 1. The preparation method is as follows: add the inclusion material to purified water, then add an anti-adherent agent to prepare a 3% inclusion material solution; add vitamin D3 and an antioxidant to 99.5% ethanol and stir to dissolve, to prepare a 1% vitamin D3 solution; mix the inclusion material solution and the vitamin D3 solution and stir until uniform; start the spray dryer, set the inlet air temperature to no less than 80°C, and preheat for at least 5 minutes. During the spray drying process, adjust the air direction to ensure good material flow in the spray dryer. Pass the solution through a 60-mesh sieve.

[0041] Table 1 Components and ratios

[0042]

[0043] Example 2

[0044] The preparation method is the same as that of Example 1, and the proportions are as follows: 0.2% vitamin D3, 90.80% hydroxypropyl-β-cyclodextrin, 3% BHT, 2% vitamin E, 3% sodium ascorbyl palmitate, and 1% talc.

[0045] Example 3

[0046] The preparation method is basically the same as that of Example 1, wherein the ethanol concentration is 60%, and the composition is as follows: vitamin D3 0.05%, hydroxypropyl-β-cyclodextrin 91.95%, BHT 1%, vitamin E 3%, sodium ascorbyl palmitate 3%, and talc 1%.

[0047] Example 4

[0048] The preparation method is basically the same as that of Example 1, and the proportions are as follows: 0.75% vitamin D3, 92.25% hydroxypropyl-β-cyclodextrin, 2% BHT, 3% vitamin E, and 2% sodium ascorbyl palmitate.

[0049] Example 5

[0050] Calcium carbonate D3 tablets were prepared using the inclusion compound prepared in Example 1 according to the proportions in Table 2. The preparation method was as follows: purified water and a binder were weighed, and the binder was slowly added under stirring until completely dissolved to obtain a clear, transparent solution, which was then allowed to stand for use. Calcium carbonate and a diluent were added to a granulation pot and thoroughly mixed. A 5% binder solution was added for granulation and drying. After drying, the granules were granulated using a granulator. The dried granules were added to a column hopper mixer, and the vitamin D3 inclusion compound, disintegrant, and lubricant were added and mixed at a mixing speed of 10 rpm for 10 minutes. After mixing, a sample was taken to check the mixing uniformity. The total mixed granules were pressed into plain tablets containing 600 mg of calcium carbonate and 125 IU of vitamin D. A coating solution was prepared and the plain tablets were placed in a coating pot with an inlet air temperature of 50-80°C and an atomization pressure of 1-2 bar. After preheating the plain tablets for approximately 15 minutes, a spray gun was used to spray the film coating solution, resulting in a coating weight gain of approximately 2.5%.

[0051] Table 2 Components and ratios

[0052]

[0053] Example 6

[0054] Calcium carbonate D3 tablets were prepared using the inclusion compound obtained in Example 2, with reference to the proportions and methods of Example 5.

[0055] Example 7

[0056] Calcium carbonate D3 tablets were prepared using the inclusion compound obtained in Example 3, with reference to the proportions and methods of Example 5.

[0057] Comparative Example 1

[0058] The preparation method is the same as that of Example 1, and the proportions are as follows: 0.25% vitamin D3, 90.75% hydroxypropyl-β-cyclodextrin, 3.5% BHT, 3.5% vitamin E, and 2% talc.

[0059] Comparative Example 2

[0060] The preparation method is the same as that of Example 1, and the proportions are as follows: 0.25% vitamin D3, 90.75% hydroxypropyl-β-cyclodextrin, 4.0% BHT, 3.0% vitamin E, and 2% talc.

[0061] Comparative Example 3

[0062] The preparation method is the same as that of Example 1, and the proportions are as follows: 0.25% vitamin D3, 90.75% hydroxypropyl-β-cyclodextrin, 3.0% vitamin E, 4% sodium ascorbyl palmitate, and 2% talc.

[0063] Comparative Example 4

[0064] The preparation method is the same as that of Example 1, and the proportions are as follows: 0.25% vitamin D3, 90.75% hydroxypropyl-β-cyclodextrin, 3.5% BHT, 3.5% sodium ascorbyl palmitate, and 2% talc.

[0065] Performance Testing

[0066] 1. Determination of inclusion rate

[0067] Take appropriate amounts of the vitamin D3 inclusion complexes prepared in Examples 1-4 and Comparative Examples 1-4, observe the spray drying process, measure the D3 inclusion rate and yield, and examine the stability. Calculate the inclusion rate: Vitamin D3 inclusion rate = (Vitamin D3 feed amount - Vitamin D3 content on the surface of the vitamin D3 inclusion complex) / Vitamin D3 feed amount × 100%.

[0068] Table 3 Inclusion rate, yield and spray drying process

[0069]

[0070] The investigation results show that when the ratio of vitamin D3 and hydroxypropyl-β-cyclodextrin is 0.01-0.75%:80.00-99.50%, the inclusion rate is greater than 95%, which meets the requirements (>90%); especially when the ratio of vitamin D3 and hydroxypropyl-β-cyclodextrin is 0.25:90.75, the inclusion rate reaches more than 98%.

[0071] 2. Yield Investigation

[0072] Yield calculation method: Yield = vitamin D3 inclusion complex below 60 mesh / weight of input materials for vitamin D3 inclusion complex preparation * 100%.

[0073] Table 4 Inclusion rate, yield and spray drying process

[0074]

[0075] The results show that the yields of the examples and comparative examples are both above 85%, meeting the requirements (>80%). The addition of talc, an anti-sticking agent, further improves the sticking phenomenon and increases the yield to over 90%. The yield of Example 1 reaches 95.5%.

[0076] 3. Content Investigation

[0077] Take appropriate amounts of the vitamin D3 inclusion compounds prepared in Examples 1-4 and Comparative Examples 1-4, and examine the D3 content at 0, 3, 6, 12, 24, and 36 months.

[0078] Table 5 Investigation of vitamin D3 content under long-term conditions

[0079]

[0080] NA: Not determined.

[0081] The content test results show that the antioxidants butylated hydroxytoluene (BHT), vitamin E, and sodium ascorbate have a crucial impact on the long-term stability of the inclusion complex. All three are indispensable. When the three are mixed in a ratio of 1-2:2-3:1-3, the vitamin D3 content of the prepared inclusion complex remains above 90% for 24 months. When the ratio is 2:3:2, the vitamin D3 content of the inclusion complex remains above 90% for 36 months. However, the content of the control sample drops below 90% after 3 or 6 months, which does not meet the requirements.

[0082] 3. Quality Inspection of Calcium Carbonate D3 Tablets

[0083] The calcium carbonate D3 tablets prepared in Examples 5, 6, and 7 were taken as samples 1, 2, and 3, and the Huiercaltek calcium carbonate tablets were taken as comparison 1. The uniformity and content of vitamin D3 content were determined according to the British Pharmacopoeia BP2019 content uniformity method. The results are shown in Tables 6 and 7.

[0084] Table 6 Content uniformity inspection results

[0085]

[0086] Table 7 Results of investigation on vitamin D3 content

[0087]

[0088] The results of the investigation show that the calcium carbonate D3 tablets prepared using the vitamin D3 inclusion compound prepared by the present invention as raw material and according to the prescription and preparation method of the present invention have high D3 content and the content is stable within 36 months.

[0089] In summary, the vitamin D3 inclusion compound provided by the present invention has a high inclusion rate, high yield, and long stable storage time; the vitamin D preparation containing the vitamin D3 inclusion compound of the present invention has high uniformity, long stable storage time, and low cost.

[0090] Obviously, the above embodiments of the present invention are merely examples for the purpose of clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific implementation methods of the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the claims of the present invention shall be included within the scope of protection of the claims of the present invention.

Claims

1. A vitamin D3 inclusion compound, characterized in that: In percentage by mass, including: Vitamin D3 0.05-0.75%; Hydroxypropyl-β-cyclodextrin 80.00~92.25%; Antioxidants 1.00-10.00%; and Anti-adhesive agent 0.00~5.00%; The antioxidant is butylated hydroxytoluene, vitamin E and sodium ascorbate; the mass ratio of the butylated hydroxytoluene, vitamin E and sodium ascorbate is 2:3:2; and the anti-sticking agent is talc.

2. The vitamin D3 inclusion compound according to claim 1, characterized in that The mass percentage of the anti-sticking agent is 0.5-5.00%.

3. The vitamin D3 inclusion compound according to claim 1, characterized in that The vitamin D3 inclusion compound consists of the following components and mass percentages: 0.25% vitamin D3, 90.75% hydroxypropyl-β-cyclodextrin, 2% butylated hydroxytoluene, 3% vitamin E, 2% sodium ascorbate and 2% talc.

4. The method for preparing the vitamin D3 inclusion compound according to any one of claims 1 to 3, wherein: The preparation method comprises the following steps: S1: Dissolve vitamin D3 and antioxidant in ethanol to obtain solution 1; S2: Dissolve hydroxypropyl-β-cyclodextrin in purified water and add an anti-adhesive agent to obtain solution 2; S3: Mix solution 1 and solution 2 to obtain solution 3; S4: drying solution 3 using a spray dryer to obtain a vitamin D3 inclusion complex; S5: Pass through a 60-mesh sieve.

5. The method for preparing the vitamin D3 inclusion compound according to claim 4, wherein: The ethanol concentration is 60% to 99.5%.

6. The method for preparing the vitamin D3 inclusion compound according to claim 5, wherein: The ethanol concentration is 99.5%.

7. A calcium carbonate D3 tablet comprising a vitamin D3 inclusion compound prepared by the preparation method according to claim 5 or 6, characterized in that: It is composed of the following components and mass fractions: 0.1% vitamin D3 inclusion complex, 82% calcium carbonate, 10.4% microcrystalline cellulose, 3% cross-linked polyvinylpyrrolidone, 4% povidone and 0.5% magnesium stearate.

8. A calcium carbonate D3 chewable tablet comprising a vitamin D3 inclusion complex prepared by the preparation method according to claim 5 or 6, characterized in that: It is composed of the following components and mass fractions: vitamin D3 inclusion complex 0.05%, calcium carbonate 62.5%, mannitol 30.45%, sorbitol 5%, silicon dioxide 1%, strawberry flavor 0.5% and magnesium stearate 0.5%.

9. A calcium carbonate D3 particle comprising a vitamin D3 inclusion complex prepared by the preparation method according to claim 5 or 6, characterized in that: It is composed of the following components and mass fractions: 0.1% vitamin D3 inclusion complex, 82% calcium carbonate, 5% mannitol, 5.4% sucrose, 3% pregelatinized starch, 4% povidone and 0.5% sweet orange flavor.

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