Vitamin D3 inclusion compound as well as preparation and preparation method thereof

Abstract

The invention discloses a vitamin D3 clathrate compound and a preparation method thereof, and further discloses a calcium carbonate D3 tablet containing the vitamin D3 clathrate compound and a preparation method of the calcium carbonate D3 tablet. The vitamin D3 inclusion compound disclosed by the invention comprises the following components in percentage by mass: 0.05-0.75% of vitamin D3; 80.00 to 99.5 percent of hydroxypropyl-beta-cyclodextrin, and the balance of water; 1.00% to 10.00% of an antioxidant; 0.00 to 5.00% of an anti-sticking agent; wherein the antioxidant is butylated hydroxytoluene (BHT), vitamin E and sodium ascorbate. The invention also provides a preparation method of the vitamin D3 clathrate compound. The preparation method comprises the following steps: dissolving the vitamin D3 and the antioxidant in ethanol; the preparation method comprises the following steps: dissolving hydroxypropyl-beta-cyclodextrin in purified water, and then adding an anti-sticking agent; mixing the two solutions; and drying by using a spray dryer to prepare the vitamin D3 inclusion compound. The vitamin D3 inclusion compound prepared by the invention is high in inclusion rate and yield and can be stably stored for a long time, and a preparation (such as a calcium carbonate D3 tablet) prepared from the inclusion compound meets medicinal requirements, and is good in long-term stability, high in uniformity, simple to prepare and relatively low in 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 calcium carbonate D3 tablets) containing the vitamin D3 inclusion compound and a preparation method thereof. Background Art

[0002] Vitamin D3 has important functions such as promoting calcium absorption, inducing calcium and phosphorus deposition, and preventing rickets. However, vitamin D3 deficiency is common among the people, and a large number of people need additional vitamin D3 supplements. In order to meet the human body's demand for vitamin D3 supplementation, industry technical researchers have developed calcium carbonate-vitamin D3 compound oral solid preparations (including granules, tablets, chewable tablets, etc.), alendronate sodium vitamin D3 tablets and other preparations.

[0003] However, there are many technical difficulties in developing preparations containing vitamin D3, including: vitamin D3 is sensitive to light, oxygen, and acid, and is easily degraded under the above conditions, with poor stability, resulting in reduced content and increased impurities; the unit dose of vitamin D3 in the preparation is extremely low, and the preparation usually contains only 60~200 IU (1.5~5.0μg), so when mixed with a large number of other main drugs and excipients, it is difficult to mix evenly and it is difficult to meet the pharmaceutical standard of preparation mixing uniformity RSD <6. Therefore, the pretreatment of vitamin D3 (i.e., the preparation of preparation inclusion complex) is particularly important.

[0004] British patent GB2037773A discloses a method for preparing a vitamin D3 and β-cyclodextrin inclusion compound, wherein the reaction molar ratio of vitamin D to cyclodextrin is 1:2-6. However, the inventors found that although this method can fully dissolve vitamin D3 and achieve the required dispersion uniformity, the inclusion compound obtained during the preparation process has poor stability and cannot meet the pharmaceutical requirements of long-term stability.

[0005] Chinese patent CN112716904A discloses a composite formulation of calcium carbonate and vitamin D3, which aims to reduce the hygroscopicity of the vitamin D3 and cyclodextrin inclusion compound, overcome the sticking problem, and reduce the hygroscopicity of the preparation. However, the inventors found that this solution also failed to overcome the long-term stability and uniformity problems of the inclusion compound and the preparation.

[0006] Although technicians in this field have tried various means to improve the stability and uniformity of vitamin D3, there are still only one or two companies whose vitamin D3 preparation inclusion compounds meet the 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 defect 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: Vitamin D3 0.05~0.75%; Hydroxypropyl-β-cyclodextrin 80.00~99.50%; Antioxidants 1.00~10.00%; Anti-adhesive agent 0.00~5.00%.

[0010] 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 compound 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 compound thus prepared can be stored at room temperature for more than 36 months.

[0011] Preferably, the anti-adhesive agent is talcum powder, and the mass percentage of the anti-adhesive agent is 0.5-5.00%. Thus, when preparing the inclusion compound, wall adhesion can be avoided, and the yield is higher.

[0012] More preferably, 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 (BHT), 3% vitamin E, 2% sodium ascorbate, and 2% talc. 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.

[0013] The method for preparing the vitamin D3 inclusion compound provided by the present invention comprises the following steps: S1: Dissolve vitamin D3 and antioxidant in ethanol to obtain solution 1; S2: adding hydroxypropyl-β-cyclodextrin to purified water, and then adding an anti-adhesive agent to obtain solution 2; S3: mixing solution 1 and solution 2 to obtain solution 3; S4: spray drying solution 3 using a spray dryer to obtain a vitamin D3 inclusion compound; S5: Pass through a 60-mesh sieve.

[0014] Preferably, the ethanol concentration is 60% to 99.5%, more preferably, the ethanol concentration is 99.5%.

[0015] 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: Vitamin D3 inclusion compound 0.01~1%; Active substance A 30~90%; Diluent 5~60%; Disintegrant 1~10%; Adhesive 1~10%; Lubricant 0.1~3%.

[0016] The active substance A is calcium salt or sodium alendronate, the diluent is microcrystalline cellulose, the disintegrant is cross-linked polyvinylpyrrolidone, the binder is polyvinylpyrrolidone, and the lubricant is magnesium stearate.

[0017] In some embodiments, the calcium salt is calcium carbonate.

[0018] 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% polyvinylpyrrolidone, and 0.5% magnesium stearate.

[0019] Preferably, the preparation containing vitamin D3 inclusion complex is calcium carbonate D3 chewable tablets, 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.

[0020] Preferably, the preparation containing vitamin D3 inclusion complex is calcium carbonate D3 particles, consisting of the following composition 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.

[0021] Preferably, the preparation containing the vitamin D3 inclusion compound is alendronate sodium tablet, which is composed of the following components and mass fractions: 23% vitamin D3 inclusion compound, 7% alendronate sodium, 30% microcrystalline cellulose, 30% lactose, 5% pregelatinized starch, 4% cross-linked sodium carboxymethyl cellulose, 0.5% colloidal silicon dioxide, and 0.5% magnesium stearate. Preferably, the preparation containing the vitamin D3 inclusion compound is a calcium carbonate D3 tablet, including: 0.1% vitamin D3 inclusion compound, 82% calcium carbonate, 10.4% microcrystalline cellulose, 3% cross-linked polyvinylpyrrolidone, 4% polyvinylpyrrolidone, and 0.5% magnesium stearate.

[0022] Preferably, the preparation containing the vitamin D3 inclusion complex is a pharmaceutical preparation. Implementation

[0023] In order to make the purpose, technical solution and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with specific implementation methods. It should be understood that the specific implementation methods described here are only used to explain the present invention and do not limit the scope of protection of the present invention.

[0024] Example 1

[0025] Vitamin D3 inclusion compound was prepared according to the proportions in Table 1. The preparation method was as follows: adding the inclusion material to purified water, and then adding the anti-adhesive agent to prepare a 3% inclusion material solution; adding vitamin D3 and antioxidant to 99.5% ethanol, stirring to dissolve, and preparing a 1% vitamin D3 solution; mixing the inclusion material solution and the vitamin D3 solution, stirring evenly; turning on the spray dryer, setting the air inlet temperature to not less than 80°C, and preheating for at least 5 minutes. Start spraying and spray drying process, adjusting the wind direction to ensure good material flow in the spray dryer. Pass through a 60-mesh sieve.

[0026] Table 1 Components and ratios

[0028] Example 2

[0029] 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 vitamin C, and 1% talc.

[0030] Example 3 The preparation method is basically the same as that of Example 1, wherein the ethanol concentration is 60%, and the proportions are as follows: 0.05% vitamin D3, 91.95% hydroxypropyl-β-cyclodextrin, 1% BHT, 3% vitamin E, 3% sodium vitamin C, and 1% talc.

[0031] Example 4 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 vitamin C.

[0032] Example 5 The inclusion compound prepared in Example 1 was used to prepare calcium carbonate D3 tablets. The calcium carbonate D3 tablets were prepared according to the proportions in Table 2. The preparation method was as follows: Weigh purified water and binder, slowly add the binder under stirring, stir until completely dissolved, obtain a clear and transparent solution, and stand for use. Calcium carbonate and diluent were added to the granulation pot and fully mixed; a 5% binder solution was added for granulation and drying; after drying, a granulator was used for granulation, the dry granules were added to the column hopper mixer, and then vitamin D3 inclusion compound, disintegrant, and lubricant were added for mixing, the mixing speed was 10 rpm, the mixing time was 10 minutes, and the mixing uniformity was tested after the mixing was completed; the total mixed granules were pressed into tablets according to 600 mg of calcium carbonate and 125 IU of vitamin D; the coating solution was prepared, the tablets were put into the coating pot, the air inlet temperature was set to 50-80°C, the atomization pressure was 1-2 bar, and the tablets were preheated for about 15 minutes before the spray gun was turned on to spray the film coating solution, and the coating weight gain was about 2.5%.

[0033] Table 2 Components and ratios Example 6

[0034] Calcium carbonate D3 tablets were prepared using the inclusion compound obtained in Example 2 with reference to the proportion and method of Example 5.

[0035] Example 7 Calcium carbonate D3 tablets were prepared by using the inclusion compound obtained in Example 3 and referring to the proportion and method of Example 5.

[0036] Comparative Example 1 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.

[0037] Comparative Example 2 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.

[0038] Comparative Example 3 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 vitamin C, and 2% talc.

[0039] Comparative Example 4 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 vitamin C, and 2% talc.

[0040] Performance Testing 1. Determination of inclusion rate Take appropriate amounts of the vitamin D3 inclusion complexes prepared in Examples 1-4 and Comparative Examples 1-4, observe the spray drying process, determine the D3 inclusion rate and yield, and examine the stability. Inclusion rate calculation method: 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%.

[0041] Table 3 Inclusion rate, yield and spray drying process

[0042] From the investigation results, it can be seen 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%.

[0043] 2. Yield Investigation Yield calculation method: Yield = vitamin D3 inclusion complex below 60 mesh / weight of input materials for vitamin D3 inclusion complex preparation*100%.

[0044] Table 4 Inclusion rate, yield and spray drying process

[0045] The results of the investigation show that the yields of the examples and the comparative examples are both higher than 85%, which meets the requirements (>80%). The addition of the anti-sticking agent talc can further improve the wall sticking phenomenon, thereby increasing the yield to more than 90%. The yield of Example 1 is 95.5%.

[0046] 3. Content Investigation Take appropriate amounts of the vitamin D3 inclusion complexes prepared in Examples 1-4 and Comparative Examples 1-4, and examine the D3 content at 0, 3, 6, 12, 24, and 36 months.

[0047] Table 5 Investigation of vitamin D3 content under long-term conditions

[0048] NA: Not determined.

[0049] From the results of the content investigation, it can be seen that the antioxidant butylated hydroxytoluene (BHT), vitamin E and sodium ascorbate have a crucial influence on the long-term stability of the inclusion compound. The three are indispensable. When the three are in a ratio of 1~2:2~3:1~3, the vitamin D3 content of the prepared inclusion compound remains above 90% within 24 months, and when the three are in a ratio of 2:3:2, the vitamin D3 content of the prepared inclusion compound remains above 90% for 36 months. The content of the control ratio drops below 90% in 3 or 6 months, which does not meet the requirements.

[0050] 3. Quality inspection of calcium carbonate D3 tablets The calcium carbonate D3 tablets prepared in Examples 5, 6, and 7 were taken as samples 1, 2, and 3, and the Felcalcium 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.

[0051] Table 6 Content uniformity inspection results

[0052] Table 7 Results of investigation on vitamin D3 content

[0053] It can be seen from the investigation results that the calcium carbonate D3 tablets prepared using the vitamin D3 inclusion compound prepared by the present invention as a raw material and according to the prescription and preparation method of the present invention have high content and the content is stable within 36 months.

[0054] In summary, the vitamin D3 inclusion compound provided by the present invention has a high inclusion rate, a high yield, and a long stable storage time; the vitamin D preparation containing the vitamin D3 inclusion compound of the present invention has high uniformity, a long stable storage time, and a low cost.

[0055] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the technical solution 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 in the protection scope of the claims of the present invention.

Claims

1. A vitamin D3 inclusion compound, characterized in that: In terms of mass percentage, it includes: Vitamin D3 0.05~0.75%; Hydroxypropyl-β-cyclodextrin 80.00~99.50%; Antioxidant 1.00~10.00%; Anti-adhesive agent 0.00~5.00%; The antioxidant is butylated hydroxytoluene (BHT), vitamin E and sodium ascorbate; the mass ratio of the butylated hydroxytoluene (BHT), vitamin E and sodium ascorbate is 1-2:2-3:1-3; and the anti-sticking agent is talcum powder.

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

3. The vitamin D3 inclusion compound according to claim 2, characterized in that The mass ratio of the butylated hydroxytoluene (BHT), vitamin E and sodium ascorbate is 2:3:

2.

4. The vitamin D3 inclusion compound according to claim 3, 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 (BHT), 3% vitamin E, 2% sodium ascorbate, and 2% talc.

5. The method for preparing the vitamin D3 inclusion compound according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: S1: Dissolve vitamin D3 and antioxidant in ethanol to obtain solution 1; S2: dissolving hydroxypropyl-β-cyclodextrin in purified water, and then adding 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 compound; S5: Pass through a 60-mesh sieve.

6. The method for preparing the vitamin D3 inclusion compound according to claim 5, characterized in that: The ethanol concentration is 60% to 99.5%.

7. The method for preparing the vitamin D3 inclusion compound according to claim 6, characterized in that: The ethanol concentration is 99.5%.

8. A calcium carbonate D3 tablet comprising the vitamin D3 inclusion compound prepared according to claim 6 or 7, 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% polyvinylpyrrolidone, and 0.5% magnesium stearate.

9. A calcium carbonate D3 chewable tablet comprising the vitamin D3 inclusion compound prepared according to claim 6 or 7, characterized in that: It 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.

10. A calcium carbonate D3 particle comprising the vitamin D3 inclusion compound prepared according to claim 6 or 7, 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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