A uniform and stable calcium carbonate D3 tablet preparation and its preparation method and application

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a uniform and stable calcium carbonate D3 tablet preparation and its preparation method and application. The preparation method is realized by controlling the process of controlling the particle size of vitamin D3 powder and calcium carbonate particles; the particle size range of the vitamin D3 powder is 80-120 mesh, and the particle size range of calcium carbonate particles is ≤100 mesh, accounting for not less than 70%. The calcium carbonate D3 tablet preparation provided by the present invention has the advantages of high uniformity and stability of vitamin D3, which is of great significance for ensuring drug efficacy, improving patient compliance, extending shelf life, improving safety and maintaining drug efficacy.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a uniform and stable calcium carbonate D3 tablet preparation and a preparation method and application thereof. Background Art

[0002] Calcium carbonate D3 tablets are indicated as calcium supplements for pregnant and lactating women, menopausal women, the elderly, etc., and help prevent and treat osteoporosis. Calcium carbonate D3 tablets are a compound preparation composed of calcium carbonate and vitamin D3. Among them, the role of vitamin D3 is to improve the body's absorption of calcium and phosphorus, so that the levels of plasma calcium and plasma phosphorus reach saturation, promote growth and bone calcification, promote healthy teeth, increase phosphorus absorption through the intestinal wall, and increase phosphorus reabsorption through the renal tubules. Therefore, calcium carbonate D3 tablets have the advantages of high calcium content and good absorption rate.

[0003] The research on calcium carbonate D3 tablets mainly faces the following technical difficulties: first, vitamin D3 has poor stability and can be degraded by heat, light, oxygen, and acid; second, vitamin D3 accounts for a very low proportion in the prescription, making the mixing process very difficult. Therefore, inventing a calcium carbonate D3 preparation with uniform vitamin D3 content and good stability has become an urgent need in this technical field. Summary of the invention

[0004] In order to solve the above problems, the present invention provides a uniform and stable calcium carbonate D3 tablet preparation, which is achieved by controlling the particle size of vitamin D3 powder and the particle size of calcium carbonate particles.

[0005] In one aspect, the present invention provides a method for preparing a uniform and stable calcium carbonate D3 tablet preparation, comprising controlling the particle size of vitamin D3 powder and the particle size of calcium carbonate particles.

[0006] Specifically, the particle size range of the vitamin D3 powder can be 80-120 mesh, and the calcium carbonate particles with a particle size range of ≤100 mesh account for no less than 70%.

[0007] Preferably, the particle size range of the vitamin D3 powder can be 100-120 mesh, and the calcium carbonate particles with a particle size range of ≤100 mesh account for no less than 80%.

[0008] Specifically, the vitamin D3 powder is prepared by spray drying, fluidized bed drying or drum drying.

[0009] More specifically, the vitamin D3 powder is prepared by spray drying.

[0010] Preferably, the spray drying conditions can be: the air inlet temperature is 100-150°C, the air flow rate is 0.4-0.5m 3 / min, the atomization pressure is 0.2-0.5MPa.

[0011] Further preferably, the spray drying conditions may be: the air inlet temperature is 120-140°C, the air flow rate is 0.42-0.49m 3 / min, the atomization pressure is 0.3-0.5MPa.

[0012] Specifically, the calcium carbonate particles include calcium carbonate, a binder and a disintegrant.

[0013] More specifically, the binder may be one or more of povidone, starch slurry, powdered sugar and syrup, polyethylene glycol, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose or ethyl cellulose;

[0014] The disintegrant may be one or more of sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone.

[0015] Preferably, the adhesive may be povidone;

[0016] The disintegrant may be sodium carboxymethyl starch.

[0017] Specifically, the calcium carbonate particles are obtained by wet granulation.

[0018] Specifically, the steps are as follows:

[0019] S1. Preparation of vitamin D3 powder;

[0020] S2. Preparation of calcium carbonate particles;

[0021] S3, mixing the vitamin D3 powder prepared in step S1 with a disintegrant and a filler to obtain a mixture 1;

[0022] S4, adding 25%-50% of the calcium carbonate particles prepared in step S2 to the mixture 1 in step S3 to obtain a mixture 2;

[0023] S5, adding the remaining calcium carbonate particles prepared in step S2 to the mixture 2 in step S4 to obtain a mixture 3;

[0024] S6, adding a lubricant to the mixture 3 of step S5 to obtain a mixture 4;

[0025] S7, tableting the mixture 4 of step S6 to obtain plain tablets;

[0026] S8, film coating the plain tablets of step S7.

[0027] Specifically, the preparation of the vitamin D3 powder in step S1 also includes particle size screening; the screening can be performed by screening or crushing + screening to obtain a material with a suitable particle size.

[0028] Specifically, the disintegrant in step S3 may be one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose or cross-linked sodium carboxymethyl cellulose;

[0029] The filler may be one or more of microcrystalline cellulose, starch, sucrose, dextrin, lactose, pregelatinized starch, inorganic salts or mannitol.

[0030] Preferably, the disintegrant in step S3 may be cross-linked polyvinylpyrrolidone;

[0031] The filler may be microcrystalline cellulose.

[0032] Specifically, the content of calcium carbonate in the plain tablet in step S7 can be 80-90% w / w.

[0033] Preferably, the content of calcium carbonate in the plain tablet in step S7 may be 85-90% w / w.

[0034] Further preferably, the content of calcium carbonate in the plain tablet in step S7 may be 85-88% w / w.

[0035] Specifically, the content of vitamin D3 powder in the plain tablet in step S7 can be 0.05-16% w / w.

[0036] More specifically, the content of vitamin D3 powder in the plain tablet in step S7 can be 0.05-10% w / w.

[0037] Preferably, more specifically, the content of vitamin D3 powder in the plain tablet in step S7 can be 0.08-1% w / w.

[0038] In another aspect, the present invention provides the use of the aforementioned preparation method in preparing a uniform and stable calcium carbonate D3 tablet preparation.

[0039] In another aspect, the present invention provides a uniform and stable calcium carbonate D3 tablet preparation, which is obtained by the aforementioned preparation method.

[0040] The technical effects achieved by the present invention are:

[0041] (1) The vitamin D3 content in the calcium carbonate D3 tablet preparation provided by the present invention is uniform, and the uniformity can reach 10.5-14.9.

[0042] (2) The vitamin D3 in the calcium carbonate D3 tablet preparation provided by the present invention has good stability, and the content can reach 93% or more after accelerated growth for 6 months. DETAILED DESCRIPTION

[0043] The present invention will be further described in detail below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only intended to illustrate the present invention. The experimental methods used in the following examples are generally conventional, unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available, unless otherwise specified.

[0044] Basic Example

[0045] 1.1 Preparation of calcium carbonate D3 tablets

[0046] This embodiment provides a uniform and stable calcium carbonate D3 tablet preparation.

[0047] The raw materials and auxiliary materials and their dosage of the calcium carbonate D3 tablet preparation are shown in Table 1:

[0048] Table 1

[0049]

[0050] The preparation process of the calcium carbonate D3 tablet preparation is shown in Table 2:

[0051] Table 2

[0052]

[0053] Examples 1-4

[0054] The particle size of the vitamin D3 powder and the particle size of the calcium carbonate particles (particle ratio below 100 mesh) of Examples 1-4 are shown in Table 3, and the rest are the same as the basic example.

[0055] Table 3

[0056]

[0057] Comparative Examples 1-16

[0058] The particle sizes of vitamin D3 powder and calcium carbonate particles (particle ratio under 100 mesh) of comparative examples 1-16 are shown in Table 4, and the rest are the same as the basic example.

[0059] Table 4

[0060]

[0061] Test example

[0062] 1. Experimental methods

[0063] (1) Homogeneity test

[0064] Detection method:

[0065] Uniformity of vitamin D3 content: Operate in a dark environment and use high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition) to determine.

[0066] Test sample solution: Take 10 tablets of the test sample and place them in different 50mL volumetric bottles, add 5mL of water, shake to dissolve, add 35mL of methanol, water bath at 40±5℃ and ultrasonic for 15min, shake from time to time, cool to room temperature, add methanol to dilute to the scale, shake well, centrifuge, filter the supernatant with a glass fiber filter membrane, and take the filtrate.

[0067] Reference solution: Take an appropriate amount of vitamin D3 reference substance (each 1 mg is equivalent to 40,000 IU), weigh it accurately, add 90% methanol solution to dissolve it and quantitatively dilute it to make a solution containing 2.5 IU per 1 mL.

[0068] Chromatographic conditions: Octadecylsilane bonded silica gel is used as the filler (Yuexu Utimate C18, 4.6mm×150mm, 3μm or a chromatographic column with equivalent column efficiency), methanol-water (95:5) is used as the mobile phase, the detection wavelength is 264nm, the flow rate is 1.0mL per minute, the column temperature is 35℃, and the injection volume is 100μL.

[0069] Limit: The result of each tablet should be within the range of 85%-115% of the average value; if one tablet exceeds the above range, but does not exceed 75%-125% of the average value, take another 20 tablets and measure in the same way; if at most 1 tablet out of 30 tablets has a content outside the range of 85%-115% of the average content, and none of the other tablets exceeds 75%-125% of the average content, then it meets the requirements.

[0070] (2) Stability test (content determination)

[0071] Detection method:

[0072] Accurately measure the test solution, reference solution and mixed reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate the correction factor of vitamin D3 and previtamin D3 respectively, and calculate the content (the sum of previtamin D3 content and vitamin D3 content) by peak area according to the external standard method.

[0073] 2. Results and analysis

[0074] The results of the uniformity and stability of vitamin D3 in the calcium carbonate D3 tablet preparations prepared in Examples 1-4 and Comparative Examples 1-16 are shown in Table 5:

[0075] Table 5

[0076]

[0077] From the results in Table 5, it can be seen that when vitamin D3 powder and calcium carbonate particles are mixed, the finer the particle size of the material with a lower proportion and the closer it is to the particle size of the material with a higher proportion, the easier it is to mix evenly. Vitamin D3 is unstable. The finer its particle size, the larger its specific surface area, and the easier it is to contact with external oxygen, resulting in product instability. Therefore, if both product uniformity and stability need to be taken into account, the particle size range of vitamin D3 powder and the particle size range of calcium carbonate particles need to be controlled.

Claims

1. A method for preparing a uniform and stable calcium carbonate D3 tablet preparation, characterized in that: Including controlling the particle size range of vitamin D3 powder to 80-120 mesh, and the particle size range of calcium carbonate particles to ≤100 mesh, accounting for no less than 70%; The specific steps of the preparation method are as follows: S1. Preparation of vitamin D3 powder; S2. Preparation of calcium carbonate particles; the calcium carbonate particles include calcium carbonate, a binder and a disintegrant; S3, mixing the vitamin D3 powder prepared in step S1 with a disintegrant and a filler to obtain a mixture 1; S4, adding 25%-50% of the calcium carbonate particles prepared in step S2 to the mixture 1 in step S3 to obtain a mixture 2; S5, adding the remaining calcium carbonate particles prepared in step S2 to the mixture 2 in step S4 to obtain a mixture 3; S6, adding a lubricant to the mixture 3 of step S5 to obtain a mixture 4; S7, tableting the mixture 4 of step S6 to obtain plain tablets; S8, film coating the plain tablets of step S7; In step S7, the content of calcium carbonate in the plain tablet is 80-90% w / w; the content of vitamin D3 powder in the plain tablet is 0.08-16% w / w.

2. The preparation method according to claim 1, characterized in that: The vitamin D3 powder is prepared by spray drying, fluidized bed drying or drum drying.

3. The preparation method according to claim 2, characterized in that: The vitamin D3 powder is prepared by spray drying; the spray drying conditions are: the air inlet temperature is 100-150°C, the air flow rate is 0.4-0.5m 3 / min, the atomization pressure is 0.2-0.5MPa.

4. The preparation method according to claim 1, characterized in that: The adhesive in step S2 is one or more of povidone, starch slurry, powdered sugar and syrup, polyethylene glycol, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose or ethyl cellulose; The disintegrant is one or more of sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The calcium carbonate particles are obtained by wet granulation.

6. The preparation method according to claim 1, characterized in that: The disintegrant in step S3 is one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose or cross-linked sodium carboxymethyl cellulose; The filler is one or more of microcrystalline cellulose, starch, sucrose, dextrin, lactose, pregelatinized starch, inorganic salts or mannitol.

7. The preparation method according to any one of claims 1 to 6 is used in preparing a uniform and stable calcium carbonate D3 tablet preparation.

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