Method for preparing composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules

Abstract

The present invention discloses a method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules. The method comprises: subjecting calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose to wet granulation, drying and sizing to obtain prefabricated granules; premixing microencapsulated vitamin D3 powder with microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose by an equal-increment method under light-shielded conditions, followed by low-shear mixing with the prefabricated granules; and then adding silicon dioxide and magnesium stearate, mixing, and tableting. The method can improve the moldability, disintegration and release, calcium release level, content uniformity of trace vitamin D3 and storage stability of the composite calcium tablet.

Description

[0001] DESCRIPTION

[0002] Method for Preparing Composite Calcium Tablet Based on Organic Calcium-Casein Phosphopeptide Prefabricated Granules TECHNICAL FIELD

[0003] The present invention belongs to the technical field of nutritional supplements and food preparations, and particularly relates to a method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules.

[0004] BACKGROUND

[0005] Calcium is one of the essential minerals for the human body. Common calcium supplements include calcium carbonate, calcium citrate, calcium lactate, calcium gluconate, calcium citrate malate and the like. Among existing calcium supplementation products, calcium carbonate is widely used because of its relatively high calcium content and low cost, but its dissolution process has a strong dependence on the gastric acid environment. Organic calcium sources such as calcium citrate malate and calcium lactate have good formulation adaptability and are suitable for the development of composite calcium tablets.

[0006] Existing composite calcium tablets are mostly prepared by simply combining calcium sources with ingredients such as vitamin D3, vitamin K2 and casein phosphopeptide. Such products are prone to the following problems during production: when the dosage of the calcium source is high, tablet moldability, hardness, friability and disintegration time are difficult to balance; vitamin D3 is added in a low amount, and direct mixing is likely to result in insufficient content uniformity; vitamin D3 is sensitive to light, temperature and air, and if it participates in wet granulation and drying, the content stability may be affected; and the dispersibility and soluble calcium release level of calcium-containingDESCRIPTION

[0007] granules in simulated gastrointestinal environments still have room for improvement.

[0008] Therefore, it is necessary to provide a method for preparing a composite calcium tablet with a defined formulation composition, stable process sequence and suitability for industrial production, so as to improve tablet moldability, disintegration and release, trace component uniformity and vitamin D3 storage stability.

[0009] SUMMARY

[0010] In order to overcome the above defects in the prior art, the present invention provides a method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules, thereby solving the problems in the prior art that composite calcium tablets have poor moldability, uneven vitamin D3 mixing, easy degradation of vitamin D3 during wet granulation, and a low calcium release level.

[0011] To achieve the above purpose, the present invention provides the following technical solution:

[0012] A method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules comprises the following steps:

[0013] (1) based on the total mass of the composite calcium tablet, weighing the following components by weight percentage: 49.0% to 51.0% calcium citrate malate, 14.0% to 16.0% calcium L-lactate, 2.2% to 2.8% casein phosphopeptide, 4.5% to 5.5% inulin, 1.5% to 2.5% resistant dextrin, 0.8% to 1.2% hydroxypropyl methylcellulose, 11.5% to 13.0% microcrystalline cellulose, 8.5% to 9.5%DESCRIPTION

[0014] mannitol, 1.5% to 2.1% croscarmellose sodium, 0.15% to 0.25% microencapsulated vitamin D3 powder, 0.4% to 0.7% silicon dioxide and 0.6% to 1.0% magnesium stearate, wherein the sum of the weight percentages of all components is 100%; wherein the total mass refers to the mass of the finally prepared composite calcium tablet;

[0015] (2) mixing the calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose for 4 to 6 minutes, adding purified water to prepare a wet mass, wherein the amount of purified water is 8% to 12% of the weight of the mixed dry powder in step (2), granulating through an 18 to 24 mesh sieve, drying at 45 to 50°C until the moisture content is 1.5% to 3.0%, and sizing through a 20 to 30 mesh sieve to obtain organic calcium-casein phosphopeptide prefabricated granules;

[0016] (3) mixing the microencapsulated vitamin D3 powder with microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose by an equal-increment method under light- shielded conditions to obtain vitamin D3 premixed powder; wherein the equal-increment method means that the microencapsulated vitamin D3 powder is first mixed with an equal mass of microcrystalline cellulose, and then microcrystalline cellulose in an amount equal to or less than the already mixed material is successively added and mixed until all of the microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose has been added; wherein the total amount of microcrystalline cellulose refers to the total amount of microcrystalline cellulose weighed in step (1);

[0017] (4) mixing the organic calcium-casein phosphopeptide prefabricated granules, the vitamin D3 premixed powder, the remaining microcrystalline cellulose,DESCRIPTION

[0018] mannitol and croscarmellose sodium at 15 to 25 rpm for 8 to 12 minutes, then adding silicon dioxide and magnesium stearate, mixing for 2 to 3 minutes, and then tableting to obtain the composite calcium tablet; wherein the remaining microcrystalline cellulose refers to the balance obtained after deducting, from the total amount of microcrystalline cellulose weighed in step (1), the microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose used in step (3).

[0019] Preferably, in step (1), based on the total mass of the composite calcium tablet, the components consist of the following weight percentages: 50.000% calcium citrate malate, 15.000% calcium L-lactate, 2.500% casein phosphopeptide, 5.000% inulin, 2.000% resistant dextrin, 1.000% hydroxypropyl methylcellulose, 12.150% microcrystalline cellulose, 9.000% mannitol, 1.800% croscarmellose sodium, 0.200% microencapsulated vitamin D3 powder, 0.550% silicon dioxide and 0.800% magnesium stearate.

[0020] Preferably, in step (1), the calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose are respectively passed through a 60-mesh sieve after weighing, and then the mixing operation of step (2) is performed.

[0021] Preferably, in step (1), the potency of the microencapsulated vitamin D3 powder is 90000 to 110000 lU / g.

[0022] Preferably, in step (2), the mixing time is 5 minutes; the amount of purified water is 10% of the weight of the mixed dry powder in step (2); the sieve mesh for granulation is 20 mesh; the drying temperature is 48°C; drying is carried out until the moisture content is 2.0% to 2.5%; and the sieve mesh for sizing is 24 mesh.

[0023] Preferably, the composite calcium tablet contains no calcium carbonate,DESCRIPTION

[0024] calcium citrate, calcium acetate or vitamin K.

[0025] Preferably, in step (4), the tableting is performed using a rotary tablet press. Preferably, in step (4), the hardness of the composite calcium tablet is 70 to 95 N, the friability is not greater than 0.8%, and the disintegration time is 15 to 25 minutes; wherein the hardness is measured by a tablet hardness determination method, the friability is measured by a tablet friability test method, and the disintegration time is measured by a disintegration time test method.

[0026] Preferably, in step (4), the mixing of the organic calcium-casein phosphopeptide prefabricated granules, the vitamin D3 premixed powder, the remaining microcrystalline cellulose, mannitol and croscarmellose sodium is performed in a mixer.

[0027] The technical effects and advantages of the method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules of the present invention are as follows:

[0028] 1. In the invention, calcium citrate malate and calcium L-lactate are wet-granulated in advance with casein phosphopeptide, inulin and resistant dextrin, so that the calcium sources and calcium-ab sorption-promoting components are uniformly dispersed and closely combined at the granule level, thereby improving the dispersibility of the calcium-containing granules and the soluble calcium release level in a simulated gastrointestinal environment. Casein phosphopeptide is in full contact with the calcium sources in the prefabricated granules and can effectively chelate calcium ions in the weakly alkaline intestinal environment, preventing formation of insoluble calcium salt precipitates. Inulin and resistant dextrin, as dietary fiber components, can improve the wettability and disintegration performance of the granules and promote rapid release of calcium from theDESCRIPTION

[0029] preparation. Experiments show that the composite calcium tablet prepared by the method of the present invention achieves a calcium release rate of 84.7% in artificial gastric juice at 30 minutes and a soluble calcium retention rate of 61.5% in artificial intestinal juice at 60 minutes, which are significantly superior to the comparative example without casein phosphopeptide and inulin and the comparative example in which vitamin D3 participates in wet granulation.

[0030] 2. In the invention, the microencapsulated vitamin D3 powder bypasses the wet granulation and hot-air drying processes and is premixed with a specified proportion of microcrystalline cellulose by the equal-increment method under light- shielded conditions only after drying and sizing of the granules, thereby effectively avoiding degradation loss of vitamin D3 under hot and humid conditions. Accelerated stability experiments (40°C / 75% RH, 3 months) show that the vitamin D3 retention rate can reach 93.4%, which is significantly superior to that of the comparative example in which vitamin D3 participates in wet granulation (84.6%).

[0031] 3. In the invention, the microencapsulated vitamin D3 powder is premixed with microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose by the equal-increment method, effectively solving the problem of insufficient mixing uniformity of trace vitamin D3 in a large amount of excipients. Through stepwise proportional expansion mixing, the trace vitamin D3 powder is gradually and uniformly dispersed in the microcrystalline cellulose carrier, thereby avoiding agglomeration and uneven distribution caused by differences in powder particle size and density during direct final mixing. Experiments show that the RSD of vitamin D3 content can be as low as 2.8%, which is superior to that of the comparative example using direct mixing (5.7%).DESCRIPTION

[0032] 4. In the invention, the moldability of the composite calcium tablet is improved by the prefabricated granule process and a reasonable final mixing sequence. After wet granulation, the organic calcium source forms granules having a certain particle size and pore structure. In combination with fillers such as mannitol and microcrystalline cellulose and a disintegrant such as croscarmellose sodium, the obtained tablet can have a hardness of 70 to 95 N, a friability of not greater than 0.8%, and a disintegration time of 15 to 25 minutes, with excellent overall performance and suitability for industrial production.

[0033] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flow chart of the method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules proposed by the present invention.

[0034] DETAILED DESCRIPTION

[0035] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are merely some rather than all embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0036] It should be noted that, in this text, relational terms such as first and second are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms include, comprise, or any other variations thereof are intended to cover non-exclusive inclusion, suchDESCRIPTION

[0037] that a process, method, article or apparatus comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article or apparatus. Without further limitation, an element defined by the phrase comprising ... does not exclude the presence of another identical element in the process, method, article or apparatus comprising the element.

[0038] With reference to FIG. 1, the present invention provides a method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules, comprising the following steps: based on the total mass of the composite calcium tablet, weighing 49.0% to 51.0% calcium citrate malate, 14.0% to 16.0% calcium L-lactate, 2.2% to 2.8% casein phosphopeptide, 4.5% to 5.5% inulin, 1.5% to 2.5% resistant dextrin, 0.8% to 1.2% hydroxypropyl methylcellulose, 11.5% to 13.0% microcrystalline cellulose, 8.5% to 9.5% mannitol, 1.5% to 2.1% croscarmellose sodium, 0.15% to 0.25% microencapsulated vitamin D3 powder, 0.4% to 0.7% silicon dioxide and 0.6% to 1.0% magnesium stearate, wherein the sum of the weight percentages of all components is 100%; mixing the calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose for 4 to 6 minutes, adding purified water to prepare a wet mass, wherein the amount of purified water is 8% to 12% of the weight of the mixed dry powder, granulating through an 18 to 24 mesh sieve, drying at 45 to 50°C until the moisture content is 1.5% to 3.0%, and sizing through a 20 to 30 mesh sieve to obtain organic calcium-casein phosphopeptide prefabricated granules; mixing the microencapsulated vitamin D3 powder with microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose by anDESCRIPTION

[0039] equal-increment method under light-shielded conditions to obtain vitamin D3 premixed powder; wherein the equal-increment method means first mixing the microencapsulated vitamin D3 powder with an equal mass of microcrystalline cellulose, and then successively adding and mixing microcrystalline cellulose in an amount equal to or less than the already mixed material until all of the microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose has been added; mixing the organic calcium-casein phosphopeptide prefabricated granules, the vitamin D3 premixed powder, the remaining microcrystalline cellulose, mannitol and croscarmellose sodium at 15 to 25 rpm for 8 to 12 minutes, then adding silicon dioxide and magnesium stearate, mixing for 2 to 3 minutes, and tableting to obtain the composite calcium tablet.

[0040] EXAMPLE 1

[0041] Based on the total mass of the composite calcium tablet, the following components are weighed. Details are shown in Table 1.

[0042] Table 1 Parameters of Composite Calcium Tablet Components

[0043] WEIGHT COMPONENT COMPONENT WEIGHT PERCENTAGE PERCENTAGE

[0044] Calcium citrate malate 50.000% Calcium L-lactate 15.000%

[0045] Casein phosphopeptide 2.500% Inulin 5.000%

[0046] Hydroxypropyl

[0047] Resistant dextrin 2.000% 1.000%

[0048] methylcellulose

[0049] Microcrystalline cellulose 12.150% Mannitol 9.000%

[0050] Microencapsulated vitamin

[0051] Croscarmellose sodium 1.800% 0.200%

[0052] D3 powder

[0053]

[0054] DESCRIPTION

[0055] Silicon dioxide 0.550% Magnesium stearate 0.800%

[0056] Total 100.000%

[0057]

[0058] Calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose are respectively passed through a 60-mesh sieve and then added to a wet granulator, followed by mixing for 5 minutes. Purified water equivalent to 10% of the weight of the above mixed dry powder is added to prepare a wet mass. The wet mass is granulated through a 20-mesh sieve, dried at 48°C until the moisture content is 2.2%, and sized through a 24-mesh sieve to obtain organic calcium-casein phosphopeptide prefabricated granules.

[0059] The microencapsulated vitamin D3 powder and microcrystalline cellulose accounting for 10% of the total amount of microcrystalline cellulose are premixed by the equal-increment method under light-shielded conditions to obtain vitamin D3 premixed powder. The equal-increment method is as follows: first, the microencapsulated vitamin D3 powder is mixed with an equal mass of microcrystalline cellulose, and then microcrystalline cellulose in an amount equal to the already mixed material is successively added and mixed until all of the microcrystalline cellulose accounting for 10% of the total amount of microcrystalline cellulose has been added.

[0060] The organic calcium-casein phosphopeptide prefabricated granules, vitamin D3 premixed powder, remaining microcrystalline cellulose, mannitol and croscarmellose sodium are added to a three-dimensional mixer and mixed at 20 rpm for 10 minutes. Silicon dioxide and magnesium stearate are then added, followed by continued mixing for 3 minutes. The mixture is tableted by a rotaryDESCRIPTION

[0061] tablet press to obtain the composite calcium tablet.

[0062] EXAMPLE 2

[0063] Based on the total mass of the composite calcium tablet, the following components are weighed: 49.0% calcium citrate malate, 16.0% calcium L-lactate, 2.2% casein phosphopeptide, 5.5% inulin, 1.5% resistant dextrin, 1.2% hydroxypropyl methylcellulose, 11.5% microcrystalline cellulose, 9.5% mannitol, 1.5% croscarmellose sodium, 0.25% microencapsulated vitamin D3 powder, 0.7% silicon dioxide and 0.65% magnesium stearate, wherein the sum of the weight percentages of all components is 100%.

[0064] Calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose are respectively passed through a 60-mesh sieve and then added to a wet granulator, followed by mixing for 4 minutes. Purified water equivalent to 8% of the weight of the above mixed dry powder is added to prepare a wet mass. The wet mass is granulated through an 18-mesh sieve, dried at 45°C until the moisture content is 3.0%, and sized through a 20-mesh sieve to obtain organic calcium-casein phosphopeptide prefabricated granules.

[0065] The microencapsulated vitamin D3 powder and microcrystalline cellulose accounting for 5% of the total amount of microcrystalline cellulose are premixed by the equal-increment method under light-shielded conditions to obtain vitamin D3 premixed powder. The organic calcium-casein phosphopeptide prefabricated granules, vitamin D3 premixed powder, remaining microcrystalline cellulose, mannitol and croscarmellose sodium are added to a three-dimensional mixer and mixed at 15 rpm for 12 minutes. Silicon dioxide and magnesium stearate are then added, followed by continued mixing for 2 minutes. The mixture is tableted by aDESCRIPTION

[0066] rotary tablet press to obtain the composite calcium tablet.

[0067] EXAMPLE 3

[0068] Based on the total mass of the composite calcium tablet, the following components are weighed: 51.0% calcium citrate malate, 14.0% calcium L-lactate, 2.8% casein phosphopeptide, 4.5% inulin, 2.5% resistant dextrin, 0.8% hydroxypropyl methylcellulose, 13.0% microcrystalline cellulose, 8.5% mannitol, 2.1% croscarmellose sodium, 0.15% microencapsulated vitamin D3 powder, 0.4% silicon dioxide and 1.0% magnesium stearate, wherein the sum of the weight percentages of all components is 100%.

[0069] Calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose are respectively passed through a 60-mesh sieve and then added to a wet granulator, followed by mixing for 6 minutes. Purified water equivalent to 12% of the weight of the above mixed dry powder is added to prepare a wet mass. The wet mass is granulated through a 24-mesh sieve, dried at 50°C until the moisture content is 1.5%, and sized through a 30-mesh sieve to obtain organic calcium-casein phosphopeptide prefabricated granules.

[0070] The microencapsulated vitamin D3 powder and microcrystalline cellulose accounting for 15% of the total amount of microcrystalline cellulose are premixed by the equal-increment method under light-shielded conditions to obtain vitamin D3 premixed powder. The organic calcium-casein phosphopeptide prefabricated granules, vitamin D3 premixed powder, remaining microcrystalline cellulose, mannitol and croscarmellose sodium are added to a three-dimensional mixer and mixed at 25 rpm for 8 minutes. Silicon dioxide and magnesium stearate are then added, followed by continued mixing for 3 minutes. The mixture is tableted by aDESCRIPTION

[0071] rotary tablet press to obtain the composite calcium tablet.

[0072] COMPARATIVE EXAMPLE 1

[0073] Compared with Example 1, Comparative Example 1 does not include casein phosphopeptide or inulin, and the amount of microcrystalline cellulose is adjusted to 19.650%; the remaining components and preparation method are the same as those in Example 1.

[0074] COMPARATIVE EXAMPLE 2

[0075] Compared with Example 1, in Comparative Example 2, the microencapsulated vitamin D3 powder participates in wet granulation and drying together with calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose (i.e., the microencapsulated vitamin D3 powder is added in step (2)); the remaining components and preparation method are the same as those in Example 1.

[0076] COMPARATIVE EXAMPLE 3

[0077] Compared with Example 1, in Comparative Example 3, all raw materials are not subjected to prefabricated granule treatment, that is, all components (except magnesium stearate and silicon dioxide) are directly mixed and then tableted; the remaining components and preparation method are the same as those in Example 1.

[0078] Test Methods:

[0079] Tablet hardness: measured using a tablet hardness tester; 10 tablets are sampled and the average value is calculated.

[0080] Friability: measured by a tablet friability test method.

[0081] Disintegration time: measured by a disintegration time test method, using water as the medium at a temperature of 37 °C.

[0082] Calcium release rate in artificial gastric juice at 30 minutes: a sample is placedDESCRIPTION

[0083] in artificial gastric juice with a pH of 1.2, the temperature is controlled at 37°C, and after shaking for 30 minutes, the sample is filtered. The calcium content released into the solution is determined by EDTA titration or atomic absorption spectroscopy, and the calcium release rate is calculated. Calcium release rate (%) = (released calcium amount / total calcium amount of the sample) x 100%.

[0084] Soluble calcium retention rate in artificial intestinal juice at 60 minutes: the sample treated with artificial gastric juice is transferred into artificial intestinal juice with a pH of 6.8, the temperature is controlled at 37°C, and after shaking for 60 minutes, the sample is filtered. The soluble calcium content in the solution is determined, and the soluble calcium retention rate is calculated. Soluble calcium retention rate (%) = (soluble calcium amount in intestinal juice / total calcium amount of the sample) x 100%.

[0085] RSD of vitamin D3 content: samples are taken from different positions of the final mixed material (upper, middle, lower, left, right and other positions, with at least 10 sampling points), and the vitamin D3 content in each sample is determined by high-performance liquid chromatography (HPLC), followed by calculation of the relative standard deviation (RSD).

[0086] Vitamin D3 retention rate: the sample is placed under conditions of 40°C and 75% relative humidity for 3 months. The vitamin D3 content before and after storage is determined by HPLC, and the retention rate is calculated. Retention rate (%) = (content after storage / content before storage) x 100%.DESCRIPTION

[0087] Experimental results: details are shown in Table 2.

[0088] Table 2 Comparison of Experimental Result Parameters

[0089] COMPARATIVE COMPARATIVE COMPARATIVE TEST ITEM EXAMPLE 1

[0090] EXAMPLE 1 EXAMPLE 2 EXAMPLE 3

[0091] Tablet hardness / N 82 78 80 69

[0092] Friability / % 0.42 0.58 0.51 0.86

[0093] Disintegration time /

[0094] 18.6 22.4 21.3 27.8 min

[0095] 30-min gastric Ca

[0096] 84.7 76.2 78.5 70.4 release / %

[0097] 60-min intestinal

[0098] 61.5 50.8 52.1 46.7 soluble Ca retention / %

[0099] Vitamin D3 content

[0100] 2.8 3.6 4.9 5.7 RSD / %

[0101] Vitamin D3 retention (3

[0102] months, 40°C / 75%RH) 93.4 91.2 84.6 88.5

[0103] / %

[0104]

[0105] Analysis of Experimental Results:

[0106] The experimental results show the following:

[0107] (1) Moldability: the tablet hardness of Example 1 is 82 N, and the friability is only 0.42%, both of which are superior to those of all comparative examples. Comparative Example 3 (direct mixing and tableting) has the lowest hardness (69 N) and the highest friability (0.86%), indicating that the prefabricated granule process can significantly improve the moldability of tablets. Comparative ExampleDESCRIPTION

[0108] 1 (without casein phosphopeptide and inulin) has a hardness of 78 N and a friability of 0.58%, while Comparative Example 2 (vitamin D3 participating in wet granulation) has a hardness of 80 N and a friability of 0.51%, both inferior to Example 1. This indicates that, after casein phosphopeptide, inulin and the calcium source are combined through the prefabricated granule process, the compression molding performance of the granules can be optimized.

[0109] (2) Disintegration time: the disintegration time of Example 1 is 18.6 minutes, which is superior to those of Comparative Example 1 (22.4 minutes), Comparative Example 2 (21.3 minutes) and Comparative Example 3 (27.8 minutes). This indicates that the addition of casein phosphopeptide and inulin and the prefabricated granule process help improve the disintegration performance of the tablets. Inulin and resistant dextrin, as water-soluble dietary fibers, have good wettability and water-absorbing swelling properties, which can promote rapid penetration of water into the interior of the tablet and accelerate disintegration.

[0110] (3) Calcium release level: in Example 1, the calcium release rate in artificial gastric juice at 30 minutes reaches 84.7%, and the soluble calcium retention rate in artificial intestinal juice at 60 minutes reaches 61.5%, both of which are significantly superior to those of all comparative examples. This indicates that, after casein phosphopeptide and the organic calcium source are combined through the prefabricated granule process, casein phosphopeptide can fully contact the calcium source inside the granules, be released together with calcium in gastric juice, and then effectively chelate calcium ions in a weakly alkaline intestinal environment, preventing formation of insoluble calcium salt precipitates, thereby significantly improving the release and soluble retention levels of calcium in simulated gastrointestinal environments.DESCRIPTION

[0111] (4) Vitamin D3 mixing uniformity: the RSD of vitamin D3 content in Example 1 is 2.8%, which is superior to those of Comparative Example 1 (3.6%), Comparative Example 2 (4.9%) and Comparative Example 3 (5.7%). This indicates that, after the microencapsulated vitamin D3 powder is premixed with a specified proportion of microcrystalline cellulose by the equal-increment method and then subjected to low-shear mixing with the prefabricated granules, the distribution uniformity of trace vitamin D3 in the final mixed material can be effectively improved. Comparative Example 3 has an RSD as high as 5.7% due to direct mixing, indicating the poorest uniformity.

[0112] (5) Vitamin D3 storage stability: under accelerated conditions (40°C / 75% RH, 3 months), the vitamin D3 retention rate of Example 1 reaches 93.4%, which is significantly superior to that of Comparative Example 2 (84.6%, in which vitamin D3 participates in wet granulation and drying). This indicates that allowing microencapsulated vitamin D3 to bypass the wet granulation and hot-air drying processes can effectively reduce its degradation loss under hot and humid conditions. Although Comparative Example 3 (88.5%) does not undergo wet granulation, vitamin D3 is directly mixed with all raw materials without premixing, resulting in poor dispersion uniformity in the final mixed material. A locally high concentration may cause microenvironmental instability, and therefore the retention rate is lower than that of Example 1.

[0113] In summary, Example 1 adopts the organic calcium-casein phosphopeptide prefabricated granule process and adds the microencapsulated vitamin D3 powder under light-shielded conditions after drying and sizing. Compared with all comparative examples, Example 1 exhibits excellent performance in tablet hardness, friability, disintegration time, calcium release rate in artificial gastricDESCRIPTION

[0114] juice, soluble calcium retention rate in artificial intestinal juice, vitamin D3 mixing uniformity and accelerated stability.

[0115] The method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules provided by the present invention uses readily available raw materials, has a stable process and simple operation, and is suitable for large-scale industrial production. The prepared composite calcium tablet has good moldability, disintegration performance, calcium release performance and vitamin D3 stability, and can be widely applied in the fields of nutritional supplements and health foods.

[0116] The above merely describes specific embodiments of the present application, and the protection scope of the present application is not limited thereto. Any change or substitution that can be readily conceived by a person skilled in the art within the technical scope disclosed in the present application shall fall within the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope of the claims.

[0117] Finally, the above merely describes preferred embodiments of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, improvement or the like made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

CLAIMS1. A method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules, characterized by comprising the following steps:(1) based on the total mass of the composite calcium tablet, weighing the following components by weight percentage: 49.0% to 51.0% calcium citrate malate, 14.0% to 16.0% calcium L-lactate, 2.2% to 2.8% casein phosphopeptide, 4.5% to 5.5% inulin, 1.5% to 2.5% resistant dextrin, 0.8% to 1.2% hydroxypropyl methylcellulose, 11.5% to 13.0% microcrystalline cellulose, 8.5% to 9.5% mannitol, 1.5% to 2.1% croscarmellose sodium, 0.15% to 0.25% microencapsulated vitamin D3 powder, 0.4% to 0.7% silicon dioxide and 0.6% to 1.0% magnesium stearate, wherein the sum of the weight percentages of all components is 100%; wherein the total mass refers to the mass of the finally prepared composite calcium tablet;(2) mixing the calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose for 4 to 6 minutes, adding purified water to prepare a wet mass, wherein the amount of purified water is 8% to 12% of the weight of the mixed dry powder in step (2), granulating through an 18 to 24 mesh sieve, drying at 45 to 50°C until the moisture content is 1.5% to 3.0%, and sizing through a 20 to 30 mesh sieve to obtain organic calcium-casein phosphopeptide prefabricated granules;(3) mixing the microencapsulated vitamin D3 powder with microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose by an equal-increment method under light- shielded conditions to obtain vitamin D3 premixed powder; wherein the equal-increment method means that the microencapsulated vitamin D3 powder is first mixed with an equal mass ofCLAIMSmicrocrystalline cellulose, and then microcrystalline cellulose in an amount equal to or less than the already mixed material is successively added and mixed until all of the microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose has been added; wherein the total amount of microcrystalline cellulose refers to the total amount of microcrystalline cellulose weighed in step (1);(4) mixing the organic calcium-casein phosphopeptide prefabricated granules, the vitamin D3 premixed powder, the remaining microcrystalline cellulose, mannitol and croscarmellose sodium at 15 to 25 rpm for 8 to 12 minutes, then adding silicon dioxide and magnesium stearate, mixing for 2 to 3 minutes, and then tableting to obtain the composite calcium tablet; wherein the remaining microcrystalline cellulose refers to the balance obtained after deducting, from the total amount of microcrystalline cellulose weighed in step (1), the microcrystalline cellulose accounting for 5% to 15% of the total amount of microcrystalline cellulose used in step (3).

2. The method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules according to claim 1 , characterized in that, in step (1), based on the total mass of the composite calcium tablet, the components consist of the following weight percentages: 50.000% calcium citrate malate, 15.000% calcium L-lactate, 2.500% casein phosphopeptide, 5.000% inulin, 2.000% resistant dextrin, 1.000% hydroxypropyl methylcellulose, 12.150% microcrystalline cellulose, 9.000% mannitol, 1.800% croscarmellose sodium, 0.200% microencapsulated vitamin D3 powder, 0.550% silicon dioxide and 0.800% magnesium stearate.

3. The method for preparing a composite calcium tablet based on organicCLAIMScalcium-casein phosphopeptide prefabricated granules according to claim 1, characterized in that, in step (1), the calcium citrate malate, calcium L-lactate, casein phosphopeptide, inulin, resistant dextrin and hydroxypropyl methylcellulose are respectively passed through a 60-mesh sieve after weighing, and then the mixing operation of step (2) is performed.

4. The method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules according to claim 1, characterized in that, in step (1), the potency of the microencapsulated vitamin D3 powder is 90000 to 110000 lU / g.

5. The method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules according to claim 1 , characterized in that, in step (2), the mixing time is 5 minutes; the amount of purified water is 10% of the weight of the mixed dry powder in step (2); the sieve mesh for granulation is 20 mesh; the drying temperature is 48°C; drying is carried out until the moisture content is 2.0% to 2.5%; and the sieve mesh for sizing is 24 mesh.

6. The method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules according to claim 1, characterized in that the composite calcium tablet contains no calcium carbonate, calcium citrate, calcium acetate or vitamin K.

7. The method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules according to claim 1, characterized in that, in step (4), the tableting is performed using a rotary tablet press.

8. The method for preparing a composite calcium tablet based on organicCLAIMScalcium-casein phosphopeptide prefabricated granules according to claim 1, characterized in that, in step (4), the hardness of the composite calcium tablet is 70 to 95 N, the friability is not greater than 0.8%, and the disintegration time is 15 to 25 minutes; wherein the hardness is measured by a tablet hardness determination method, the friability is measured by a tablet friability test method, and the disintegration time is measured by a disintegration time test method.

9. The method for preparing a composite calcium tablet based on organic calcium-casein phosphopeptide prefabricated granules according to claim 1, characterized in that, in step (4), the mixing of the organic calcium-casein phosphopeptide prefabricated granules, the vitamin D3 premixed powder, the remaining microcrystalline cellulose, mannitol and croscarmellose sodium is performed in a mixer.

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