Calcium carbonate D3 granule formula and production process thereof

Abstract

The invention discloses a calcium carbonate D3 granule formula and a production process thereof, and relates to the technical field of calcium carbonate D3 granules, the calcium carbonate D3 granule formula comprises a component A and a component B, the mass ratio of the component A to the component B is 1.245-1.255: 1; the component A comprises the following components in percentage by weight: 33.0%-33.3% of calcium carbonate, 33.0%-33.3% of a sweetening agent, 33.0%-33.3% of sucrose powder I and 0.1%-1.0% of vitamin D3 powder. The invention relates to the technical field of calcium carbonate D3 granules, chitosan is selected as a base material, the good biocompatibility and degradability of the chitosan provide guarantee for the safety of products, and in the synthesis process, the content of the vitamin D3 powder in the component A is reduced; the introduced 2-acrylamido-2-methylpropanesulfonic acid (AMPS) contains an ionizable sulfonic acid group, the ionization degree of the AMPS can be changed in different pH environments, and the AMPS can promote synergistic absorption of vitamin D3 and calcium carbonate in gastrointestinal tracts in a gastric acid environment (pH is about 1-3) and in the aspect of human body absorption, so that the bioavailability of calcium is improved; a remarkable optimization effect is brought to the application of the calcium supplement, and the calcium supplement requirement of a patient is better met.

Description

Technical Field

[0001] The present invention relates to the technical field of calcium carbonate D3 granules, and specifically to a calcium carbonate D3 granule formulation and its production process. Background Art

[0002] Calcium carbonate D3 granules are a chemical drug used as a calcium supplement for children, pregnant and lactating women, menopausal women, the elderly, etc., and help prevent and treat osteoporosis. Vitamin D3 is an essential vitamin for the human body, and the daily dose of vitamin D3 supplementation is 400 - 1000 IU / d, which is equivalent to 10 μg - 25 μg; There are certain defects in the prior art. Firstly, the production process of calcium carbonate D3 granules usually lacks effective guarantee measures for the stability and absorption efficiency of vitamin D3. The traditional formulation and process do not consider the influence of different pH environments in the gastrointestinal tract on vitamin D3, and it is unable to effectively protect vitamin D3 from being destroyed in the gastric acid environment, resulting in a decrease in its activity. In the neutral to weakly alkaline environment of the intestine, it is also difficult to achieve the slow release of vitamin D3 and the synergistic promotion effect with the dissolution and absorption of calcium carbonate. Secondly, the existing vitamin D3 is extremely unstable and is easily decomposed by light, heat, oxygen, and acid. How to ensure the uniform mixing of vitamin D3 and reduce its decomposition has always been a difficulty in the preparation of calcium carbonate D3 granules. For this reason, we propose a calcium carbonate D3 granule formulation and its production process. Summary of the Invention

[0003] The purpose of the present invention is to provide a calcium carbonate D3 granule formulation and its production process.

[0004] To solve the problems raised in the above background art, the present invention provides the following technical solution: A calcium carbonate D3 granule formulation, the calcium carbonate D3 granule formulation includes two components, A and B, and the mass ratio of component A to component B is 1.245 - 1.255:1; Component A includes the following components by weight percentage: Calcium carbonate 33.0% - 33.3%, sweetener 33.0% - 33.3%, sucrose powder 1 33.0% - 33.3%, vitamin D3 powder 0.1% - 1.0%, and 0.5% - 1.5% of a polymer CS - g - AMPS - CA synthesized based on chitosan with pH responsiveness and vitamin D3 affinity. The sum of the weight percentages of each component is 100%; Component B includes the following components by weight percentage: Calcium carbonate 43% - 44%, sucrose powder 2 53% - 54%, excipient 1% - 2%, essence 1.2% - 1.4%. The sum of the weight percentages of each component is 100%.

[0005] As a further aspect of the present invention: The polymer CS-g-AMPS-CA is synthesized by the following method: First, chitosan is dissolved in a dilute acetic acid solution to prepare a mixed monomer solution with a mass fraction of 4%-6%. After stirring evenly at 45°C-55°C, chitosan and 2-acrylamido-2-methylpropanesulfonic acid (AMPS) are added in a molar ratio of chitosan to 2-acrylamido-2-methylpropanesulfonic acid of 1:2.5-3.5. Subsequently, ammonium persulfate (APS) as an initiator is added, and the amount of ammonium persulfate used is 0.8%-1.2% of the total mass of the mixed monomer solution. The reaction is carried out at 60°C-70°C for 8h-12h under a nitrogen atmosphere to obtain a chitosan-g-AMPS copolymer. Subsequently, the above chitosan-g-AMPS copolymer is further modified to introduce a vitamin D3 specific binding group, and then the chitosan-g-AMPS copolymer and cholic acid are subjected to an esterification reaction under the catalysis of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). The amounts of dicyclohexylcarbodiimide and 4-dimethylaminopyridine used are 1.5%-2.5% and 0.3%-0.7% of the mass of cholic acid respectively, and the reaction is carried out at room temperature for 20h-28h to obtain a polymer CS-g-AMPS-CA with pH responsiveness and vitamin D3 affinity.

[0006] As a further aspect of the present invention: The sweetener is one or more of mannitol, acesulfame potassium, and sorbitol; The auxiliary materials are one or more of povidone, copovidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; The essence is a powder essence.

[0007] In addition, the present invention also provides a production process for calcium carbonate D3 granules, including the following steps: Step 1: Take components A and B according to the mass ratio. Sucrose I uses a 60-mesh sieve plate, and sucrose II uses a 100-mesh sieve plate, and they are respectively pulverized in a pulverizer. Step 2: Component A is granulated by dry granulation, including: a1, Take vitamin D3 powder and calcium carbonate for equal increment mixing, and pass through 80-mesh, 60-mesh, 50-mesh, 24-mesh, and 14-mesh sieves before each mixing step. Then mix with the sweetener, sucrose powder I, and the polymer CS-g-AMPS-CA, pass through a 14-mesh sieve, and put it into a mixing pot. The mixing speed is 15r / min-20r / min; b1. Feed the well-mixed Component A into a dry granulator. The operating parameters of the dry granulator are as follows: the extrusion pressure is 25 MPa - 45 MPa, the extrusion speed is 5 r / min - 10 r / min, and the feeding speed is 15 r / min - 25 r / min to obtain Component A granules. c1. Screen through an 80-mesh sieve, and the fine powder under the sieve is further subjected to secondary dry granulation. d1. Manually mix the materials obtained from the first and second granulations. Component B is granulated in one step, including: a2. Inhale the Component B material into a fluidized bed dryer. Set the drying parameters according to the inlet air frequency of 35 Hz - 50 Hz, the inlet air temperature of 70 °C - 80 °C, the material temperature of 45 °C - 65 °C, the flow rate of 800 - 920 r / min, the internal atomization pressure of 0.2 MPa - 0.4 MPa, and the external atomization pressure of 0.2 MPa - 0.4 MPa, and run. When the material temperature reaches 50 °C, stop spraying the liquid, and end the drying when the particle moisture is less than 1.5%. b2. Discharge the material, screen through a 14-mesh sieve, and collect the material B1 under the 14-mesh sieve. c2. Collect the particles on the 14-mesh sieve for size reduction. Use a 2.0 mm - 2.5 mm sieve mesh, and the size reduction speed is 110 r / min - 130 r / min to collect the material B2 after size reduction. d2. Mix B1 and B2 to obtain Component B granules. Step Three: Mix the granules prepared from Component A and Component B in Step Two, including: a3. Take the granules prepared from Component A and Component B according to the mass ratio of Component A to Component B of 1.245 - 1.255:1. b3. Feed the materials into the mixing pot in sequence. Set the mixing parameters according to the mixing speed of 8 r / min - 10 r / min and the premixing time of 25 min - 30 min, and run to obtain uniformly mixed calcium carbonate D3 granules. Step Four: Pack the calcium carbonate D3 granules prepared in Step Three.

[0008] Adopting the above technical solution, compared with the prior art, the beneficial effects of the present invention are as follows: 1. The present invention selects chitosan as the base material, and its good biocompatibility and degradability ensure the safety of the product. During the synthesis process, 2-acrylamido-2-methylpropanesulfonic acid (AMPS) introduced contains ionizable sulfonic acid groups, and its ionization degree changes in different pH environments. In the gastric acid environment (pH about 1 - 3), the sulfonic acid groups are protonated, causing the polymer molecular chain to contract and form a compact structure, effectively protecting vitamin D3 from gastric acid erosion. In the neutral to weakly alkaline environment (pH about 6 - 8) of the intestine, the sulfonic acid groups are deprotonated, and the molecular chain stretches, facilitating the release of vitamin D3. At the same time, under the catalysis of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), an esterification reaction is carried out with cholic acid. The cholic acid molecule has a unique hydrophobic structure and spatial conformation, which can form specific hydrophobic interactions and hydrogen bond bindings with vitamin D3, thereby enhancing the affinity for vitamin D3, improving the loading efficiency and stability of vitamin D3, making the prepared calcium carbonate D3 granules have a great improvement in the stability of vitamin D3, effectively reducing its decomposition during production, storage, and in the gastrointestinal tract. In terms of human absorption, it can promote the synergistic absorption of vitamin D3 and calcium carbonate in the gastrointestinal tract, improve the bioavailability of calcium, bring a significant optimization effect to the application of calcium supplements, and better meet the calcium supplementation needs of patients; 2. The present invention prepares high-quality calcium carbonate D3 granules by using two completely different granulation technologies, dry granulation and one-step granulation. In the whole preparation process, the dry granulation technology effectively avoids the contact of vitamin D3 with excessive moisture and high-temperature environment through its unique extrusion, crushing and other operation steps, reducing the decomposition risk of vitamin D3 caused by moisture and heat, and ensuring the stability of vitamin D3. The one-step granulation technology, on the other hand, makes the material achieve an efficient granulation process in the fluidized bed dryer by precisely controlling parameters such as the inlet air frequency, temperature, material temperature, flow rate, and atomization pressure, ensuring the uniformity of the granules. This process combination method not only has a simple and clear operation process, is easy for operators to master and execute, but also has high adaptability in large-scale batch production, and can stably produce calcium carbonate D3 granule products with consistent quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 It is a schematic diagram of mixed sampling in the embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0010] The following further describes the specific embodiments of the present invention in conjunction with the drawings. It should be noted here that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation to the present invention.

[0011] In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0012] Please refer to the appendix Figure 1 , a calcium carbonate D3 granule formulation of the present invention, the calcium carbonate D3 granule formulation includes two components A and B, and the mass ratio of component A to component B is 1.247:1; Component A includes the following components by weight percentage: Calcium carbonate 33.023%, sweetener 33.023%, sucrose powder 1 33.023%, vitamin D3 powder 0.331%, and 0.600% of a polymer CS-g-AMPS-CA synthesized based on chitosan and having pH responsiveness and vitamin D3 affinity. The sum of the weight percentages of each component is 100%; Component B includes the following components by weight percentage: Calcium carbonate 43.621%, sucrose powder 2 53.894%, excipient 1.243%, essence 1.242%, and the sum of all components is 100%.

[0013] Furthermore, the sweetener is mannitol, the excipient is polyvinylpyrrolidone K30, and the essence is orange powder essence.

[0014] Among them, the vitamin D3 powder in this embodiment is selected with a standard of 200 international units. Taking the total batch of 151.7 kg as an example, the specific components and dosages are as follows:

[0015] A production process of calcium carbonate D3 granules includes the following steps: Step 1: Take components A and B according to the mass ratio. Sucrose 1 uses a 60-mesh sieve plate, and sucrose 2 uses a 100-mesh sieve plate, and respectively pulverize them in a turbo self-cooling dust-free pulverizer; Step 2, Component A is granulated by dry granulation, and component B is granulated by one-step granulation; Step 3, Mix the granules prepared from component A and component B in step 2 to obtain calcium carbonate D3 granules; Step 4, Package the calcium carbonate D3 granules prepared in step 3.

[0016] Furthermore, the dry granulation of component A in step 2 includes the following steps: a1, Take the vitamin D3 powder and calcium carbonate for equal increment mixing. Before each step of mixing, pass through 80-mesh, 60-mesh, 50-mesh, 24-mesh, and 14-mesh sieves respectively, and finally mix with the sweetener and sucrose powder 1, pass through a 14-mesh sieve, and put it into the mixing pot with a mixing speed of 15 r / min; b1. Put the well - mixed Component A into a dry granulator. The working parameters of the dry granulator are: extrusion pressure is 25 MPa - 45 MPa, extrusion speed is 5 r / min - 10 r / min, and feeding speed is 15 r / min - 25 r / min. Obtain Component A granules; c1. Screen with an 80 - mesh sieve, and the fine powder under the sieve is continuously granulated by dry granulation for the second time; d1. Manually mix the materials granulated for the first and second times.

[0017] In this embodiment, confirm that the weighing area, equipment, and tools used for batching are clean. Turn on the electronic scale, confirm that the electronic scale is in normal working condition, calibrate it with the specified weights, weigh according to the following table, record the sample weighing amount after weighing each material, and replace the clean weighing spoon and gloves. Dry granulation (taking the total batch of 151.7 kg as an example): The total amount of materials is 84.19 kg, and the prescription is as follows:

[0018] Then, select an electronic platform scale with a range of 0 - 15 kg to weigh materials in the range of 0 - 5.0 kg, and select an electronic platform scale with a range of 0 - 60 kg to weigh materials in the range of 5.0 kg - 60.0 kg. After weighing each material, fill in the relevant records, and stick a material label on the inner - layer medicinal low - density polyethylene bag of each raw and auxiliary material, indicating the material name, batch number, and quantity. After weighing the materials, store the remaining materials in the raw and auxiliary material temporary storage area, store the prepared materials in the batching temporary storage area, and clean the site after batching.

[0019] Confirm that the total mixing chamber and the 100L mixing pot of the mixing equipment are clean. The operator installs the mixing hopper and accessories according to the job requirements, and manually mix the materials by the equal - increment method. The operator takes vitamin D3 powder and calcium carbonate and manually mixes them by the equal - increment method. Pass through 80 - mesh, 60 - mesh, 50 - mesh, 24 - mesh, and 14 - mesh sieves before each step of mixing, and finally mix with mannitol and sucrose powder, pass through a 14 - mesh sieve, and put them into the mixing pot, and mix according to the following parameters.

[0020]

[0021] At this time, it is necessary to confirm that the dry granulator is clean. The operator installs the equipment and accessories according to the job requirements, set the drying parameters according to the following table, and run:

[0022] Record the real - time pressure during the operation. When the real - time pressure is less than 24, perform hydraulic operation to adjust the pressure. After the first - stage dry granulation is completed, screen with an 80 - mesh sieve, and the fine powder under the sieve is continuously granulated by dry granulation for the second time. Manually mix the materials granulated for the first and second times.

[0023] In an implementable manner, the one-step granulation of component B in step two includes the following steps: a2. Inhale the component B material into the fluidized bed dryer, set the drying parameters according to the inlet air frequency of 35 Hz - 50 Hz, the inlet air temperature of 70°C - 80°C, the material temperature of 45°C - 65°C, the flow rate of 800 r / min - 920 r / min, the internal atomization pressure of 0.2 MPa - 0.4 MPa, and the external atomization pressure of 0.2 MPa - 0.4 MPa, and run. When the material temperature reaches 50°C, stop spraying the liquid, and end the drying when the particle moisture is less than 1.5%; b2. Discharge the material, manually pass it through a 14-mesh sieve, and collect the material B1 under the 14-mesh sieve; c2. Collect the particles on the 14-mesh sieve for sizing. Use a 2.0-mm sieve mesh, with a sizing speed of 110 r / min, and collect the sized material B2; d2. Mix B1 and B2 to obtain the component B particles.

[0024] Specifically, on the basis of the above embodiment, confirm that the weighing area, equipment, and tools used for batching have been cleaned. Turn on the electronic scale, confirm that the electronic scale is in normal working condition, calibrate it with the specified weights, weigh according to the following table, record the sample weighing amount after weighing each material, and replace the clean weighing spoon and gloves. One-step granulation (taking a total batch of 151.7 kg as an example): The total amount of material per pot is 67.51 kg, and the prescription is as follows:

[0025] Select an electronic platform scale with a range of 0 - 15 kg to weigh materials in the range of 0 - 5.0 kg, select an electronic platform scale with a range of 0 - 60 kg to weigh materials in the range of 5.0 kg - 60.0 kg. After weighing each material, fill in the relevant records, and stick a material label on the inner layer of the medicinal low-density polyethylene bag of each raw and auxiliary material, indicating the material name, batch number, and quantity. After weighing the materials, store the remaining materials in the raw and auxiliary material temporary storage area, store the prepared materials in the batching temporary storage area, and clean the site after batching.

[0026] Confirm that the fluidized bed has been cleaned. The operator installs the fluidized bed equipment and accessories according to the job requirements, inhales the sucrose powder second-class one-step granulation material into the fluidized bed dryer, sprays the liquid for granulation, stops spraying the liquid when the material temperature reaches 50°C, and ends the drying when the particle moisture is less than 1.5%. Set the drying parameters according to the following table:

[0027] (1) Record parameters such as the fan frequency, inlet air temperature, material temperature, and exhaust air temperature during the operation process; (2) After the spraying is completed, take samples to detect the particle properties. When the particle moisture is less than 1.5%, stop the drying; (3) Discharge the materials, sieve them manually through a 14-mesh sieve, and collect the materials B1 under the 14-mesh sieve; (4) Collect the particles on the 14-mesh sieve for granulation. Use a 2.0-mm sieve mesh and a granulation speed of 110 r / min. Collect the materials B2 after granulation; (5) Mix B1 and B2 to obtain the B-component particles.

[0028] In an implementable manner, the mixing of the particles prepared from the A component and the B component in step two in step three includes the following steps: a3. Take the particles prepared from the A component and the B component according to the mass ratio of the A component to the B component of 1.245 - 1.255:1; b3. Put the materials into the mixing pot in sequence, set the mixing parameters according to a mixing speed of 8 r / min and a premixing time of 25 minutes, and run to obtain the uniformly mixed calcium carbonate D3 particles.

[0029] Specifically, confirm that the total mixing chamber and the mixing equipment have been cleaned. The operator installs the mixing hopper and accessories according to the post requirements. The operator goes to the intermediate product temporary storage room to collect the dry granulation materials and one-step granulation materials according to the batch production record, checks and confirms the material name, batch number, and quantity, weighs the materials. The operator goes to the weighing room according to the batch production record to weigh the dry granulation materials and one-step granulation materials required for mixing.

[0030] Charging (taking the total batch of 151.7 kg as an example): The operator puts the materials into the 500-L mixing pot in sequence, sets the mixing parameters according to the following table, and runs:

[0031] After the total mixing stage is completed, sample as shown in the "Mixing Sampling Diagram" attached, take a total of 10 sampling points, and measure the mixing uniformity. Figure 1

[0032] (1) Transfer the mixed intermediate to the intermediate station for weighing, complete the filling of the product label, and then store it in the specified area.

[0033] (2) Calculate the material balance and product yield, and fill in the batch production record and other relevant records in a timely manner.

[0034] (3) Clean the equipment after mixing.

[0035] Results and Analysis The uniformity results of the vitamin D3 content in the calcium carbonate D3 particles prepared in the examples are shown in the following table:

[0036] The results show that the RSD is 1.50. For the calcium carbonate D3 particles prepared by this method, the vitamin D3 content is uniform and stable. ​

[0037] Experimental verification: Experiment 1: Vitamin D3 stability comparison experiment 1.1 Experimental purpose: To verify the stability protection effect of calcium carbonate D3 particles containing polymer CS-g-AMPS-CA on vitamin D3 under different environments, and the synergistic release and absorption effect of vitamin D3 and calcium carbonate in the gastrointestinal tract simulation environment; 1.2 Experimental materials Sample preparation: Experimental group (A2): Prepared according to the example, with a polymer addition amount of 1.0%; Control group (B1): The polymer CS-g-AMPS-CA was removed, and the rest of the formula was the same as A2; Main reagents: Vitamin D3 standard (purity ≥ 98%, Sigma-Aldrich), hydrochloric acid buffer solution (pH 1.2, containing 0.3% pepsin), methanol (chromatographically pure), HPLC mobile phase (methanol: water = 95:5, v / v); Instrumentation: Constant temperature incubator, light box, high performance liquid chromatograph, vortex oscillator; 1.3 Experimental methods 1.31 High temperature stability test Take 5 g of samples from the experimental group (A2) and the control group (B1) respectively, seal them in aluminum foil bags, and place them in a constant temperature oven at 40 °C and 60 °C respectively. Samples are taken at 0, 7, 14, 21, and 28 days, and the vitamin D3 content is determined by HPLC; HPLC detection conditions: Chromatographic column: C18 column (250 mm × 4.6 mm, 5 μm); Flow rate: 1.0 mL / min, detection wavelength: 264 nm, injection volume: 20 μL, column temperature: 30 °C; Degradation rate calculation:

[0038] 1.3.2 Light stability test The samples are placed in a light box with a light intensity of 4500 lx and a temperature of 25 °C. Samples are taken at 0, 7, 14, 21, and 28 days, and the vitamin D3 content is detected by HPLC, and the degradation rate is calculated (the method is the same as 1.3.1); 1.3.3 Acidic environment stability test Weigh 0.5 g of the sample, add 50 mL of hydrochloric acid buffer solution with pH 1.2 (containing 0.3% pepsin), shake in a water bath at 37 °C (100 r / min), take samples at 0, 15, 30, 60, and 120 min, centrifuge at 10000 r / min for 10 min, take the supernatant, detect the residual amount of vitamin D3 by HPLC, and calculate the residual rate:

[0039] 1.4 Experimental results: As shown in Table

[0040] 1.5 Result analysis The degradation rate of vitamin D3 in the experimental group under high temperature, light, and acidic conditions was significantly lower than that in the control group (p < 0.05), indicating that the polymer CS-g-AMPS-CA effectively improved the stability of vitamin D3 through pH-responsive molecular chain contraction (protecting D3 in gastric acid) and cholic acid affinity (reducing photothermal degradation); Experiment 2: Gastrointestinal simulation release and co-absorption experiment 2.1 Experimental purpose Verify the sustained-release characteristics of vitamin D3 and the co-dissolution and absorption effect with calcium carbonate in the simulated gastric (pH 1.2) and intestinal (pH 6.8) environments of calcium carbonate D3 granules.

[0041] 2.2 Experimental materials Samples: The same as in Experiment 1 (Experimental group A2, Control group B1); Main reagents: Hydrochloric acid buffer solution (pH 1.2), phosphate buffer solution (pH 6.8, containing 0.1% bile salt), lanthanum nitrate (used for AAS detection of calcium release); Instrument and equipment: Dissolution tester, atomic absorption spectrometer, pH meter; 2.3 Experimental method 2.3.1 Simulated gastrointestinal release experiment Gastric stage (0 - 2 h): Weigh 0.5 g of the sample, put it into the dissolution cup, add 500 mL of hydrochloric acid buffer solution with pH 1.2, at 37 °C, rotation speed 50 r / min, take 10 mL of samples at 0, 0.5, 1, 1.5, and 2 h (while adding 10 mL of the same-temperature buffer solution at the same time), take the supernatant after centrifugation, detect the concentration of vitamin D3 by HPLC, and detect the concentration of Ca²⁺ by AAS.

[0042] Intestinal stage (after 2 h): Replace it with 500 mL of phosphate buffer solution with pH 6.8 (containing 0.1% bile salt), continue dissolution until 6 h, the sampling time points are 3, 4, 5, and 6 h, and the detection method is the same as above; 2.3.2 Detection method Cumulative release rate of vitamin D3:

[0043] Cumulative dissolution rate of calcium ions:

[0044] Synergistic absorption index:

[0045] 2.4 Experimental results: As shown in Table

[0046] 2.5 Result analysis pH-responsive release: In the gastric acid environment, the release rate of D3 in the experimental group was significantly lower than that in the control group (32% vs 65% within 2 h), indicating that the polymer formed a protective layer. In the intestinal environment, the release rate of D3 in the experimental group accelerated (reaching 95% at 6 h), meeting the "gastric acid protection - intestinal sustained release" design.

[0047] Calcium ion dissolution synergy: In the gastric acid stage, the experimental group had a higher dissolution rate (85% vs 75% at 2 h), and the dissolution was more complete in the intestinal stage (99% vs 90% at 6 h). The synergistic absorption index increased with time, proving a significant synergistic absorption effect between the two in the gastrointestinal tract (p < 0.01); Experiment 3: Cell absorption experiment (Caco-2 cell model) 3.1 Experimental purpose To verify the promoting effect of the polymer on the transmembrane transport of vitamin D3 and calcium ions through the intestinal absorption model and evaluate the improvement effect of bioavailability; 3.2 Experimental materials Cell line: Caco-2 cells, cultured for 21 days to form a confluent monolayer; Reagents: DMEM medium (containing 10% fetal bovine serum, 1% double antibody), Transwell chamber (0.4 μm pore size, Corning), 25-hydroxyvitamin D3 ELISA kit, ICP-MS standard; 3.3 Experimental method Cell culture: Caco-2 cells were seeded at 5×10 4 cells / well in the Transwell chamber and cultured for 21 days, with the medium changed every 2 days.

[0048] Sample preparation: Dissolve particles A2 and B1 in pH 6.8 buffer to prepare a solution containing 100 nM vitamin D3 and 1 mM Ca 2+ ions.

[0049] Transmembrane transport measurement: Add 200 μL of the sample solution to the apical side, add 500 μL of the buffer solution to the basolateral side, incubate at 37 °C, and take 100 μL of the solution from the basolateral side at 0, 15, 30, 60, and 120 min. Detect the concentration of 25-hydroxyvitamin D3 by ELISA and detect Ca 2+ concentration.

[0050] Calculation of transport rate:

[0051] Where: is the transport rate, is the membrane area, is the initial concentration on the apical side; 3.4 Experimental results: As shown in Table

[0052] 3.5 Result analysis The transmembrane transport rates of vitamin D3 and Ca²⁺ in the experimental group were significantly higher than those in the control group (p < 0.01), indicating that the polymer CS-g-AMPS-CA improved the intestinal absorption efficiency by enhancing their co-transport; Experimental conclusion Stability verification: The protection effect of calcium carbonate D3 granules containing the polymer CS-g-AMPS-CA on vitamin D3 in high temperature, light, and acidic environments was significantly better than that of the control group, and the degradation rate decreased by 50% - 60% at a 1.0% addition amount; Release synergistic effect: The polymer achieved "gastric acid protection - intestinal slow release" through a pH-responsive structure, and at the same time promoted the dissolution of calcium ions from calcium carbonate. The co-absorption index of the two increased by 85% - 110% compared with the control group; Improvement of bioavailability: Cell experiments confirmed that the transmembrane transport rates of vitamin D3 and calcium ions in the experimental group were significantly increased.

[0053] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

[0054] Although the present invention is disclosed above in a preferred embodiment, it is not used to limit the present invention. Any person skilled in the art can make possible changes and modifications without departing from the spirit and scope of the present invention. Therefore, any modification, equivalent change, and modification made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention shall fall within the protection scope defined by the claims of the present invention.

Claims

1. A calcium carbonate D3 granule formulation, characterized in that: The calcium carbonate D3 granule formula includes two components, A and B, and the mass ratio of component A to component B is 1.245 - 1.255:1; Component A includes the following components by weight percentage: Calcium carbonate 33.0% - 33.3%, sweetener 33.0% - 33.3%, sucrose powder 1 33.0% - 33.3%, vitamin D3 powder 0.1% - 1.0%, and 0.5% - 1.5% of polymer CS-g-AMPS-CA. The sum of the weight percentages of each component is 100%; Component B includes the following components by weight percentage: Calcium carbonate 43% - 44%, sucrose powder 2 53% - 54%, excipient 1% - 2%, essence 1.2% - 1.4%. The sum of the weight percentages of each component is 100%.

2. The calcium carbonate D3 granule formulation according to claim 1, characterized in that The polymer CS-g-AMPS-CA is synthesized by the following method: First, dissolve chitosan in a dilute acetic acid solution to prepare a mixed monomer solution with a mass fraction of 4% - 6%. After stirring evenly at 45°C - 55°C, add chitosan and 2-acrylamido-2-methylpropanesulfonic acid (AMPS) according to the molar ratio of chitosan to 2-acrylamido-2-methylpropanesulfonic acid of 1:2.5 - 3.

5. Subsequently, add initiator ammonium persulfate (APS). The dosage of ammonium persulfate is 0.8% - 1.2% of the total mass of the mixed monomer solution. React at 60°C - 70°C for 8h - 12h under a nitrogen atmosphere to obtain chitosan-g-AMPS copolymer. Then, carry out an esterification reaction on the chitosan-g-AMPS copolymer and cholate under the catalysis of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). The dosages of dicyclohexylcarbodiimide and 4-dimethylaminopyridine are 1.5% - 2.5% and 0.3% - 0.7% of the mass of cholate respectively. The reaction is carried out at room temperature for 20h - 28h to obtain the polymer CS-g-AMPS-CA with pH responsiveness and vitamin D3 affinity.

3. The calcium carbonate D3 granule formulation according to claim 1, characterized in that: The sweetener is one or more of mannitol, acesulfame potassium, and sorbitol; The excipient is one or more of polyvinylpyrrolidone, copovidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; The essence is powder essence.

4. A production process of calcium carbonate D3 granules, which is applicable to the formula of the calcium carbonate D3 granules described in any one of claims 1-3, and is characterized in that, It includes the following steps: Step 1: Take components A and B according to the mass ratio, and crush sucrose 1 and sucrose 2 respectively; Step 2: Component A is granulated by dry granulation: Mix vitamin D3 powder with calcium carbonate, then mix with the sweetener, sucrose powder 1, and polymer CS-g-AMPS-CA, and put them into a dry granulator for granulation. After that, screen, and the fine powder under the sieve is subjected to secondary dry granulation. Finally, collect the materials from the first and second granulations and mix them; Component B is granulated by one-step granulation: Inhale the component B materials into a fluidized bed dryer for granulation. After drying, discharge and screen. Screen the particles on the sieve, and then mix the materials under the sieve with the sized materials; Step 3: Mix the particles produced from Component A and Component B in Step 2. Take the particles produced from Component A and Component B according to the mass ratio of Component A to Component B of 1.245 - 1.255:1, and put them into a mixing pot for mixing to obtain uniformly mixed calcium carbonate D3 particles; Step 4: Pack the calcium carbonate D3 particles produced in Step 3.

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