Heavy-light composite calcium particle and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a heavy-light composite calcium particle and a preparation method of the heavy-light composite calcium particle. The collagen peptide calcium modified calcium carbonate is prepared from 100 kg to 200 kg of calcium carbonate, 30 kg to 80 kg of collagen peptide calcium, 2 kg to 7 kg of light calcium carbonate, 0.1 kg to 1 kg of Arabic gum, 0.1 kg to 1 kg of starch sodium octenylsuccinate, 0.5 kg to 2 kg of corn starch, 1 kg to 2 kg of sodium carboxymethyl starch, 1 kg to 3 kg of microcrystalline cellulose, 0.1 kg to 1 kg of hydroxypropyl methyl cellulose, 10 kg to 18 kg of maltodextrin and 10 kg to 20 kg of water. Compared with the prior art, the treating agent is used for treating the light calcium carbonate to solve the problem that the light calcium carbonate absorbs water and goes bad when exposed to a high-humidity environment, the calcium carbonate, the collagen peptide calcium, the light calcium carbonate and various auxiliary materials are combined, the calcium ion release efficiency is improved, the absorption effect is enhanced, and the problem that the dissolution speed is low when the calcium carbonate is singly used is solved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to heavy-light composite calcium particles and a preparation method thereof. Background Art

[0002] Calcium is the most abundant mineral and one of the most important metals in the human body. While calcium maintains a certain degree of dynamic balance, it is more susceptible to calcium deficiency in adolescents during their critical developmental period and in the elderly. This deficiency can lead to complications such as developmental delays, rickets, osteoporosis, and muscle cramps. Therefore, topical calcium supplements are the preferred choice for those with calcium deficiency, with inorganic calcium being the primary ingredient.

[0003] Calcium carbonate is a common inorganic calcium supplement and gastric acid neutralizing drug. It has a high calcium content, is widely available, and is inexpensive. Calcium carbonate particles are prepared using it. Patent No. 201711059370.2 discloses a pediatric calcium carbonate D3 particle, which specifically discloses 740-760 parts of calcium carbonate particles, 0.8-1.2 parts of vitamin D3 inclusion powder particles, 245-250 parts of excipients, and 0.5-0.8 parts of tocopherol. The invention obtains good high-temperature stability of calcium carbonate particles through precise process conditions, but the calcium release of calcium carbonate requires a large amount of gastric acid, and it takes longer to absorb than other calcium types. Calcium is one of the most abundant mineral elements and important metal elements in the human body. It is necessary to find a short-acting release of calcium ions and calcium carbonate ions to meet the needs of various groups of people. Summary of the Invention

[0004] The purpose of the present invention is to provide a heavy-light composite calcium particle and a preparation method thereof, aiming to solve the problems of strong adsorption of light calcium, easy moisture absorption and deterioration, and slow calcium release of calcium carbonate.

[0005] To achieve the above-mentioned purpose, the present invention provides a heavy-light composite calcium particle, which comprises: calcium carbonate, collagen peptide calcium, light calcium carbonate, gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water.

[0006] Preferably, in the above technical scheme, by mass, 100-200 kg of calcium carbonate, 30-80 kg of collagen peptide calcium, 2-7 kg of light calcium carbonate, 0.1-1 kg of gum arabic, 0.1-1 kg of sodium starch octenylsuccinate, 0.5-2 kg of corn starch, 1-2 kg of sodium carboxymethyl starch, 1-3 kg of microcrystalline cellulose, 0.1-1 kg of hydroxypropyl methylcellulose, 10-18 kg of maltodextrin and 10-20 kg of water.

[0007] The present invention also provides a method for preparing heavy-light composite calcium particles, the preparation method comprising:

[0008] S1, add 100-200kg calcium carbonate powder and 30-80kg collagen peptide calcium into a high-speed mixing granulator and start mixing, the mixing frequency is controlled at 5-50Hz, and the pre-prepared gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water are added, and shearing is started, the shearing frequency is controlled at 5-50Hz, and the mixing frequency and shearing frequency are maintained at 5-50Hz and 5-50Hz, the temperature is 10-50℃, and the duration is 5-30min. After the mixing and shearing is completed, the primary mixture is obtained;

[0009] S2, treating light calcium carbonate with 0.5%-1% treating agent, placing the treated light calcium carbonate and the primary mixed material into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein, the operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz.

[0010] Preferably, in the above technical solution, the preparation method of the collagen peptide calcium is as follows:

[0011] S11, adding calcium carbonate to a weak acid solution, stirring at 35-45° C. for 25-35 minutes, and drying to obtain activated calcium carbonate; taking the activated calcium carbonate, ethanol-water mixed solution, and dispersant and grinding at a speed of 250-350 rpm for 2-4 hours to obtain a calcium carbonate suspension, adding sodium dihydrogen phosphate dropwise to the calcium carbonate suspension, reacting at 55-65° C. for 1-1.5 hours, adding sodium alginate and continuing the reaction for 30-40 minutes, treating at 120-130° C. for 2-3 hours, and standing at 4° C. for 20-28 hours, and drying to obtain calcium carbonate powder;

[0012] S12, taking fish collagen peptide, adding it to 40-50°C water, stirring and dissolving it to prepare a collagen peptide solution, slowly adding calcium carbonate powder to the collagen peptide solution, adjusting the pH to 4.0-5.0, stirring at 300-400 rpm under a temperature condition of 35-40°C until no bubbles are generated, adjusting the pH to 6.5-7.0, adding 0.1% xanthan gum, rotating at a speed of 9000-10,000 rpm, ultrafiltration membrane permeate, and freeze-drying to obtain collagen peptide calcium.

[0013] Preferably, in the above technical solution, the mass ratio of calcium carbonate to weak acid is 1:8-10.

[0014] Preferably, in the above technical solution, the weak acid solution is one or both of citric acid and acetic acid.

[0015] Preferably, in the above technical solution, the mass ratio of the collagen peptide solution to the calcium carbonate powder is 4-5:1.

[0016] Preferably, in the above technical solution, the solution for adjusting pH is hydrochloric acid and / or NaHCO3.

[0017] According to the above technical solution, the present invention improves the chelation rate of calcium carbonate powder with collagen peptide solution by pre-treating calcium carbonate. The principle is as follows: calcium carbonate is treated with weak acid to dissolve impurities on the surface of calcium carbonate, forming a calcium citrate transition layer, improving the dispersibility of activated calcium carbonate, adding activated calcium carbonate, ethanol water mixed solution and polyvinyl pyrrolidone, and electrostatic repulsion and steric hindrance effect to inhibit the agglomeration of activated calcium carbonate. After treatment with sodium dihydrogen phosphate and sodium alginate, low-temperature aging is carried out to form a stable amorphous calcium phosphate coating layer on the calcium carbonate powder, which promotes its chelation with collagen peptide solution.

[0018] Preferably, in the above technical solution, the treatment method of the light calcium carbonate is as follows: weigh the treatment agent and dissolve it in 30-70L of solvent, dissolve it in a 60°C water bath, add light calcium carbonate to the solution, stir and react at 60°C, filter, wash, and dry to obtain light calcium carbonate with low adsorption.

[0019] Preferably, in the above technical solution, the treatment agent includes one of sodium starch octenylsuccinate, stearic acid, glycerin, seaweed polysaccharide and hydroxypropyl methylcellulose.

[0020] Preferably, in the above technical solution, the solvent includes one of anhydrous ethanol and water.

[0021] Preferably, in the above technical solution, the operating parameters of the wet granulator for wet granulation are a frequency of 5-50 Hz, and the operating parameters of the boiling drying tower for boiling drying are a fan frequency of 20-50 Hz and an air inlet temperature of 180-190°C.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] (1) The combination of calcium carbonate, collagen peptide calcium and treated light calcium carbonate, especially collagen peptide calcium, can quickly release calcium ions, reduce gastric acid consumption, and at the same time improve the short-term release efficiency of calcium ions, enhance the absorption effect, and overcome the slow dissolution rate of calcium carbonate alone;

[0024] (2) Using a treatment agent to treat light calcium carbonate to overcome the problem of light calcium carbonate absorbing water and deteriorating when exposed to a high humidity environment;

[0025] (3) Add excipients to mask the powdery or astringent taste of calcium carbonate, improve the taste, promote product disintegration, accelerate the release of calcium ions, and increase the calcium ion release rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The purpose, features and advantages of the present invention will be further described with reference to the accompanying drawings and in conjunction with the embodiments.

[0027] Figure 1 This is a flow chart of the preparation process of heavy-light composite calcium particles of the present invention;

[0028] Figure 2 1 is a graph showing the calcium chelation rates of collagen peptides according to Example 2, Example 3, Comparative Example 2, and Comparative Example 3 of the present invention. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort shall fall within the scope of protection of the present invention.

[0030] Example 1

[0031] A heavy-light composite calcium particle comprises calcium carbonate, collagen peptide calcium, light calcium carbonate, gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water.

[0032] The preparation steps of the heavy-light composite calcium particles include:

[0033] S1, add calcium carbonate powder and collagen peptide calcium into a high-speed mixing granulator and start mixing, the mixing frequency is controlled at 5-50 Hz, and the pre-prepared gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water are added, and shearing is started, the shearing frequency is controlled at 5-50 Hz, and the mixing frequency and shearing frequency are maintained at 5-50 Hz and 5-50 Hz, the temperature is 10-50 ° C, and the duration is 5-30 min. After the mixing and shearing are completed, a primary mixture is obtained; wherein, the preparation method of the collagen peptide calcium is specifically as follows:

[0034] S11, adding calcium carbonate to a citric acid solution, stirring at 40°C for 30 minutes, and transferring to a drying and dehumidifying device for drying to obtain activated calcium carbonate; taking the activated calcium carbonate, an ethanol-water mixed solution, and a dispersant and grinding at a speed of 300 rpm for 3 hours to obtain a calcium carbonate suspension, adding sodium dihydrogen phosphate dropwise to the calcium carbonate suspension, reacting at 60°C for 1 hour, adding sodium alginate and continuing to react for 30 minutes, treating at 120°C for 2 hours, and standing at 4°C for 24 hours, and transferring to a drying and dehumidifying device for drying to obtain calcium carbonate powder, wherein the ethanol-water mixed solution has a volume ratio of ethanol to water of 1:1;

[0035] S12, heating deionized water to 40°C, taking fish collagen peptide and adding it to the deionized water and stirring for 30 minutes to completely dissolve the fish collagen peptide to prepare a collagen peptide solution with a concentration of 2-5% w / v, slowly adding calcium carbonate powder (MCP:Ca mass ratio of 5:1) to the collagen peptide solution, adding hydrochloric acid dropwise to pH = 4.0-4.5, stirring at 300 rpm under a temperature of 37°C until no bubbles are generated, adjusting the pH to 6.5-7.0 with NaHCO3, adding 0.1% xanthan gum, rotating at a speed of 10,000 rpm for 2 minutes, ultrafiltration membrane permeate, and freeze-drying to obtain collagen peptide calcium;

[0036] S2, treating light calcium carbonate with 0.5%-1% treatment agent, placing the treated light calcium carbonate and the primary mixed material into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein the operating parameter of the wet granulator for wet granulation is a frequency of 5-50Hz; wherein,

[0037] The operating parameters of the wet granulator for wet granulation are frequency 5-50H;

[0038] The working parameters of the boiling drying tower for boiling drying are to control the fan frequency to 20-50Hz and the inlet air temperature to 180-190℃.

[0039] Example 2

[0040] A heavy-light composite calcium particle, comprising: 150kg calcium carbonate, 70kg collagen peptide calcium, 5kg light calcium carbonate, 0.5kg gum arabic, 0.8kg sodium starch octenylsuccinate, 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose, 14kg maltodextrin and 15kg water.

[0041] The preparation steps of the heavy-light composite calcium particles include:

[0042] S1, add 150kg calcium carbonate powder and 70kg collagen peptide calcium into a 300L high-speed mixing granulator and start mixing, the mixing frequency is controlled at 40Hz, and the pre-prepared 0.5kg gum arabic, 0.8kg sodium starch octenylsuccinate, 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose, 14kg maltodextrin and 15kg water are added, and shearing is started, maintaining the mixing frequency at 40Hz, the shear frequency at 40Hz, the temperature at 30°C, and the duration for 30min. After the mixing and shearing is completed, the primary mixture is obtained; wherein,

[0043] The preparation method of the collagen peptide calcium is as follows:

[0044] S11, adding 49 kg of calcium carbonate to 300 L of citric acid solution, stirring at 40° C. for 30 min, and transferring to a drying and dehumidifying device for drying to obtain activated calcium carbonate; taking the activated calcium carbonate, an ethanol-water mixed solution, and polyvinyl pyrrolidone and grinding at a speed of 300 rpm for 3 h to obtain a calcium carbonate suspension, adding sodium dihydrogen phosphate dropwise to the calcium carbonate suspension, reacting at 60° C. for 1 hour, adding 1% sodium alginate and continuing to react for 30 min, treating at 120° C. for 2 hours, standing at 4° C. for 24 h, and transferring to a drying and dehumidifying device for drying to obtain calcium carbonate powder, wherein the ethanol-water mixed solution has a volume ratio of ethanol to water of 1:1;

[0045] S12, heating deionized water to 40°C, taking 94 kg of fish collagen peptide and adding it to the deionized water and stirring for 30 minutes to completely dissolve the fish collagen peptide to prepare a collagen peptide solution with a concentration of 5% w / v, slowly adding the above-mentioned calcium carbonate powder (MCP:Ca mass ratio of 5:1) to the collagen peptide solution, adding hydrochloric acid dropwise to pH = 4.0-4.5, stirring at 300 rpm under a temperature of 37°C until no bubbles are generated, adjusting the pH to 6.5-7.0 with NaHCO3, adding 0.1% xanthan gum, rotating at a speed of 10,000 rpm for 2 minutes, ultrafiltration membrane permeate, and freeze-drying to obtain collagen peptide calcium;

[0046] S2, treating light calcium carbonate with sodium starch octenylsuccinate solution, placing 5 kg of the treated light calcium carbonate and the primary mixture into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein the operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz; wherein,

[0047] The operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz;

[0048] The working parameters of the boiling drying tower for boiling drying are to control the fan frequency to 50Hz and the inlet air temperature to 180℃;

[0049] The sodium starch octenylsuccinate solution is obtained by dissolving 100 g of sodium starch octenylsuccinate in 50 L of solvent.

[0050] Example 3

[0051] A heavy-light composite calcium particle, comprising: 170 kg calcium carbonate, 50 kg collagen peptide calcium, 7 kg light calcium carbonate, 0.8 kg gum arabic, 1 kg sodium starch octenylsuccinate, 1.3 kg corn starch, 1.8 kg sodium carboxymethyl starch, 2.2 kg microcrystalline cellulose, 0.8 kg hydroxypropyl methylcellulose, 16 kg maltodextrin and 18 kg water.

[0052] The preparation steps of the heavy-light composite calcium particles include:

[0053] S1, add 170kg calcium carbonate powder and 50kg collagen peptide calcium into a 300L high-speed mixing granulator and start mixing, the mixing frequency is controlled at 50Hz, and the pre-prepared gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water are added, and shearing is started, maintaining the mixing frequency at 50Hz, the shear frequency at 50Hz, the temperature at 30°C, and the duration for 20min. After the mixing and shearing is completed, the primary mixture is obtained; wherein,

[0054] S11, adding 35kg of calcium carbonate to 200L of citric acid solution, stirring at 40°C for 30min, and transferring to a drying and dehumidifying device for drying to obtain activated calcium carbonate; taking the activated calcium carbonate, ethanol-water mixed solution and polyvinyl pyrrolidone and grinding at 300rpm for 3h to obtain a calcium carbonate suspension, adding sodium dihydrogen phosphate dropwise to the calcium carbonate suspension, reacting at 60°C for 1h, adding 1% sodium alginate and continuing to react for 30min, treating at 130°C for 2h, standing at 4°C for 24h, and transferring to a drying and dehumidifying device for drying to obtain calcium carbonate powder, wherein the ethanol-water mixed solution has a volume ratio of ethanol to water of 1:1;

[0055] S12, the preparation method of the collagen peptide calcium is as follows: heating deionized water to 40°C, taking 66.5 kg of fish collagen peptide and adding it to the deionized water and stirring for 30 minutes to completely dissolve the fish collagen peptide to prepare a 5% w / v collagen peptide solution, slowly adding the above-mentioned calcium carbonate powder (MCP:Ca mass ratio of 5:1) to the collagen peptide solution, adding hydrochloric acid dropwise to a pH of 4.0-4.5, stirring at 300 rpm at 35°C until no bubbles are generated, adjusting the pH to 6.5-7.0 with NaHCO3, adding 0.1% xanthan gum, rotating at 10,000 rpm for 2 minutes, ultrafiltration membrane permeate, and freeze-drying to obtain collagen peptide calcium;

[0056] S2, treating light calcium carbonate with a seaweed polysaccharide solution, placing the treated light calcium carbonate and the primary mixture into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80° C., and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein the operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz;

[0057] The working parameters of the boiling drying tower for boiling drying are to control the fan frequency to 50Hz and the inlet air temperature to 180-190℃;

[0058] The seaweed polysaccharide solution is obtained by dissolving 140 g of seaweed polysaccharide in 70 L of solvent.

[0059] Example 4

[0060] A heavy-light composite calcium particle, comprising: 130 kg of calcium carbonate, 40 kg of collagen peptide calcium, 3 kg of light calcium carbonate, 0.5 kg of gum arabic, 0.8 kg of sodium starch octenylsuccinate, 1 kg of corn starch, 1 kg of sodium carboxymethyl starch, 1 kg of microcrystalline cellulose, 0.3 kg of hydroxypropyl methylcellulose, 11 kg of maltodextrin and 12 kg of water.

[0061] The preparation steps of the heavy-light composite calcium particles include:

[0062] S1, add 130kg calcium carbonate powder and 40kg collagen peptide calcium into a 300L high-speed mixing granulator and start mixing, the mixing frequency is controlled at 50Hz, and the pre-prepared gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water are added, and shearing is started, maintaining the mixing frequency at 50Hz, the shear frequency at 50Hz, the temperature at 50°C, and the duration for 20min. After the mixing and shearing is completed, the primary mixture is obtained; wherein,

[0063] S11, adding 35kg of calcium carbonate to 200L of citric acid solution, stirring at 45°C for 30min, and transferring to a drying and dehumidifying device for drying to obtain activated calcium carbonate; taking the activated calcium carbonate, an ethanol-water mixed solution, and polyvinyl pyrrolidone and grinding at a speed of 350rpm for 2.5h to obtain a calcium carbonate suspension, adding sodium dihydrogen phosphate dropwise to the calcium carbonate suspension, reacting at 60°C for 1h, adding 1% sodium alginate and continuing to react for 30min, treating at 110°C for 2h, standing at 4°C for 24h, and transferring to a drying and dehumidifying device for drying to obtain calcium carbonate powder, wherein the ethanol-water mixed solution has a volume ratio of ethanol to water of 1:1;

[0064] S12, heating deionized water to 40°C, taking 66.5 kg of fish collagen peptide and adding it to the deionized water and stirring for 30 minutes to completely dissolve the fish collagen peptide to prepare a collagen peptide solution with a concentration of 5% w / v, slowly adding calcium carbonate powder (MCP:Ca mass ratio of 5:1) to the collagen peptide solution, adding hydrochloric acid dropwise to a pH of 4.0-4.5, stirring at 400 rpm under a temperature of 40°C until no bubbles are generated, adjusting the pH to 6.5-7.0 with NaHCO3, adding 0.1% xanthan gum, rotating at 9,000 rpm for 2 minutes, ultrafiltration membrane permeate, and freeze-drying to obtain collagen peptide calcium;

[0065] S2, treating light calcium carbonate with sodium starch octenylsuccinate solution, placing 3 kg of the treated light calcium carbonate and the primary mixture into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a sieving machine to obtain heavy-light composite calcium particles; wherein,

[0066] The operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz;

[0067] The working parameters of the boiling drying tower for boiling drying are to control the fan frequency to 50Hz and the inlet air temperature to 180-190℃;

[0068] The sodium starch octenylsuccinate solution is obtained by dissolving 60 g of sodium starch octenylsuccinate in 30 L of solvent.

[0069] The prepared heavy-light composite calcium particles were tested according to the implementation standard GB26687-2011, and the results are shown in Table 1.

[0070] Table 1 Heavy and light composite calcium particles

[0071]

[0072]

[0073] Comparative Example 1

[0074] A heavy-light composite calcium particle, comprising: 220kg calcium carbonate, 5kg light calcium carbonate, 0.5kg gum arabic, 0.8kg sodium starch octenylsuccinate, 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose and 14kg maltodextrin, and the above raw materials are pressed into sheets by a direct pressing method.

[0075] Comparative Example 2

[0076] A heavy-light composite calcium particle, comprising: 150kg calcium carbonate, 70kg collagen peptide calcium, 5kg light calcium carbonate, 0.5kg gum arabic, 0.8kg sodium starch octenylsuccinate, 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose, 14kg maltodextrin and 15kg water.

[0077] The preparation steps of the heavy-light composite calcium particles include:

[0078] S1, add 150kg calcium carbonate powder and 70kg collagen peptide calcium into a 300L high-speed mixing granulator and start mixing, the mixing frequency is controlled at 40Hz, and the pre-prepared 0.5kg gum arabic, 0.8kg sodium starch octenylsuccinate, 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose, 14kg maltodextrin and 15kg water are added, and shearing is started, maintaining the mixing frequency at 40Hz, the shear frequency at 40Hz, the temperature at 30°C, and the duration for 30min. After the mixing and shearing is completed, the primary mixture is obtained; wherein,

[0079] The preparation method of the collagen peptide calcium is as follows:

[0080] Heat deionized water to 40°C, take 94 kg of fish collagen peptide and add it to the deionized water and stir for 30 minutes to completely dissolve the fish collagen peptide to prepare a 5% w / v collagen peptide solution, slowly add the above-mentioned calcium carbonate powder (MCP:Ca mass ratio 5:1) to the collagen peptide solution, add hydrochloric acid dropwise to pH = 4.0-4.5, stir at 300 rpm under 37°C temperature until no bubbles are generated, adjust the pH to 6.5-7.0 with NaHCO3, add 0.1% xanthan gum, rotate at 10,000 rpm for 2 minutes, ultrafilter the permeate, and freeze-dry to obtain collagen peptide calcium;

[0081] S2, treating light calcium carbonate with sodium starch octenylsuccinate solution, placing 5 kg of the treated light calcium carbonate and the primary mixture into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein the operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz; wherein,

[0082] The operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz;

[0083] The working parameters of the boiling drying tower for boiling drying are to control the fan frequency to 50Hz and the inlet air temperature to 180℃;

[0084] The sodium starch octenylsuccinate solution is obtained by dissolving 100 g of sodium starch octenylsuccinate in 50 L of solvent.

[0085] Comparative Example 3

[0086] A heavy-light composite calcium particle, comprising: 150kg calcium carbonate, 70kg collagen peptide calcium, 5kg light calcium carbonate, 0.5kg gum arabic, 0.8kg sodium starch octenylsuccinate, 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose, 14kg maltodextrin and 15kg water.

[0087] The preparation steps of the heavy-light composite calcium particles include:

[0088] S1, add 150kg calcium carbonate powder and 70kg collagen peptide calcium into a 300L high-speed mixing granulator and start mixing, the mixing frequency is controlled at 40Hz, and the pre-prepared 0.5kg gum arabic, 0.8kg sodium starch octenylsuccinate, 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose, 14kg maltodextrin and 15kg water are added, and shearing is started, maintaining the mixing frequency at 40Hz, the shear frequency at 40Hz, the temperature at 30°C, and the duration for 30min. After the mixing and shearing is completed, the primary mixture is obtained; wherein,

[0089] The preparation method of the collagen peptide calcium is as follows:

[0090] S11, adding 49 kg of calcium carbonate to 300 L of citric acid solution, stirring at 40° C. for 30 min, and transferring to a drying and dehumidifying device for drying to obtain activated calcium carbonate; grinding the activated calcium carbonate and ethanol-water mixed solution at a speed of 300 rpm for 3 h, and transferring to a drying and dehumidifying device for drying to obtain calcium carbonate powder, wherein the ethanol-water mixed solution has a volume ratio of ethanol to water of 1:1;

[0091] S12, heating deionized water to 40°C, taking 94 kg of fish collagen peptide and adding it to the deionized water and stirring for 30 minutes to completely dissolve the fish collagen peptide to prepare a collagen peptide solution with a concentration of 5% w / v, slowly adding the above-mentioned calcium carbonate powder (MCP:Ca mass ratio of 5:1) to the collagen peptide solution, adding hydrochloric acid dropwise to pH = 4.0-4.5, stirring at 300 rpm under a temperature of 37°C until no bubbles are generated, adjusting the pH to 6.5-7.0 with NaHCO3, adding 0.1% xanthan gum, rotating at a speed of 10,000 rpm for 2 minutes, ultrafiltration membrane permeate, and freeze-drying to obtain collagen peptide calcium;

[0092] S2, treating light calcium carbonate with sodium starch octenylsuccinate solution, placing 5 kg of the treated light calcium carbonate and the primary mixture into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein the operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz; wherein,

[0093] The operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz;

[0094] The working parameters of the boiling drying tower for boiling drying are to control the fan frequency to 50Hz and the inlet air temperature to 180℃;

[0095] The sodium starch octenylsuccinate solution is obtained by dissolving 100 g of sodium starch octenylsuccinate in 50 L of solvent.

[0096] Comparative Example 4

[0097] A heavy-light composite calcium particle comprises: 220 kg of calcium carbonate, 1 kg of corn starch, 1.5 kg of sodium carboxymethyl starch, 2 kg of microcrystalline cellulose, 0.5 kg of hydroxypropyl methylcellulose, 14 kg of maltodextrin and water.

[0098] The preparation steps of the heavy-light composite calcium particles include:

[0099] S1, add 220kg calcium carbonate powder and pre-prepared 1kg corn starch, 1.5kg sodium carboxymethyl starch, 2kg microcrystalline cellulose, 0.5kg hydroxypropyl methylcellulose, 14kg maltodextrin and 15kg water into a 300L high-speed mixing granulator, turn on shearing, maintain mixing frequency 40Hz, shear frequency 40Hz, temperature 30°C, duration 30min, and obtain the primary mixture after mixing and shearing.

[0100] S2, transferring the primary mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein the operating parameter of the wet granulator for wet granulation is a frequency of 50Hz; wherein,

[0101] The operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz;

[0102] The working parameters of the boiling drying tower for boiling drying are to control the fan frequency to 50 Hz and the inlet air temperature to 180°C.

[0103] The collagen peptide calcium chelation rate of Example 2 (S1), Example 3 (S2), Comparative Example 2 (D1) and Comparative Example 3 (D2) was tested. The ratio of the collagen peptide calcium content to the calcium content of the added calcium carbonate was calculated as follows: collagen peptide calcium chelation rate (%) = [(total calcium content - free calcium content) ÷ total calcium content] × 100%. The results are as follows: Figure 2 shown.

[0104] Thirty minutes after the start of normal discharge, samples of the heavy-light composite calcium granules were collected. The sampling bag label should clearly indicate the sampling time, sample name, and serial number. The samples were sent to the analysis laboratory for testing to determine if they contained black spots, foreign matter, or metallic foreign matter. The results are shown in Table 2.

[0105] Table 2 Calcium content and foreign matter detection of heavy and light composite calcium particles

[0106] Calcium content (%) Black dots per 100g Iron Stainless steel Non-ferrous metals Example 2 39.10 ≤5 ≤1.5mm ≤2.5mm ≤2.5mm Example 3 39.18 ≤5 ≤1.5mm ≤2.5mm ≤2.5mm Comparative Example 1 39.26 ≤5 ≤1.5mm ≤2.5mm ≤2.5mm Comparative Example 2 37.43 ≤5 ≤1.5mm ≤2.5mm ≤2.5mm Comparative Example 3 38.08 ≤5 ≤1.5mm ≤2.5mm ≤2.5mm Comparative Example 4 35.41 ≤5 ≤1.5mm ≤2.5mm ≤2.5mm

[0107] The above-mentioned heavy-light composite calcium particles were pressed into tablets respectively, and three groups of gastric acid simulation experiments were set up for 0.5h, 1h, and 3h. Each group of experiments had three repetitions. 15 tablets of each type of tablet were taken, and only one tablet was placed in each gastric acid simulation liquid. The time was counted and the tablets were left to stand. After the experiment, the tablets were filtered out, and samples were taken after slight stirring. The calcium content in each gastric acid simulation liquid was tested, and the average value of the three repeated experiments was calculated.

[0108] Table 3 Calcium release of tablets in various specific examples in gastric acid simulated solution

[0109] 0.5h 1h 3h Example 2 13.57 26.51 35.16 Example 3 13.15 27.36 35.61 Comparative Example 1 7.86 16.82 26.78 Comparative Example 2 10.58 20.42 31.62 Comparative Example 3 11.85 22.75 32.35 Comparative Example 4 4.36 11.07 23.46

[0110] Ten tablets were placed in an environment at 25°C and a relative humidity of 90%±5% for 20 days. Samples were taken on the first and 21st days to detect changes in tablet quality.

[0111] Table 4: Changes in the quality of tablets in various specific examples

[0112] Mass on day 1 (g) Mass on day 21 (g) Example 2 11.3 11.4 Example 3 10.6 10.8 Comparative Example 1 11.5 13.1 Comparative Example 2 12.2 12.2 Comparative Example 3 11.5 11.7 Comparative Example 4 11.4 11.4

[0113] Selection of treatment agents for light calcium carbonate and its treatment methods:

[0114] The treatment agents are: a. stearic acid, b. sodium carboxymethyl starch, c. gelatin, d. seaweed polysaccharide, and f. sodium starch octenylsuccinate.

[0115] Treatment method A: spray light calcium carbonate with the treatment agent, and repeat the spraying after an interval of 10 minutes;

[0116] Treatment method B: Weigh the treatment agent and dissolve it in 50L of solvent (deionized water or anhydrous ethanol), dissolve it in a 60℃ water bath, add the solution to light calcium carbonate, stir and react at 60℃, filter, wash and dry;

[0117] The experimental design is as follows: the treated light calcium carbonate powder is placed in an environment of 25°C and a relative humidity of 90%±5% for 20 days, samples are taken on the 0th and 21st days, and the quality changes of the treated light calcium carbonate are detected; among them, the blank control is the light calcium carbonate powder without any treatment.

[0118] Table 5 Changes in the quality of light calcium carbonate in each group

[0119]

[0120]

[0121] From the blank control in the above table, it can be seen that light calcium carbonate has adsorptive properties and is prone to absorb moisture in the environment and cause deterioration in an environment with high relative humidity. However, after being treated with certain treatment agents, the absorption of moisture by light calcium carbonate and the resulting deterioration can be inhibited to a certain extent.

[0122] The present invention can be implemented in various ways and is not limited to the embodiments described above. A person skilled in the art will appreciate that the present invention can be implemented in other specific ways without changing the technical concept or essential features of the present invention. Therefore, it should be understood that the embodiments described above are illustrative and not intended to limit the present invention.

Claims

1. A heavy-light composite calcium particle, characterized in that: The heavy-light composite calcium particles include: calcium carbonate, collagen peptide calcium, light calcium carbonate, gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water.

2. The heavy-light composite calcium particles according to claim 1, characterized in that Calculated by mass: 100-200kg calcium carbonate, 30-80kg collagen peptide calcium, 2-7kg light calcium carbonate, 0.1-1kg gum arabic, 0.1-1kg sodium starch octenylsuccinate, 0.5-2kg corn starch, 1-2kg sodium carboxymethyl starch, 1-3kg microcrystalline cellulose, 0.1-1kg hydroxypropyl methylcellulose, 10-18kg maltodextrin and 10-20kg water.

3. A method for preparing heavy-light composite calcium particles according to any one of claims 1-2, characterized in that: The preparation method comprises: S1, add 100-200kg calcium carbonate powder and 30-80kg collagen peptide calcium into a high-speed mixing granulator and start mixing, the mixing frequency is controlled at 5-50Hz, and the pre-prepared gum arabic, sodium starch octenylsuccinate, corn starch, sodium carboxymethyl starch, microcrystalline cellulose, hydroxypropyl methylcellulose, maltodextrin and water are added, and shearing is started, the shearing frequency is controlled at 5-50Hz, and the mixing frequency and shearing frequency are maintained at 5-50Hz and 5-50Hz, the temperature is 10-50℃, and the duration is 5-30min. After the mixing and shearing is completed, the primary mixture is obtained; S2, treating light calcium carbonate with 0.5%-1% treating agent, placing the treated light calcium carbonate and the primary mixed material into a wet granulator for wet granulation to obtain a mixture, transferring the mixture to a boiling drying tower for boiling drying, stopping the drying when the outlet air temperature of the boiling drying tower reaches 80°C, and sieving on a screening machine to obtain heavy-light composite calcium particles; wherein, the operating parameter of the wet granulator for wet granulation is a frequency of 50 Hz.

4. The heavy-light composite calcium particles according to claim 3, characterized in that The preparation method of the collagen peptide calcium is as follows: S11, adding calcium carbonate to a weak acid solution, stirring at 35-45° C. for 25-35 minutes, and drying to obtain activated calcium carbonate; taking the activated calcium carbonate, ethanol-water mixed solution, and dispersant and grinding at a speed of 250-350 rpm for 2-4 hours to obtain a calcium carbonate suspension, adding sodium dihydrogen phosphate dropwise to the calcium carbonate suspension, reacting at 55-65° C. for 1-1.5 hours, adding sodium alginate and continuing the reaction for 30-40 minutes, treating at 120-130° C. for 2-3 hours, and standing at 4° C. for 20-28 hours, and drying to obtain calcium carbonate powder; S12, taking fish collagen peptide, adding it to 40-50°C water, stirring and dissolving it to prepare a collagen peptide solution, slowly adding calcium carbonate powder to the collagen peptide solution, adjusting the pH to 4.0-5.0, stirring at 300-400 rpm under a temperature condition of 35-40°C until no bubbles are generated, adjusting the pH to 6.5-7.0, adding 0.1% xanthan gum, rotating at a speed of 9000-10,000 rpm, ultrafiltration membrane permeate, and freeze-drying to obtain collagen peptide calcium.

5. The method for preparing heavy-light composite calcium particles according to claim 4, characterized in that: The mass ratio of the calcium carbonate to the weak acid is 1:8-10.

6. The method for preparing heavy-light composite calcium particles according to claim 4, characterized in that: The weak acid solution is one or both of citric acid and acetic acid.

7. The method for preparing heavy-light composite calcium particles according to claim 4, characterized in that: The mass ratio of the collagen peptide solution to the calcium carbonate powder is 4-5:

1.

8. The method for preparing heavy-light composite calcium particles according to claim 3, wherein: The light calcium carbonate treatment method is as follows: weigh a treatment agent and dissolve it in 30-70 L of solvent, dissolve it in a 60° C. water bath, add light calcium carbonate to the solution, stir and react at 60° C., filter, wash, and dry to obtain light calcium carbonate with low adsorption.

9. The method for preparing heavy-light composite calcium particles according to claim 8, characterized in that: The treatment agent comprises one of sodium starch octenylsuccinate, stearic acid, glycerin, seaweed polysaccharide and hydroxypropyl methylcellulose.

10. The method for preparing heavy-light composite calcium particles according to claim 3, characterized in that: The operating parameters of the wet granulator for wet granulation are a frequency of 5-50 Hz, and the operating parameters of the boiling drying tower for boiling drying are a fan frequency of 20-50 Hz and an air inlet temperature of 180-190°C.

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