A compound calcium carbonate composition, its preparation method and its application

Abstract

The present invention relates to a compound calcium carbonate composition, which is composed of an active ingredient and a pharmaceutically acceptable carrier. Among them, the active ingredient is composed of calcium carbonate, VD 3 , copper oxide, magnesium oxide, zinc oxide and manganese monohydrate sulfate. The mass ratio of elemental calcium: VD 3 : elemental copper: elemental magnesium: elemental zinc: elemental manganese is (500-800): (0.001-0.1): 1: (20-100): (1-10): (1-10). The composition of the present invention promotes bone formation and growth and development, significantly increases bone density, bone strength, and the elasticity and toughness of bones, relieves bone pain, improves bone microstructure, protects bone health, delays bone aging, effectively prevents osteoporosis and pregnancy-induced hypertension, significantly improves taste, gastrointestinal function, and side effects such as flatulence, constipation, and stones, and significantly improves the safety and effectiveness of the pharmaceutical composition.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a compound calcium carbonate composition, a preparation method thereof and an application thereof. Background Art

[0002] Calcium is the most abundant inorganic element and essential nutrient in the human body, accounting for about 2% of body weight. Calcium ions (Ca 2 + ) participate in many important physiological functions, regulate bone metabolism, and maintain the normal functions of the human nervous system, skeletal muscle system, circulatory system, immune system, cell membrane and capillaries, maintain the normal excitability of nerves and muscles, reduce the permeability of capillaries, participate in the transmission of nerve information, cell secretion, muscle contraction, nerve impulse conduction, cardiac rhythm maintenance, enzyme activity and cell growth and development, etc., playing an extremely important physiological regulatory role. The body needs sufficient calcium to maintain calcium homeostasis and the growth of body bones. Calcium deficiency can cause various harms to health.

[0003] Calcium is an essential nutrient for the bones, teeth, growth and intellectual development of newborns. Calcium deficiency in children and adolescents is likely to lead to rickets and a decline in the body's immune regulation function, resulting in other related diseases caused by calcium deficiency. Pregnant women, lactating women and postmenopausal women have a higher demand for elemental calcium and need to supplement calcium preparations to maintain the body's demand for elemental calcium. Patients with hypoparathyroidism, osteoporosis, bone tumors, diabetes, etc. need to be appropriately given calcium preparations for adjuvant treatment to facilitate the recovery of the patients. Gestational hypertension (incidence rate 9.4%) is a specific disease during pregnancy and an important cause of maternal and perinatal mortality. The etiology has not been fully elucidated, and there has been no new breakthrough in the treatment effect. Often, termination of pregnancy is required to achieve the treatment goal. However, calcium deficiency is an important cause of gestational hypertensive disorders. Existing studies have shown that supplementing sufficient calcium in the second and third trimesters of pregnancy is beneficial to reducing the occurrence of calcium deficiency symptoms, preventing the occurrence of gestational hypertensive disorders, reducing the incidence of fetal growth restriction (FGR), reducing postpartum hemorrhage, being beneficial to the mother and baby, and having no adverse reactions. Good blood glucose control is the key to delaying or preventing abnormal bone mineral metabolism or osteoporosis in type 2 diabetes mellitus (T2DM) patients. Combining the use of calcium preparations and vitamin D 3 can more effectively correct the above abnormalities. The elderly have insufficient calcium intake due to reduced gastrointestinal function, reduced activity, insufficient sunlight exposure, etc., which cause insufficient synthesis of vitamin D by themselves. With the advent of global population aging, the incidence of osteoporosis and its fractures has shown a significant growth trend. Osteoporosis includes a decrease in bone density and bone quality caused by various reasons, which can cause severe pain, disability, destruction of bone microstructure, resulting in a systemic bone disease with increased bone fragility and fractures, and has become a global public health problem.

[0004] Calcium ions, as the second messenger produced after polypeptide hormones and cytokines bind to corresponding receptors on the cell membrane, activate many physiologically active enzymes or proteins in the cell and exert various physiological functions, such as calcium-dependent protein kinase C and calmodulin. Vitamin D3 can induce the intestinal mucosa to produce calcium-binding proteins, increase the permeability of the intestinal mucosa to calcium ions, promote the absorption and metabolism of calcium and phosphorus, maintain normal levels of blood calcium and blood phosphorus, assist the formation of calcium proteins and promote the formation of bone and collagen, promote human bone calcification and bone growth and development, protect teeth and benefit the growth and development of pregnant women, placenta and fetuses, effectively prevent miscarriage, premature birth, slow fetal development, etc., make bones hard, and reduce the incidence of cancer. Copper participates in the synthesis of proteins and neuroactive substances in connective tissue, bones, and blood vessels. Zinc is an essential substance for physiological activities such as human growth and development, reproductive genetics, immunity, endocrine, nerves, and body fluids, and participates in the transcription and translation of polynucleotides, which is beneficial to the recovery and growth of tissues.

[0005] Studies have shown that calcium carbonate combined with supplementation of trace elements (magnesium, zinc, manganese, copper) and vitamin D promotes the formation of collagen, thereby increasing bone elasticity and toughness, can significantly increase bone density and osteocalcin in premenopausal women, effectively improve bone symptoms, and significantly improve osteocalcin and bone symptoms in menopausal women.

[0006] In clinical practice, Calcitriol D is used as a calcium supplement for middle-aged and elderly people, postmenopausal women and those with chronic diseases (such as hypertension, diabetes, stomach problems, etc.), for the prevention and / or treatment of osteoporosis, and one tablet is taken every night. Calcitriol D tablets weigh about 1930 mg / tablet, containing 1500 mg of calcium carbonate (providing 600 mg of elemental calcium), 200 I U of vitamin D3 and trace elements (magnesium, zinc, manganese, copper). The active ingredient weighs about 1601.37 mg, and the plain tablet weighs about 1900 mg. Due to the poor compressibility of calcium carbonate and the large difference in the dosage of vitamin D3 and trace elements (magnesium, zinc, manganese, copper), the mass ratio of active ingredient: pharmaceutically acceptable carrier is about 16:3, which leads to the following problems. First, its compressibility, stability, solubility and quality uniformity need to be improved; second, vitamin D 3 It is easy to degrade under high temperature, high humidity and light conditions; third, after a trace amount of copper oxide and manganese oxide are mixed with the adhesive, they adhere to the wall and cause dosage loss, which requires excessive input (about 5-35%) in production; fourth, due to the high content of active ingredients and large differences in quality, in order to solve the problems of compressibility, stability, solubility and quality uniformity of the preparation, it is necessary to carry out complex preparation steps such as internal addition, external addition, wet granulation, whole granulation, tableting, etc., so there are problems such as long production cycle and high cost; fifth, there is unabsorbed calcium that causes adverse reactions such as constipation and stones. For this reason, it is necessary to develop new calcium preparations that are more stable, more bioavailable, safer, more effective and more economical to meet clinical needs. Summary of the invention

[0007] The object of the present invention is to provide a compound calcium carbonate composition, which is composed of an active ingredient and a pharmaceutically acceptable carrier. Among them, the active ingredient is composed of calcium carbonate, VD 3 , copper oxide, magnesium oxide, zinc oxide and manganese sulfate monohydrate. The mass ratio of elemental calcium:VD 3 : elemental copper: elemental magnesium: elemental zinc: elemental manganese is (500 - 800):(0.001 - 0.1):1:(20 - 100):(1 - 10):(1 - 10).

[0008] In a preferred technical solution of the present invention, the mass ratio of elemental calcium:VD 3 : elemental copper: elemental magnesium: elemental zinc: elemental manganese in the composition is 600:(0.005 - 0.006):1:50:7.5:1.8.

[0009] In a preferred technical solution of the present invention, the particle size distribution of calcium carbonate is 50 - 200 μm, and the bulk density is 0.676 g / cm 3 - 0.966 g / cm 3 .

[0010] In a preferred technical solution of the present invention, the particle size distribution of calcium carbonate is 75 - 150 μm.

[0011] In a preferred technical solution of the present invention, the angle of repose of calcium carbonate is 48.2°.

[0012] In a preferred technical solution of the present invention, the particle size distribution of copper oxide is 50 - 200 μm, and the bulk density is 2.241 g / cm 3 - 3.056 g / cm 3 .

[0013] In a preferred technical solution of the present invention, the particle size distribution of copper oxide is 75 - 150 μm.

[0014] In a preferred technical solution of the present invention, the angle of repose of copper oxide is 36.4°.

[0015] In a preferred technical solution of the present invention, the particle size distribution of zinc oxide is 50 - 200 μm, and the bulk density is 0.599 g / cm 3 - 0.832 g / cm 3 .

[0016] In a preferred technical solution of the present invention, the particle size distribution of zinc oxide is 75 - 150 μm.

[0017] In a preferred technical solution of the present invention, the angle of repose of zinc oxide is 44.4°.

[0018] In a preferred technical solution of the present invention, the particle size distribution of magnesium oxide is 50 - 200 μm, and the bulk density is 0.399 g / cm 3 - 0.539 g / cm 3 .

[0019] In a preferred technical solution of the present invention, the particle size distribution of magnesium oxide is 75 - 150 μm.

[0020] In a preferred technical solution of the present invention, the angle of repose of magnesium oxide is 47.6°.

[0021] In a preferred technical solution of the present invention, the pharmaceutically acceptable carrier in the composition consists of microcrystalline cellulose, polyvinylpyrrolidone K30, cross-linked polyvinylpyrrolidone, sodium lauryl sulfate, and a gastric-soluble film coating material.

[0022] In a preferred technical solution of the present invention, by weight percentage, the composition contains 65 - 85% calcium carbonate, 0.0001 - 0.1% VD3, 0.01 - 0.1% copper oxide, 1 - 10% magnesium oxide, 0.1 - 1% zinc oxide, 0.1 - 1% manganese sulfate monohydrate, 1 - 10% polyvinylpyrrolidone K30, 0.1 - 1% cross-linked polyvinylpyrrolidone, 5 - 20% microcrystalline cellulose, and 0.01 - 1% sodium lauryl sulfate.

[0023] In a preferred technical solution of the present invention, by weight percentage, the composition contains 70 - 80% calcium carbonate, 0.0001 - 0.1% VD3, 0.05 - 0.1% copper oxide, 2 - 5% magnesium oxide, 0.1 - 0.5% zinc oxide, 0.1 - 0.5% manganese sulfate monohydrate, 1 - 5% polyvinylpyrrolidone K30, 0.2 - 0.5% cross-linked polyvinylpyrrolidone, 10 - 15% microcrystalline cellulose, and 0.02 - 0.08% sodium lauryl sulfate.

[0024] In a preferred technical solution of the present invention, by weight percentage, the composition contains 78.728% calcium carbonate, 0.0003% VD3, 0.0658% copper oxide, 4.3534% magnesium oxide, 0.4904% zinc oxide, 0.291% manganese sulfate monohydrate, 3.1512% polyvinylpyrrolidone K30, 0.2626% cross-linked polyvinylpyrrolidone, 12.605% microcrystalline cellulose, and 0.0525% sodium lauryl sulfate.

[0025] In a preferred technical solution of the present invention, the preparation of the composition comprises the following steps:

[0026] (1) Weigh the required amount of VD 3 , dissolve it with a 95% ethanol solution to obtain a VD 3 ethanol solution;

[0027] (2) Weigh the required amounts of manganese sulfate monohydrate, sodium dodecyl sulfate, and povidone K30, dissolve them in water, and after obtaining the manganese sulfate solution, add the VD prepared in step (1). 3 ethanol solution, and after uniform mixing, obtain a mixed solution;

[0028] (3) Weigh the required amount of calcium carbonate, place it in a fluidized bed, and then spray the mixed solution prepared in step (2), and dry to obtain Composition One;

[0029] (4) Using the equal increment method, uniformly mix the required amounts of copper oxide, zinc oxide, magnesium oxide, microcrystalline cellulose, and crospovidone, and then uniformly mix it with Composition One prepared in step (3), and press tablets to obtain the product.

[0030] In the preferred technical solution of the present invention, the average particle size of microcrystalline cellulose is 50 - 200 μm, and the bulk density is 0.28 g / cm 3 - 0.33 g / cm 3 .

[0031] In the preferred technical solution of the present invention, the microcrystalline cellulose is microcrystalline cellulose PH102.

[0032] In the preferred technical solution of the present invention, the average particle size of microcrystalline cellulose is 75 - 150 μm.

[0033] In the preferred technical solution of the present invention, the angle of repose of microcrystalline cellulose is 34°.

[0034] In the preferred technical solution of the present invention, the average particle size of crospovidone is 50 - 200 μm, and the bulk density is 0.29 - 0.32 g / cm 3 .

[0035] In the preferred technical solution of the present invention, the average particle size of crospovidone is 75 - 150 μm.

[0036] In the preferred technical solution of the present invention, the prepared tablets are coated with a gastric-soluble film coating material.

[0037] In the preferred technical solution of the present invention, the gastric-soluble film coating material is made of polyvinyl alcohol, polyethylene glycol, phospholipid, talc powder, aluminum lake of quinoline yellow, aluminum lake of carmine, and titanium dioxide.

[0038] In the preferred technical solution of the present invention, the coating weight gain is 1 - 3.5%, preferably 2 - 3%.

[0039] In the preferred technical solution of the present invention, the composition is a gastric-soluble coated tablet.

[0040] Another object of the present invention is to provide a method for preparing a compound calcium carbonate composition, the composition consisting of an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient consists of calcium carbonate, VD 3 , copper oxide, magnesium oxide, zinc oxide and manganese sulfate monohydrate, and the mass ratio of elemental calcium: VD 3 : elemental copper: elemental magnesium: elemental zinc: elemental manganese is (500 - 800): (0.001 - 0.1): 1: (20 - 100): (1 - 10): (1 - 10). The pharmaceutically acceptable carrier consists of microcrystalline cellulose, polyvinylpyrrolidone K30, cross-linked polyvinylpyrrolidone, sodium lauryl sulfate, and gastric-soluble film coating material, and includes the following steps:

[0041] (1) Weigh the required amount of VD 3 , dissolve it with a 95% ethanol solution to obtain a VD 3 ethanol solution;

[0042] (2) Weigh the required amounts of manganese sulfate monohydrate, sodium lauryl sulfate, and polyvinylpyrrolidone K30, dissolve them in water to obtain a manganese sulfate solution, and then add the VD 3 ethanol solution prepared in step (1), and mix evenly to obtain a mixed solution;

[0043] (3) Weigh the required amount of calcium carbonate, place it in a fluidized bed, spray the mixed solution prepared in step (2), and dry it to obtain Composition One;

[0044] (4) Using the equal increment method, mix the required amounts of copper oxide, zinc oxide, magnesium oxide, microcrystalline cellulose, and cross-linked polyvinylpyrrolidone evenly, and then mix them evenly with Composition One prepared in step (3), and press tablets to obtain the product.

[0045] In the preferred technical solution of the present invention, the mass ratio of elemental calcium: VD 3 : elemental copper: elemental magnesium: elemental zinc: elemental manganese is 600: (0.005 - 0.006): 1: 50: 7.5: 1.8.

[0046] In the preferred technical solution of the present invention, the particle size distribution of calcium carbonate is 50 - 200 μm, and the bulk density is 0.676 g / cm 3 - 0.966 g / cm 3 .

[0047] In the preferred technical solution of the present invention, the particle size distribution of calcium carbonate is 75 - 150 μm.

[0048] In the preferred technical solution of the present invention, the angle of repose of calcium carbonate is 48.2°.

[0049] In the preferred technical solution of the present invention, the particle size distribution of copper oxide is 50 - 200 μm, and the bulk density is 2.241 g / cm 3 - 3.056 g / cm 3 .

[0050] In the preferred technical solution of the present invention, the particle size distribution of copper oxide is 75 - 150 μm.

[0051] In the preferred technical solution of the present invention, the angle of repose of copper oxide is 36.4°.

[0052] In the preferred technical solution of the present invention, the particle size distribution of zinc oxide is 50 - 200 μm, and the bulk density is 0.599 g / cm 3 - 0.832 g / cm 3 .

[0053] In the preferred technical solution of the present invention, the particle size distribution of zinc oxide is 75 - 150 μm.

[0054] In the preferred technical solution of the present invention, the angle of repose of zinc oxide is 44.4°.

[0055] In the preferred technical solution of the present invention, the particle size distribution of magnesium oxide is 50 - 200 μm, and the bulk density is 0.399 g / cm 3 - 0.539 g / cm 3 .

[0056] In the preferred technical solution of the present invention, the particle size distribution of magnesium oxide is 75 - 150 μm.

[0057] In the preferred technical solution of the present invention, the angle of repose of magnesium oxide is 47.6°.

[0058] In the preferred technical solution of the present invention, by weight percentage, the composition contains 65 - 85% of calcium carbonate, 0.0001 - 0.1% of VD3, 0.01 - 0.1% of copper oxide, 1 - 10% of magnesium oxide, 0.1 - 1% of zinc oxide, 0.1 - 1% of manganese sulfate monohydrate, 1 - 10% of polyvinylpyrrolidone K30, 0.1 - 1% of cross-linked polyvinylpyrrolidone, 5 - 20% of microcrystalline cellulose and 0.01 - 1% of sodium dodecyl sulfate.

[0059] In the preferred technical solution of the present invention, by weight percentage, the composition contains 70 - 80% of calcium carbonate, 0.0001 - 0.1% of VD3, 0.05 - 0.1% of copper oxide, 2 - 5% of magnesium oxide, 0.1 - 0.5% of zinc oxide, 0.1 - 0.5% of manganese sulfate monohydrate, 1 - 5% of polyvinylpyrrolidone K30, 0.2 - 0.5% of cross-linked polyvinylpyrrolidone, 10 - 15% of microcrystalline cellulose and 0.02 - 0.08% of sodium dodecyl sulfate.

[0060] In a preferred technical solution of the present invention, by weight percentage, the composition contains 78.728% of calcium carbonate, 0.0003% of VD3, 0.0658% of copper oxide, 4.3534% of magnesium oxide, 0.4904% of zinc oxide, 0.291% of manganese sulfate monohydrate, 3.1512% of polyvinylpyrrolidone K30, 0.2626% of cross-linked polyvinylpyrrolidone, 12.605% of microcrystalline cellulose, and 0.0525% of sodium lauryl sulfate.

[0061] In a preferred technical solution of the present invention, the average particle size of the microcrystalline cellulose is 50 - 200 μm, and the bulk density is 0.28 g / cm 3 - 0.33 g / cm 3 .

[0062] In a preferred technical solution of the present invention, the microcrystalline cellulose is microcrystalline cellulose PH102.

[0063] In a preferred technical solution of the present invention, the average particle size of the microcrystalline cellulose is 75 - 150 μm.

[0064] In a preferred technical solution of the present invention, the angle of repose of the microcrystalline cellulose is 34°.

[0065] In a preferred technical solution of the present invention, the average particle size of the cross-linked polyvinylpyrrolidone is 50 - 200 μm, and the bulk density is 0.29 - 0.32 g / cm 3 .

[0066] In a preferred technical solution of the present invention, the average particle size of the cross-linked polyvinylpyrrolidone is 75 - 150 μm.

[0067] In a preferred technical solution of the present invention, the prepared tablets are coated with a gastric-soluble film coating material.

[0068] In a preferred technical solution of the present invention, the gastric-soluble film coating material is made of polyvinyl alcohol, polyethylene glycol, phospholipid, talc, quinoline yellow aluminum lake, carmine aluminum lake, and titanium dioxide.

[0069] In a preferred technical solution of the present invention, the coating weight gain is 1 - 3.5%, preferably 2 - 3%.

[0070] In a preferred technical solution of the present invention, the composition is a gastric-soluble coated tablet.

[0071] Another object of the present invention is to provide the use of the compound calcium carbonate composition of the present invention in the preparation of a calcium supplement or a drug for preventing and treating osteoporosis, rickets, osteomalacia, and correcting the abnormal bone mineral metabolism or osteoporosis of type II diabetes mellitus (T2DM) patients or any one of its complications.

[0072] In a preferred technical solution of the present invention, the compound calcium carbonate composition is used for calcium supplementation in the elderly, adults, middle-aged and elderly people, pregnant women, lactating women, postmenopausal women, children and other populations in need of calcium supplementation.

[0073] Unless otherwise specified, the present invention uses atomic absorption spectrophotometry (General Rules 0406, Method 1, Volume IV of Chinese Pharmacopoeia 2015 Edition) to detect elemental calcium, elemental zinc, elemental manganese, elemental magnesium and elemental copper contained in the composition, and uses Chinese Pharmacopoeia (General Rules 0931, Method 2, Volume IV of 2015 Edition) to detect the dissolution and release of the composition.

[0074] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between a liquid and a solid, the percentage is volume / weight percentage; when the present invention relates to the percentage between a solid and a liquid, the percentage is weight / volume percentage; the rest is weight / weight percentage.

[0075] Compared with the prior art, the present invention has the following beneficial effects:

[0076] 1. The present invention scientifically screens the components, ratio, particle size distribution, bulk density, etc. of the compound calcium carbonate composition, selects calcium carbonate with a high elemental calcium content (40%), a high calcium absorption rate (39%) and an excellent cost-effectiveness ratio as the calcium supplement, uses gastric acid to convert it into a highly soluble calcium agent, and combines with VD 3 and trace elements (magnesium, zinc, manganese, copper) to promote the absorption and utilization of calcium and trace elements by the body, and uses calcium carbonate as the absorption carrier of VD 3 and manganese sulfate, and uses the lubricating or glidant properties of magnesium oxide to efficiently solve the technical problems such as compressibility, dissolution, friability, disintegration time limit, quality uniformity and stability of the compound calcium carbonate composition of the present invention without adding lubricants or glidants (magnesium stearate) and disintegrants cross-linked carboxymethylcellulose sodium.

[0077] 2. The compound calcium carbonate composition of the present invention has the characteristics of high calcium content, high bioavailability, convenient administration, economy and high efficiency, promotes bone formation and growth and development, effectively and durably increases bone density, bone collagen, bone strength and the elasticity and toughness of bones, relieves bone pain, improves bone microstructure, protects bone health, delays bone aging, effectively prevents osteoporosis and pregnancy-induced hypertension, significantly improves the taste, gastrointestinal function and side effects such as flatulence, constipation and stones, and significantly improves the safety and effectiveness of the pharmaceutical composition and the quality of life and medication compliance of patients.

[0078] 3. The preparation method of the compound calcium carbonate composition of the present invention omits complex preparation steps such as internal addition, external addition, wet granulation, and sizing, and has the advantages of simple preparation, significantly shortened preparation cycle, better cost performance, and suitability for industrial production. Detailed implementation manners

[0079] The present invention will be specifically described below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the essence of the present invention.

[0080] The gastric-soluble film coating material YCW-C-100110 (purchased from Anhui Shanhe) in the detailed implementation manners is made of polyvinyl alcohol, polyethylene glycol, phospholipid, talcum powder, aluminum lake of quinoline yellow, aluminum lake of carmine, and titanium dioxide.

[0081] Example 1 Preparation of the compound calcium carbonate composition of the present invention

[0082] Composition of the compound calcium carbonate composition (1500 tablets):

[0083]

[0084]

[0085] The preparation of the compound calcium carbonate composition includes the following steps:

[0086] (1) Weigh the required amount of VD 3 , dissolve it with 95% ethanol solution to obtain the VD 3 ethanol solution;

[0087] (2) Weigh the required amounts of manganese sulfate monohydrate, sodium dodecyl sulfate, and polyvinylpyrrolidone K30, dissolve them in water, and after obtaining the manganese sulfate solution, add the VD 3 ethanol solution prepared in step (1), and mix evenly (500 rpm * 15 min) to obtain a mixed solution;

[0088] (3) Weigh the required amount of calcium carbonate, place it in a fluidized bed, and then spray the mixed solution prepared in step (2), and perform fluidized drying. Set the inlet air temperature at 58 °C and the material end temperature at 45 °C to obtain Composition 1;

[0089] (4) Using the equal increment method, mix the required amounts of copper oxide, zinc oxide, magnesium oxide, microcrystalline cellulose, and cross-linked polyvinylpyrrolidone evenly (600 rpm * 20 min), and then mix them evenly with Composition 1 prepared in step (3), and press tablets, where the tablet weight variation is ±4%, the friability is ≤0.9%, and the disintegration time limit is ≤15 min;

[0090] (5) Coating the tablets prepared in step (4) with a gastric-soluble film coating material, with a coating weight gain of 2.5%, thus obtaining the product.

[0091] Example 2 Preparation of the compound calcium carbonate composition of the present invention

[0092] Composition of the compound calcium carbonate composition (60,000 tablets):

[0093]

[0094]

[0095] The preparation of the compound calcium carbonate composition includes the following steps:

[0096] (1) Weigh the required amount of VD 3 , dissolve it with a 95% ethanol solution to obtain a VD 3 ethanol solution;

[0097] (2) Weigh the required amounts of manganese sulfate monohydrate, sodium dodecyl sulfate, and polyvinylpyrrolidone K30, dissolve them in water, and after obtaining a manganese sulfate solution, add the VD 3 ethanol solution prepared in step (1), and mix evenly (600 rpm * 20 min) to obtain a mixed solution;

[0098] (3) Weigh the required amount of calcium carbonate, place it in a fluidized bed, and then spray the mixed solution prepared in step (2), and perform fluidized drying. Set the inlet air temperature at 58 °C and the material end temperature at 45 °C to obtain Composition One;

[0099] (4) Using the equal increment method, mix the required amounts of copper oxide, zinc oxide, magnesium oxide, microcrystalline cellulose, and crospovidone evenly (800 rpm * 25 min), and then mix them evenly with Composition One prepared in step (3), and press tablets, where the tablet weight variation is ±4%, the friability is ≤0.9%, and the disintegration time limit is ≤15 min;

[0100] (5) Coating the tablets prepared in step (4) with a gastric-soluble film coating material, with a coating weight gain of 2.3%, thus obtaining the product.

[0101] Example 3 Preparation of the compound calcium carbonate composition of the present invention (preparing 100,000 tablets)

[0102] Composition of the compound calcium carbonate composition (100,000 tablets):

[0103] Component Dosage (Kg) <![CDATA[Calcium carbonate, with an average particle size of 75 μm and a bulk density of 0.676 g / cm 3 > 149.9 <![CDATA[Vitamin D 3 > 0.0006 <![CDATA[Copper oxide, with an average particle size of 12.5 μm and a bulk density of 2.241 g / cm 3 > 0.1252 <![CDATA[Magnesium oxide, with an average particle size of 75 μm and a bulk density of 0.399 g / cm 3 > 8.289 <![CDATA[Zinc oxide, with an average particle size of 75 μm and a bulk density of 0.599 g / cm 3 > 0.9337 Manganese sulfate monohydrate 0.5541 Povidone K30 6 <![CDATA[Cross-linked povidone, with an average particle size of 150 μm and a bulk density of 0.29 g / cm 3 > 0.5 <![CDATA[Microcrystalline cellulose PH102, with an average particle size of 150 μm and a bulk density of 0.28 g / cm 3 > 24 Sodium lauryl sulfate 0.1

[0104] The preparation of the compound calcium carbonate composition includes the following steps:

[0105] (1) Weigh the required amount of VD3 , dissolve it in 95% ethanol solution to obtain VD 3 ethanol solution;

[0106] (2) Weigh the required amounts of manganese sulfate monohydrate, sodium dodecyl sulfate, and povidone K30, dissolve them in water. After obtaining the manganese sulfate solution, add the VD 3 ethanol solution prepared in step (1), and mix them evenly (600 rpm * 25 min) to obtain a mixed solution;

[0107] (3) Weigh the required amount of calcium carbonate, place it in a fluidized bed, and then spray the mixed solution prepared in step (2). Conduct fluidized drying, set the inlet air temperature at 58 °C, and the final temperature of the material at 45 °C to obtain Composition One;

[0108] (4) Using the equal - increment method, mix the required amounts of copper oxide, zinc oxide, magnesium oxide, microcrystalline cellulose, and crospovidone evenly (1000 rpm * 20 min), and then mix them evenly with Composition One prepared in step (3), and press tablets. Among them, the weight variation of tablets is ±4%, the friability is ≤0.9%, and the disintegration time limit is ≤15 min;

[0109] (5) Coating the tablets prepared in step (4) with a gastric - soluble film - coating material, with a coating weight gain of 2.1%, then it is obtained.

[0110] Comparative Example 1 Preparation of Compound Calcium Carbonate Composition

[0111] Composition of Compound Calcium Carbonate Composition (100,000 tablets)

[0112] Component Dosage (Kg) Calcium carbonate, passing through 14-mesh sieve 149.9 Vitamin D3 0.0006 Copper oxide, passing through 40-mesh sieve 0.1252 Magnesium oxide, passing through 40-mesh sieve 8.289 Zinc oxide, passing through 40-mesh sieve 0.9337 Manganese sulfate monohydrate 0.5541 Povidone K30 9.5 Crospovidone, passing through 40-mesh sieve 5.7 Croscarmellose sodium, passing through 40-mesh sieve 5.7 Magnesium stearate, passing through 40-mesh sieve 0.95 Microcrystalline cellulose PH102, passing through 40-mesh sieve 8.1475 Sodium lauryl sulfate 0.1

[0113] The preparation of the compound calcium carbonate composition includes the following steps:

[0114] 1) Weigh the required amount of povidone K30, add water, stir and dissolve it. Take out about 2 kg of povidone K30 solution for standby; then add the required amounts of manganese sulfate monohydrate and sodium dodecyl sulfate to the remaining povidone K30 solution, and stir and dissolve them to prepare Mixed Solution 1;

[0115] 2) Weigh the required amounts of copper oxide, zinc oxide, crospovidone, and magnesium oxide, mix them evenly (600 rpm * 25 min) to obtain a premixed material;

[0116] 3) Weigh the required amount of VD 3 , dissolve it in 95% ethanol solution to obtain VD 3 ethanol solution;

[0117] 4) Place the required amount of calcium carbonate in the mixing chamber of the granulator, then add the premixed material from step (2), mix at low speed (80 rpm) and cut at low speed (1000 rpm) for 2 min, and then successively add the VD 3 ethanol solution and the mixed solution 1 from step (1). After mixing at high speed (160 rpm) and cutting at high speed (2000 rpm) for 3 min, add the 2 kg of povidone K30 solution reserved in step (1), mix at low speed of 80 rpm and cut at high speed of 2000 rpm, and wet mix for 2 min to obtain soft materials; granulate with a 20-mesh sieve of a swing granulator; perform fluidized bed drying, set the inlet air temperature at 58 °C, and the final temperature of the material at 45 °C. Screen the obtained dried granules with a 1.2-mm aperture sieve for sizing;

[0118] 5) After uniformly mixing magnesium stearate and microcrystalline cellulose (600 rpm * 20 min), obtain the externally added mixed powder;

[0119] 6) Place the externally added mixed powder from step (5), the sized granules obtained in step (4), and cross-linked carboxymethyl cellulose sodium into a sandwich hopper mixer for mixing. Set the rotation speed at 4 rpm, mix for 50 min, and then detect the particle content after total mixing;

[0120] 7) Compress tablets, control the tablet weight variation within ±4.0% of the theoretical tablet weight, the friability ≤0.9%, and the disintegration time limit ≤15 min;

[0121] 8) Coating the tablets obtained in step (7) with a gastric-soluble film coating material, with a coating weight gain of 2.3%, and that's it.

[0122] Test Example 1 Dissolution test of the compound calcium carbonate composition of the present invention

[0123] Take the compound calcium carbonate compositions of Examples 1 - 3 and Comparative Example 1, and according to the dissolution and release determination method (General Chapter 0931, Method 2, Volume IV of the Chinese Pharmacopoeia 2015 Edition), use 0.1 mol / L hydrochloric acid as 500 ml of the dissolution medium, rotate at 75 rpm, operate according to the law. At 5 min, 10 min, 15 min, and 30 min, take 30 ml of the dissolution solution, supplement an equal volume of the dissolution medium, filter, accurately measure 25 ml of the continued filtrate, add 1 drop of methyl red test solution, the solution shows a pink color, add sodium hydroxide test solution until the red color fades to yellow, then add another 5 ml of sodium hydroxide test solution and an appropriate amount of calconcarboxylic acid indicator, and titrate with disodium edetate titrant (0.05 mol / L) until the solution changes from purple-red to blue. Each 1 ml of disodium edetate titrant (0.05 mol / L) is equivalent to 2.004 mg of calcium, and calculate the cumulative dissolution of each tablet. The results are shown in Table 1.

[0124] Table 1

[0125] Time Example 1 Example 2 Example 3 Comparative Example 1 5 79.80％ 79.98％ 79.86％ 80.14％ 10 93.84％ 92.60％ 93.09％ 94.45％ 15 99.69％ 99.27％ 99.29％ 99.34％ 30 99.94％ 99.61％ 99.51％ 99.74％

[0126] Test Example 2 Investigation on the quality uniformity of the compound calcium carbonate composition of the present invention

[0127] Detect the components and related substance contents of the compound calcium carbonate compositions of Examples 1-3 and Comparative Example 1 according to the method of the present invention, and the results are shown in Table 2.

[0128] Table 2

[0129]

[0130]

[0131] Test Example 3 Investigation on the stability of the compound calcium carbonate composition of the present invention

[0132] Investigate the stability of the compound calcium composition of Example 3 according to the following method, and the results are shown in Table 3.

[0133] Table 3

[0134]

[0135]

[0136] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or deformations according to the present invention. As long as they do not depart from the spirit of the present invention, they shall fall within the scope of protection of the claims of the present invention.

Claims

1. A compound calcium carbonate composition, the composition consisting of an active ingredient and a pharmaceutically acceptable carrier, wherein: The active ingredient is composed of calcium carbonate, VD3, copper oxide, magnesium oxide, zinc oxide and manganese sulfate monohydrate, and the mass ratio of element calcium: VD3: element copper: element magnesium: element zinc: element manganese is (500-800): (0.001-0.1): 1: (20-100): (1-10): (1-10); The preparation of the composition comprises the following steps: (1) Weigh the required amount of VD3 and dissolve it in 95% ethanol solution to prepare VD3 ethanol solution; (2) Weigh the required amounts of manganese sulfate monohydrate, sodium dodecyl sulfate and povidone K30, dissolve them in water to prepare a manganese sulfate solution, then add the VD3 ethanol solution prepared in step (1), mix evenly, and prepare a mixed solution; (3) Weighing a required amount of calcium carbonate, placing it in a fluidized bed, spraying the mixed solution prepared in step (2), and drying to obtain a composition 1; (4) Using the equal-increment method, the required amounts of copper oxide, zinc oxide, magnesium oxide, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are uniformly mixed, and then the mixture is uniformly mixed with the composition prepared in step (3), and tablets are pressed to obtain the product.

2. The composition as claimed in claim 1, wherein the mass ratio of element calcium:VD3:element copper:element magnesium:element zinc:element manganese in the composition is 600:(0.005-0.006):1:50:7.5:1.

8.

3. The composition of claim 1, wherein the particle size distribution of calcium carbonate is 50-200 μm and the bulk density is 0.676 g / cm 3 -0.966g / cm 3 .

4. The composition of claim 3, wherein the particle size distribution of the calcium carbonate is 75-150 μm.

5. The composition of claim 4, wherein the angle of repose of calcium carbonate is 48.2 。 .

6. The composition of claim 1, wherein the copper oxide has a particle size distribution of 50-200 μm and a bulk density of 2.241 g / cm 3 -3.056g / cm 3 .

7. The composition according to claim 6, wherein the copper oxide has a particle size distribution of 75-150 μm.

8. The composition of claim 7, wherein the angle of repose of copper oxide is 36.4 。 .

9. The composition of claim 1, wherein the zinc oxide has a particle size distribution of 50-200 μm and a bulk density of 0.599 g / cm 3 -0.832g / cm 3 .

10. The composition according to claim 9, wherein the zinc oxide has a particle size distribution of 75-150 μm.

11. The composition of claim 10, wherein the zinc oxide has an angle of repose of 44.4 。 .

12. The composition of claim 1, wherein the magnesium oxide has a particle size distribution of 50-200 μm and a bulk density of 0.399 g / cm 3 -0.539g / cm 3 .

13. The composition according to claim 12, wherein the magnesium oxide has a particle size distribution of 75-150 μm.

14. The composition of claim 13, wherein the magnesium oxide has an angle of repose of 47.6 。 .

15. The composition according to claim 1, wherein the pharmaceutically acceptable carrier in the composition consists of microcrystalline cellulose, povidone K30, cross-linked povidone, sodium lauryl sulfate and a gastric soluble film coating material.

16. The composition according to any one of claims 1 to 15, wherein the composition contains, by weight percentage, 65-85% calcium carbonate, 0.0001-0.1% VD3, 0.01-0.1% copper oxide, 1-10% magnesium oxide, 0.1-1% zinc oxide, 0.1-1% manganese sulfate monohydrate, 1-10% povidone K30, 0.1-1% cross-linked povidone, 5-20% microcrystalline cellulose and 0.01-1% sodium lauryl sulfate.

17. The composition of claim 16, wherein the composition contains, by weight percentage, 70-80% calcium carbonate, 0.0001-0.1% VD3, 0.05-0.1% copper oxide, 2-5% magnesium oxide, 0.1-0.5% zinc oxide, 0.1-0.5% manganese sulfate monohydrate, 1-5% povidone K30, 0.2-0.5% cross-linked polyvinylpyrrolidone, 10-15% microcrystalline cellulose and 0.02-0.08% sodium lauryl sulfate.

18. The composition of claim 17, wherein the composition comprises, by weight percentage, 78.728% calcium carbonate, 0.0003% VD3, 0.0658% copper oxide, 4.3534% magnesium oxide, 0.4904% zinc oxide, 0.291% manganese sulfate monohydrate, 3.1512% povidone K30, 0.2626% crospovidone, 12.605% microcrystalline cellulose and 0.0525% sodium lauryl sulfate.

19. The composition according to any one of claims 1 to 15, wherein the average particle size of the microcrystalline cellulose is 50 to 200 μm and the bulk density is 0.28 g / cm 3 -0.33g / cm 3 .

20. The composition of claim 19, wherein the microcrystalline cellulose is microcrystalline cellulose PH102.

21. The composition of claim 19, wherein the average particle size of the microcrystalline cellulose is 75-150 μm.

22. The composition of claim 19, wherein the microcrystalline cellulose has an angle of repose of 34 。 .

23. The composition according to any one of claims 1 to 15, wherein the average particle size of cross-linked polyvinylpyrrolidone is 50 to 200 μm and the bulk density is 0.29 to 0.32 g / cm 3 .

24. The composition of claim 23, wherein the average particle size of crospovidone is 75-150 μm.

25. The composition according to any one of claims 1 to 15, wherein the prepared tablet is coated with a gastric soluble film coating material.

26. The composition of claim 25, wherein the gastric soluble film coating material is made of polyvinyl alcohol, polyethylene glycol, lecithin, talc, quinoline yellow aluminum lake, carmine aluminum lake and titanium dioxide.

27. The composition of any one of claims 1-15, having a coating weight gain of 1-3.5%.

28. The composition of claim 27, having a coating weight gain of 2-3%.

29. The composition according to any one of claims 1 to 15, which is a gastric soluble coated tablet.

30. A method for preparing a compound calcium carbonate composition according to any one of claims 1 to 29, wherein the composition consists of an active ingredient and a pharmaceutically acceptable carrier, wherein: The active ingredients are composed of calcium carbonate, VD3, copper oxide, magnesium oxide, zinc oxide and manganese sulfate monohydrate, the mass ratio of element calcium: VD3: element copper: element magnesium: element zinc: element manganese is (500-800): (0.001-0.1): 1: (20-100): (1-10): (1-10), the pharmaceutically acceptable carrier is composed of microcrystalline cellulose, povidone K30, cross-linked povidone, sodium lauryl sulfate, and a gastric soluble film coating material, and the steps are as follows: (1) Weigh the required amount of VD3 and dissolve it in 95% ethanol solution to prepare VD3 ethanol solution; (2) Weigh the required amounts of manganese sulfate monohydrate, sodium dodecyl sulfate and povidone K30, dissolve them in water to prepare a manganese sulfate solution, then add the VD3 ethanol solution prepared in step (1), mix evenly, and prepare a mixed solution; (3) Weighing a required amount of calcium carbonate, placing it in a fluidized bed, spraying the mixed solution prepared in step (2), and drying to obtain a composition 1; (4) Using the equal-increment method, the required amounts of copper oxide, zinc oxide, magnesium oxide, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are uniformly mixed, and then the mixture is uniformly mixed with the composition prepared in step (3), and tablets are pressed to obtain the product.

31. The preparation method according to claim 30, wherein the coating weight gain is 1-3.5%.

32. The preparation method as claimed in claim 31, wherein the coating weight gain is 2-3%.

33. Use of the compound calcium carbonate composition according to any one of claims 1 to 29 in the preparation of a calcium supplement or medicine for preventing and treating osteoporosis, rickets, osteomalacia and correcting any one of abnormal bone mineral metabolism or osteoporosis or its complications in patients with type 2 diabetes (T2DM).

34. Use of the compound calcium carbonate composition as claimed in any one of claims 1 to 29 in preparing calcium supplements for the elderly, adults, middle-aged and elderly people, pregnant women, lactating women, postmenopausal women, children and other people who need calcium supplements.

Images