CN114010603A - Preparation method of oyster calcium carbonate particles - Google Patents
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Abstract
The invention discloses a preparation method of oyster calcium carbonate particles, which comprises the steps of selecting an ethanol solution as a solvent, dissolving a prescription amount of citric acid and a part of cane sugar in the ethanol solution to prepare a solution A, adding the prescription amount of oyster calcium carbonate and the rest amount of cane sugar into a wet granulator, adding the solution A, shearing, granulating, drying and finishing. The oyster calcium carbonate particles prepared by the method have the characteristics of good content uniformity, good solubility, less precipitation and stable pH value, and in addition, the preparation method has the advantages of simple process, easy operation and low production cost. The finished product prepared by the invention not only ensures the product quality in the aspect of pharmacy, but also has better clinical application effect and can improve the blood calcium concentration more quickly.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of oyster calcium carbonate particles.
Background
Calcium is one of the important elements of human body, and has very important physiological and biochemical functions. The calcium content of human body is 1.5% -2% of total body weight, wherein bone and teeth account for about 99%, and body fluid and soft tissue account for 1%. Calcium is not only a main substance constituting bones, but also is essential for maintaining nerve and muscle functions, plays an important role in maintaining normal heart, kidney, lung and blood coagulation functions and permeability of cell membranes and capillaries, and also regulates secretion and storage of neurotransmitters and hormones, uptake and utilization of amino acids, absorption of vitamin B12, and the like. The important mechanism for obtaining energy from living cells of human body is the transmembrane movement of calcium, and the calcium content of the ordinary cell membrane is 500 times higher than that of the calcium content in the cells. Neuromuscular responses, coagulation of blood, adhesion of cells, conduction of nerve impulses, maintenance of heart rate, and secretion, contraction, excitation, diffusion, differentiation of cells are all dependent on this transmembrane movement. Oyster calcium carbonate is widely used in European and American countries, is collected in Chinese, American, British and Japanese pharmacopoeias, and is clinically used as a calcium supplement preparation.
The population at each stage needs to be supplemented with sufficient calcium. The infant grows and develops rapidly, is the most vigorous stage of calcium metabolism in life, and can show a series of early symptoms such as dysphoria, hyperhidrosis, anorexia, night convulsion, convulsion and the like once the infant is lack of calcium. If the early-stage calcium deficiency condition is not corrected in time, the autoimmune decline, the upper respiratory tract infection of unknown reasons, frequent spastic abdominal pain and diarrhea can be caused, and the sick children are accompanied by the signs of thin and yellow hair, alopecia occipitalis, alopecia areata and the like. Studies have shown that women who ingest calcium on a low level during pregnancy (average 478 mg per day) have a significant decrease in bone density (as represented by lumbar vertebral density) despite a higher calcium absorption in their intestines, an average 15% decrease compared to non-pregnant women of the same age. While pregnant women who take more calcium (1274 mg per day on average) have a lower calcium absorption rate in their intestines, their bone density is not decreased, which is almost the same as that of non-pregnant women of the same age. This indicates that the increase of calcium intake during pregnancy is the basic guarantee of bone health of pregnant women, and the above evolution mechanism is far from sufficient. The metabolism of the old gradually slows down, the digestion function is weakened, and the calcium demand is relatively increased.
The key point of the calcium supplement effect is the amount of calcium absorption. The absorption site of calcium is in the upper small intestine, and the absorption is fastest in the duodenum, but the absorption amount is in the long ileum as the main absorption site of calcium. The absorption of calcium is mainly accomplished by active transport through the intestinal mucosa, except for a small amount by diffusion. The absorption rate is different at different ages: the highest absorption rate of the infant is 50% -60%; the absorption rate of teenagers is 35-40%; the adult absorption rate is lower and is 15-20%; the absorption rate of the elderly is only 10%. The concentration of the drug in the blood is an important condition for the drug to exert and maintain the therapeutic effect, and is also the basis for evaluating how much the calcium supplement is absorbed.
Oyster calcium carbonate is a conventional calcium supplement, and is used as a calcium supplement for pregnant and lactating women, climacteric women, the elderly, etc. The active ingredients of the product have extremely low solubility in water, and are easy to precipitate during storage and use, and the calcium does not exist in an ionic state and can be absorbed only after being dissociated by consuming gastric acid. This condition can cause irritation to the stomach and also affect calcium absorption. How to correctly select oral calcium preparation (Chinese rural medicine, 1998, 26, No. 1, page 17) summarizes the characteristics of high-quality calcium preparation, including good solubility and high bioavailability. How to improve the solubility of the product, reduce the precipitation and ensure the stability of quality indexes so as to improve the calcium supplement effect of the product is a problem which is always tried and not solved by pharmaceutical researchers.
CN106943427A discloses a calcium carbonate particle composition and a preparation method thereof, which are used for solving the problems of poor solubility and easy generation of precipitate of the existing preparation. The scheme composition comprises the following components in parts by weight: 100 parts of calcium carbonate, 4500 parts of powdered sugar 3000 and 180 parts of acid source.
The method comprises the following steps:
(a) weighing 100 parts of calcium carbonate, 3000-4500 parts of powdered sugar and 120-180 parts of acid source according to the weight part ratio;
(b) adding 150 parts of sugar powder by weight of 100-65 parts into purified water to prepare syrup with the mass ratio concentration of 35-65%, uniformly mixing the calcium carbonate and the sugar powder according to the mass ratio of 100:900-2000, then adding the syrup to prepare a soft material, and performing wet granulation, drying and granule stabilization to obtain calcium carbonate granules;
(c) mixing an acid source and purified water according to the mass ratio of 1:0.4-1, fully dissolving, adding the residual sugar powder, preparing into a soft material, performing wet granulation, drying, and grading to obtain acid granules;
(d) and (c) uniformly mixing the calcium carbonate particles obtained in the step (b) and the acid particles obtained in the step (c) to obtain the calcium carbonate particle composition.
In the preparation method, the finished product particles are divided into two parts, namely calcium carbonate particles and acid particles. The calcium carbonate particles are prepared by adding water into sucrose to prepare syrup, and then granulating with calcium carbonate and powdered sugar; the acid granules are prepared by adding water to acid and then granulating with the remaining sucrose. By being divided into two parts of particles, the calcium carbonate is prevented from contacting with an acid source to a certain extent, the stability of the calcium carbonate is facilitated, the solubility is improved, and the precipitation is reduced. The technical scheme of the invention, step (c), namely the acid particle drying step, adopts two methods: one is drying in a common drying oven at 25 deg.C for 5-60 hr; the other method comprises drying with 18-26 deg.C cold air for 1-20min, drying with 40-70 deg.C hot air for 10-20min, and cooling with 18-26 deg.C cold air to room temperature. The drying time of the acid particles is long (5-60 h at 25 ℃), or the operation is complicated (firstly cold air, then hot air and finally cold air drying), so that the operation difficulty is increased, the production cost is increased, and the commercial production is not facilitated. In addition, the inventor finds that the sample prepared by the method has two problems in the process of reproducing the technical scheme: 1. the content uniformity of the finished product is poor, which probably accounts for a small proportion (about 2.5%) of the main medicine of the product, and the main medicine is not easy to be mixed uniformly by adopting two parts for granulation; 2. further accelerated examination and detection results show that the acidity of the finished product is obviously improved.
Based on the requirements of clinical application on the pharmaceutical quality of the product and the defects of the prior art, further research is needed to ensure the product quality, improve the absorption and improve the clinical application effect. The oyster calcium carbonate particles are mostly prepared by a wet granulation process. Specifically, swing granulation, shear granulation, fluidized bed one-step granulation, and combinations of different granulation methods may be used. In the process of intensive research on the process, the inventor improves the technical scheme disclosed in CN106943427A, replaces the granulating solvent with ethanol with a certain concentration from purified water, dissolves citric acid in the ethanol and then granulates with sucrose, and finds that the prepared granules appear light yellow when dried, and the color deepens with the increase of the dosage of the citric acid. According to this phenomenon, the present inventors creatively mix sucrose with citric acid in an ethanol solution, and the mixed solution serves as a binder, followed by granulation. Through research on the ethanol concentration, the sucrose dissolving amount and corresponding conditions, the finished product prepared by the granulating mode is found to have better content uniformity, and simultaneously has the characteristics of good solubility, less precipitate and stable pH value. Surprisingly, by monitoring the blood calcium concentration after the calcium supplement is taken, the finished product prepared by the process has a better calcium supplement effect and can improve the blood calcium concentration more quickly.
Disclosure of Invention
The invention aims to provide a preparation method of oyster calcium carbonate particles, which adopts a wet shearing granulation process. The process is characterized in that ethanol is used as a solvent, citric acid and sucrose in a specific amount are dissolved in the ethanol, and a specific temperature is required to be controlled during dissolution.
The invention relates to a preparation method of oyster calcium carbonate particles, which comprises the following steps:
1) crushing oyster calcium carbonate and cane sugar and sieving with a 80-100 mesh sieve;
2) weighing 20-40% ethanol solution according to 6.5% of the weight of the granulated material, dissolving the citric acid and the sucrose in the amount of 6.5-8.5% in the ethanol solution, and controlling the temperature of the ethanol solution to be 40-60 ℃ during dissolution to prepare solution A;
3) adding oyster calcium carbonate and the residual sucrose in the formula amount into a wet granulator, stirring and mixing uniformly, adding the solution A in the step 2), and shearing and granulating;
4) drying the prepared granules, finishing granules and subpackaging to obtain the oyster calcium carbonate granules.
The further optimized technical scheme of the invention can be as follows:
1) crushing oyster calcium carbonate and cane sugar and sieving with a 100-mesh sieve;
2) the concentration of the ethanol solution is 30 percent;
3) dissolving sucrose with a prescription amount of 7.5% by using an ethanol solution;
4) when dissolving citric acid and sucrose, the temperature of the ethanol solution is controlled to be 50 ℃.
In addition, during the preparation of the product, according to the conditions of the granulating materials after the shearing granulation, a proper amount of ethanol solution can be added for shearing granulation, which can be judged by the skilled person according to the experience.
According to the preparation method, the oyster calcium carbonate particle formula comprises the following components in parts by weight:
oyster calcium carbonate 125 parts
4675-4710 parts of cane sugar
165-200 parts of citric acid
Further, in the preparation method of the invention, the oyster calcium carbonate particle formula contains the following components in parts by weight:
oyster calcium carbonate 125 parts
4690 parts of cane sugar
185 portions of citric acid
The prescription of the invention can also contain other pharmaceutical auxiliary materials which are suitable to be added in the preparation formulation, including pigment, essence and the like, such as 0.1 part of lemon yellow and 2.5 parts of orange essence.
In the preparation method, the oyster calcium carbonate and the sucrose are crushed and sieved by a sieve with 80-100 meshes, preferably 100 meshes, and the sieving treatment realizes the granularity control of the initial material and avoids the material agglomeration. When other sizes of screens are adopted, the application possibility exists, and only the product quality risk is increased, the cost is increased, and the like. Solution A, which is prepared by dissolving citric acid and part of sucrose in ethanol solution, is used as adhesive in the preparation process of the product. The amount of ethanol solution used was 6.5% by weight of the granulated material according to the study. The preparation method of the invention can add a small amount of ethanol according to the state of the materials after the granulation is finished, and then perform granulation. This is a problem that the person skilled in pharmacy can recognize and can judge and does not have a major or decisive influence on the quality of the product.
The following description will be made in conjunction with the prior art documents to explain the positive effects of the present invention:
the oyster calcium carbonate granule contains acid source such as citric acid. The calcium carbonate is alkaline, the citric acid is acidic, and the calcium citrate can react to generate calcium citrate precipitate when in contact. The contact between the calcium carbonate and the calcium carbonate is avoided in the production process, so that the reaction can be reduced, the precipitation is reduced, and further, the absorption is increased, and the calcium supplement effect is improved. The technical proposal disclosed in CN106943427A divides the finished product particles into two parts, namely calcium carbonate particles and acid particles. By being divided into two parts of particles, the calcium carbonate is prevented from contacting with an acid source to a certain extent, the stability of the calcium carbonate is facilitated, the solubility is improved, and the precipitation is reduced. The invention adopts ethanol as a solvent, and creatively dissolves all the prescription dose of citric acid and part of sucrose in the ethanol. The concentration of the ethanol is obtained by screening, and needs to be controlled to be 20% -40%, and the preferred concentration of the ethanol is 30%. The amount of sucrose dissolved in ethanol is determined by repeated screening, and the stability of the product can be ensured only if the amount of sucrose reaches 6.5% of the weight of the granulated material. When the dosage is less than 6.5%, the quality of the prepared finished product is not obviously different in 0 day, but in the process of drug stability inspection, the problems of increased precipitation and increased pH value can occur. When the amount of sucrose is higher than 8.5% of the weight of the granulated material, the problem of slow dissolution process of sucrose occurs, which is not beneficial to industrial production. In the preparation method of the invention, the preferable amount of sucrose dissolved in ethanol is 7.5% of the amount prescribed. The citric acid and part of cane sugar are dissolved in the ethanol, and the temperature of the ethanol is controlled to be 40-60 ℃. The material is slowly dissolved at the temperature lower than 40 ℃, which is not beneficial to production; above 60 c, the resulting particles are prone to color change, which is to be avoided during production. The finished product prepared by the method weakens the effects of citric acid and calcium carbonate, thereby having the characteristics of good solubility, less precipitation and stable pH value. In addition, the method adopts wet granulation to fully and uniformly mix, and the content uniformity of the finished product is better. Surprisingly, the blood calcium concentration can be quickly improved by monitoring the blood calcium concentration after the calcium supplement is taken, and the calcium supplement effect is better. The technical personnel constantly strive to increase the absorption and improve the effect of calcium supplement products.
The technical scheme of the invention is substantially characterized in that citric acid and specific amount of sucrose are dissolved in alcohol solution for granulation, a conventional wet granulation process is still adopted, the production process is simple, the operation is easy, the cost is low, and the method is suitable for industrial mass production. The preparation method not only ensures the product quality in the aspect of pharmacy, but also has better clinical application effect. The invention is undoubtedly a great technical progress for the calcium supplement product of oyster calcium carbonate particles, and has obvious improvement compared with the prior art.
Detailed Description
The following examples are intended only to illustrate the invention in further detail, but are not intended to limit the scope of the invention in any way.
Example 1: oyster calcium carbonate particle prescription (weight portion)
Oyster calcium carbonate 125 parts
4690 parts of cane sugar
185 portions of citric acid
The preparation method comprises the following steps:
1) the oyster calcium carbonate and the sucrose are crushed and sieved by a 100-mesh sieve.
2) Weighing 30% ethanol solution according to 6.5% of the weight of the granulated material, dissolving the citric acid and the sucrose in the amount of 7.5% in the ethanol solution, stirring and heating during dissolving, and controlling the temperature of the ethanol solution to be 50 ℃ to prepare solution A.
3) Adding the oyster calcium carbonate and the residual sucrose in the formula amount into a high-efficiency wet granulator, stirring at a low speed for 100 seconds, and uniformly mixing. And then adding the solution A obtained in the step 2) into the mixture by low-speed stirring and high-speed cutting, and stirring the mixture at a high speed and cutting the mixture at a high speed for 60 seconds after the solution A is added to obtain wet particles.
4) Drying the prepared particles by a fluidized bed, and controlling the air inlet temperature to be about 60 ℃ during drying; the dried granules were granulated with a grinding granulator.
5) And (3) hermetically packaging the granules by using a medicinal composite film bag (50 mg/bag in terms of calcium) to obtain the oyster calcium carbonate granules.
Example 2: oyster calcium carbonate particle prescription (weight portion)
1) The oyster calcium carbonate and the sucrose are crushed and sieved by a 80-mesh sieve.
2) Weighing 20% ethanol solution according to 6.5% of the weight of the granulated material, dissolving the citric acid, the lemon yellow and the sucrose with the amount of 6.5% in the ethanol solution, stirring and heating during dissolving, and controlling the temperature of the ethanol solution to be 40 ℃ to prepare the solution A.
3) Adding the oyster calcium carbonate and the residual sucrose in the formula amount into a high-efficiency wet granulator, stirring at a low speed for 100 seconds, and uniformly mixing. And then adding the solution A obtained in the step 2) into the mixture by low-speed stirring and high-speed cutting, and stirring the mixture at a high speed and cutting the mixture at a high speed for 60 seconds after the solution A is added to obtain wet particles.
4) Drying the prepared particles by a fluidized bed, and controlling the air inlet temperature to be about 60 ℃ during drying; the dried granules were granulated with a grinding granulator.
5) And (3) hermetically packaging the granules by using a medicinal composite film bag (50 mg/bag in terms of calcium) to obtain the oyster calcium carbonate granules.
Example 3: oyster calcium carbonate particle prescription (weight portion)
1) The oyster calcium carbonate and the sucrose are crushed and sieved by a 100-mesh sieve.
2) Weighing 40% ethanol solution according to 6.5% of the weight of the granulated material, dissolving the citric acid, the orange essence and the sucrose with the amount of 8.5% in the ethanol solution, stirring and heating when dissolving, and controlling the temperature of the ethanol solution to be 60 ℃ to prepare the solution A.
3) Adding the oyster calcium carbonate and the residual sucrose in the formula amount into a high-efficiency wet granulator, stirring at a low speed for 100 seconds, and uniformly mixing. Then adding the solution A obtained in the step 2) into the mixture by low-speed stirring and high-speed cutting, and stirring the mixture at a high speed and cutting the mixture at a high speed for 60 seconds after the solution A is added. After the granulation is finished, starting low-speed stirring and high-speed cutting, weighing and adding 40% ethanol solution according to the weight of 1% of the granulated material, and after the ethanol solution is added, stirring at high speed and cutting at high speed for 30 seconds to obtain wet granules.
4) Drying the prepared particles by a fluidized bed, and controlling the air inlet temperature to be about 60 ℃ during drying; the dried granules were granulated with a grinding granulator.
5) And (3) hermetically packaging the granules by using a medicinal composite film bag (50 mg/bag in terms of calcium) to obtain the oyster calcium carbonate granules.
Comparative example 1: samples were prepared as disclosed in example 1 of CN 106943427A.
1) Sieving oyster calcium carbonate and sucrose with a 80-mesh sieve respectively, weighing 75.2g of the sieved oyster calcium carbonate powder, 2809g of the sieved sucrose powder, 115.8g of citric acid and 0.044g of lemon yellow;
2) adding 93.5g of sucrose powder into purified water to prepare syrup with the mass ratio concentration of 50%, putting 75.2g of sieved oyster calcium carbonate and 1425g of white granulated sugar powder into a manual sieve, mixing for 3 times, adding the syrup and a pigment water solution prepared by dissolving 0.022g of pigment in 10g of purified water to prepare a soft material, granulating by a wet method, drying for 120min at 50 ℃, and finishing to obtain calcium carbonate particles;
3) mixing 115.8g citric acid with 47g purified water, dissolving completely, adding the rest sugar powder and pigment water solution prepared by dissolving 0.022g pigment with 10g purified water, making into soft material, wet granulating, drying at 25 deg.C for 16 hr, and grading to obtain acid granule.
4) And (3) uniformly mixing the calcium carbonate particles obtained in the step (2) and the acid particles obtained in the step (3).
5) And (3) hermetically packaging the granules by using a medicinal composite film bag (50 mg/bag in terms of calcium) to obtain the oyster calcium carbonate granules.
And (3) comparison test: the finished calcium carbonate particles prepared in examples 1 to 3 of the present invention and the finished calcium carbonate particles prepared in comparative example were examined. During detection, the test is carried out according to the national drug standard WS-10001- (HD-1037) -2002.
The content is as follows: 10 bags of each of the finished products prepared in examples 1-3 and comparative example 1 were taken, the particles were ground, an appropriate amount (about equivalent to 50mg of calcium) was precisely weighed, the mixture was placed in a 100ml measuring flask, 100ml of diluted hydrochloric acid was added, shaking was carried out to dissolve the solution, 0.1g of activated carbon was added, the solution was sufficiently shaken, the solution was diluted to a scale with water, shaking was carried out, filtration was carried out, 50ml of the subsequent filtrate was precisely weighed, 50ml of water and 1 drop of methyl red indicator solution were added, ammonia solution was added dropwise to change the solution from red to yellowish, 5ml of triethanolamine solution (1-5) was added, shaking was carried out, 18ml of sodium hydroxide solution and 0.2g of calcium purpurin indicator were added, titrated with disodium ethylenediaminetetraacetate titrating solution (0.05mo1/L) until the solution changed from magenta to pure blue, and each 1ml of disodium ethylenediaminetetraacetate titrating solution (0.05mo1/L) was equivalent to 2.004mg of Ca.
Acidity: taking a proper amount of the fine powder (about equivalent to 50mg of calcium) and adding 100ml of water, shaking for 10 minutes and filtering. Taking the filtrate, and determining according to the law (appendix VI H of the second part of the Chinese pharmacopoeia 2000 edition), wherein the pH value is 4.5-6.5.
Solubility: 10g of the product is taken, heated to 200ml of water, stirred for 5 minutes, and completely dissolved or slightly turbid or uniformly suspended without any foreign matters such as coke breeze and the like.
Content uniformity: taking 10 bags of finished products, checking the content of each bag according to a content item detection method, and calculating RSD.
(1) And (3) detection in 0 day: the calcium carbonate granules prepared in examples 1 to 3 and the calcium carbonate granules prepared in comparative example 1 were subjected to content, acidity, solubility and content uniformity tests, and the test results are shown in table 1.
TABLE 10 day Performance test of products prepared in examples 1-3 and comparative example 1
| Sample (I) | Content/% | Acidity pH | Solubility in water | Content uniformity (RSD) |
| Example 1 | 100.2 | 5.06 | All are melted and clarified | 0.96％ |
| Example 2 | 99.3 | 5.12 | All are melted and clarified | 0.83％ |
| Example 3 | 99.8 | 4.83 | All are melted and clarified | 0.78％ |
| Comparative example 1 | 99.5 | 4.96 | All are melted and clarified | 4.25％ |
And (4) evaluating the results: the oyster calcium carbonate particles prepared in the examples 1 to 3 and the oyster calcium carbonate particles prepared in the comparative example 1 have no obvious difference in the content, acidity and dissolubility of the main detection indexes in 0 day; the content uniformity items, the example samples are obviously better than the comparative example samples.
(2) Accelerating the detection for 3 months: the finished calcium carbonate particles prepared in examples 1 to 3 and the finished calcium carbonate particles prepared in comparative example 1 were subjected to accelerated examination at 40 ℃ and 75% humidity for 3 months, and the results of the examination are shown in Table 2.
Table 2 results of accelerated 3-month test after packaging for products prepared in examples 1 to 3 and comparative example 1
| Sample (I) | Content/% | Acidity of the solution | Solubility in water |
| Example 1 | 100.5 | 5.02 | All are melted and clarified |
| Example 2 | 99.7 | 5.13 | All are melted and clarified |
| Example 3 | 99.1 | 4.85 | All are melted and clarified |
| Comparative example 1 | 99.9 | 5.23 | All are melted and clarified |
And (4) evaluating the results: the oyster calcium carbonate particles prepared in examples 1 to 3 have no obvious difference in main detection indexes among batches after being accelerated for 3 months, and have no obvious change compared with 0 day. The oyster calcium carbonate particles prepared in comparative example 1 had an increase in the acidity rating compared to 0 days.
(3) The detection is accelerated for 6 months: the finished calcium carbonate particles prepared in examples 1 to 3 and the finished calcium carbonate particles prepared in comparative example were subjected to accelerated examination at 40 ℃ and 75% humidity for 6 months, and the results of the examination are shown in Table 3.
Table 3 results of accelerated 6-month test after packaging for products prepared in examples 1 to 3 and comparative example 1
| Sample (I) | Content/% | Acidity of the solution | Solubility in water |
| Example 1 | 100.0 | 5.06 | All are melted and clarified |
| Example 2 | 100.2 | 5.17 | All are melted and clarified |
| Example 3 | 99.4 | 4.88 | All are melted and clarified |
| Comparative example 1 | 99.1 | 6.06 | Slight cloudiness |
And (4) evaluating the results: the oyster calcium carbonate particles prepared in examples 1 to 3 have no obvious difference in main detection indexes among batches after being accelerated for 6 months, and have no obvious change compared with 0 day. The acidity of the oyster calcium carbonate particles prepared in the comparative example 1 is obviously increased compared with that of the oyster calcium carbonate particles prepared in the day 0; the solubility term also changes from fully clear to slightly cloudy.
According to the detection result of 0 day, the content uniformity of the sample of the embodiment is obviously better than that of the sample of the comparative example. According to the examination results of 3 months and 6 months, the samples of the examples have better acidity stability and better solubility index than the samples of the comparative examples.
Evaluation of calcium supplement efficacy
The oyster calcium carbonate particle finished product (50 mg/bag in terms of calcium) prepared in example 2 and comparative example 1 is used for calcium supplement crowds, and the blood calcium concentration before and after taking is monitored to evaluate the clinical application effect.
Volunteer grouping and method: 98 screened people suitable for calcium supplement or with calcium supplement requirements are randomly divided into two groups, and each group comprises 49 people. The oyster calcium carbonate granules of example 2 were administered to group I, and the oyster calcium carbonate granules of comparative example 1 were administered to group II. The two groups take the medicine in the same way: it is administered orally in two bags each time, three times a day, and is administered with warm boiled water. The two groups were administered continuously for 8 weeks. Venous blood was drawn at the following time points, respectively, for blood calcium concentration monitoring, data recording and analysis: before administration, 4 weeks after administration, 6 weeks after administration, and 8 weeks after administration.
TABLE 4 comparison of blood calcium concentration before and after administration of the finished products of example 2 and comparative example 1
And (4) evaluating the results: as can be seen from the blood calcium concentration monitoring, the blood calcium concentration at each monitoring time point was higher in the administration of the oyster carbo-calcium granules of example 2 than in comparative example 1. In particular, the blood calcium concentration of example 2 taken for 6 weeks was substantially close to that of control group 1 taken for 8 weeks. Therefore, the oyster calcium carbonate particles can improve the blood calcium concentration more quickly and have better calcium supplement effect.
Claims (7)
1. A preparation method of oyster calcium carbonate particles comprises the following steps:
1) crushing oyster calcium carbonate and cane sugar and sieving with a 80-100 mesh sieve;
2) weighing 20% -40% ethanol solution according to 6.5% of the weight of the granulated material, dissolving the prescription amount of citric acid and 6.5% -8.5% of the prescription amount of cane sugar in the ethanol solution, and controlling the temperature of the ethanol solution to be 40-60 ℃ during dissolving to prepare solution A;
3) adding oyster calcium carbonate and the residual sucrose in the formula amount into a wet granulator, stirring and mixing uniformly, adding the solution A in the step 2), and shearing and granulating;
4) drying the prepared granules, finishing granules and subpackaging to obtain the oyster calcium carbonate granules.
2. The method of claim 1, wherein the mesh screen is 100 mesh.
3. The method of claim 1, wherein the ethanol solution is at a concentration of 30%.
4. The method of claim 1, wherein the sucrose specified in step 2) is a prescribed amount of 7.5%.
5. The process according to claim 1, characterized in that the temperature of the ethanol solution is in particular 50 ℃.
6. The method of claim 1, wherein the oyster calcium carbonate granule formulation comprises, by weight:
oyster calcium carbonate 125 parts
4675-4710 parts of cane sugar
165-200 parts of citric acid.
7. The method of claim 1, wherein the oyster calcium carbonate granule formulation comprises, by weight:
oyster calcium carbonate 125 parts
4690 parts of cane sugar
185 parts of citric acid.
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| PCT/CN2022/098166 WO2023082626A1 (en) | 2021-11-09 | 2022-06-10 | Method for preparing oyster shell calcium granules |
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| WO2023082626A1 (en) * | 2021-11-09 | 2023-05-19 | 重庆华森制药股份有限公司 | Method for preparing oyster shell calcium granules |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4678661A (en) * | 1983-09-28 | 1987-07-07 | Gerhard Gergely | Effervescent composition and method of making same |
| JP2014034556A (en) * | 2012-08-09 | 2014-02-24 | Fancl Corp | Orally rapid disintegrating tablet |
| CN105496983A (en) * | 2016-01-21 | 2016-04-20 | 国药集团汕头金石制药有限公司 | Oyster shell calcium effervescent tablet composition and preparation method thereof |
| CN106943427A (en) * | 2017-04-12 | 2017-07-14 | 华北制药河北华诺有限公司 | A kind of calcium carbonate granule composition and preparation method thereof |
| CN109260220A (en) * | 2018-11-28 | 2019-01-25 | 重庆华森制药股份有限公司 | A kind of preparation method of oyster shell calcium particle |
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| CN114010603B (en) * | 2021-11-09 | 2023-07-11 | 重庆华森制药股份有限公司 | Preparation method of oyster calcium carbonate particles |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4678661A (en) * | 1983-09-28 | 1987-07-07 | Gerhard Gergely | Effervescent composition and method of making same |
| JP2014034556A (en) * | 2012-08-09 | 2014-02-24 | Fancl Corp | Orally rapid disintegrating tablet |
| CN105496983A (en) * | 2016-01-21 | 2016-04-20 | 国药集团汕头金石制药有限公司 | Oyster shell calcium effervescent tablet composition and preparation method thereof |
| CN106943427A (en) * | 2017-04-12 | 2017-07-14 | 华北制药河北华诺有限公司 | A kind of calcium carbonate granule composition and preparation method thereof |
| CN109260220A (en) * | 2018-11-28 | 2019-01-25 | 重庆华森制药股份有限公司 | A kind of preparation method of oyster shell calcium particle |
Non-Patent Citations (2)
| Title |
|---|
| SIMON GROTE等: "Impact of functionalized particle structure on roll compaction/dry granulation and tableting of calcium carbonate", 《INT J PHARM》, vol. 544, no. 1, pages 235 - 241 * |
| 杨红: "醇类添加剂对碳酸钙形貌及晶型的影响", 《浙江理工大学学报》, vol. 24, no. 5, pages 549 - 552 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023082626A1 (en) * | 2021-11-09 | 2023-05-19 | 重庆华森制药股份有限公司 | Method for preparing oyster shell calcium granules |
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