CN108478595B - A pharmaceutical composition containing calcium carbonate, vitamin D3, and vitamin K2 - Google Patents
A pharmaceutical composition containing calcium carbonate, vitamin D3, and vitamin K2 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/10—Carbonates; Bicarbonates
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
- A23L33/155—Vitamins A or D
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/16—Inorganic salts, minerals or trace elements
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention belongs to the technical field of medicines, health-care foods and foods, and particularly relates to a pharmaceutical composition containing calcium carbonate, vitamin D3 and vitamin K2 and a preparation method thereof. The composition comprises the following components in parts by weight: 600 parts of calcium carbonate, 5 parts of vitamin D3 and 80 parts of vitamin K2. The vitamin D3 in the product is stable and uniformly distributed, the calcium carbonate content is high, and the tabletting quality is good; the product of the invention has simple and easy production operation and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of biological medicines, health-care foods and foods, and particularly relates to a pharmaceutical composition of calcium carbonate, vitamin D3 and vitamin K2 and a preparation method thereof.
Technical Field
Calcium is an essential element of human body, is also a mineral element which is most abundant in human body, participates in the whole life process of human body, and can not be separated from bone formation, muscle contraction, heart beating, nerve and brain thinking activity until the growth and development of human body, fatigue elimination, brain strengthening, intelligence development, aging delay and the like. The normal metabolism of human bodies can be maintained and the adaptability of the human bodies to living environments can be enhanced only by taking sufficient calcium every day.
For teenagers, adolescence is the period in which skeleton development and height increase fastest in a lifetime, and fifty percent of the calcium content of bones of a human body is stored in the period, which is the period in which calcium is most needed in the lifetime. If enough calcium is taken daily, the skeleton, internal organs and brain can be fully developed, which is very important for the increase of height and weight.
For the middle-aged and the elderly, calcium deficiency can cause osteoporosis, arthritis and other diseases. Due to the lack of calcium, the bone density is reduced, the bone mass is reduced, osteoporosis is caused, and fracture is easily caused. The joint part can be susceptible to rheumatism, rheumatoid arthritis and hydrarthrosis due to the reduction of disease resistance caused by calcium deficiency, and can also be secondarily hyperosteogeny in cervical vertebra, lumbar vertebra, knee joint, heel, etc.
Calcium carbonate is the best calcium supplement material widely used, and has high calcium content, low cost and good absorption in vivo. The calcium carbonate raw material which is most commonly used at present is powdery, has poor fluidity and is difficult to be directly tabletted by adopting powder. The popularity of the calcium carbonate can be improved by wet granulation, but because the calcium carbonate does not have viscosity and accounts for a higher proportion in the prescription, the stability of the vitamin D3 and the uniformity of the mixed preparation are effectively ensured, and the main problems to be solved by the preparation are solved.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides calcium carbonate, vitamin D3 and vitamin K2 tablets and a preparation method thereof. Aims to solve the technical problems of poor stability and uniform mixing of the vitamin D3 and poor granulation of the existing solid calcium preparation.
In order to achieve the above object, the present invention has the following technical means
A pharmaceutical composition containing calcium carbonate, vitamin D3, vitamin K2 and vitamin K2 comprises the following components in parts by weight: 600 parts of calcium carbonate, 5 parts of vitamin D3 and 80 parts of vitamin K2.
A pharmaceutical composition containing calcium carbonate, vitamin D3, vitamin K2 and vitamin K2 comprises the following components in parts by weight: 600 parts of calcium carbonate, 0.005 part of vitamin D3, 0.08 part of vitamin K2, 130-160 parts of filler, 5-10 parts of lubricant, 4-10 parts of disintegrant, 10-30 parts of adhesive and 1-5 parts of oil phase.
The calcium carbonate is a mixture consisting of light calcium carbonate and heavy calcium carbonate.
The weight ratio of the light calcium carbonate to the heavy carbonic acid is (2-5): 1.
the vitamin D3 is vitamin D3 microcapsule, vitamin D3 or their mixture.
The weight ratio of the vitamin D3 microcapsule powder to the vitamin D3 in the vitamin D3 mixture is (1-4): 1.
the vitamin K2 is microcapsule.
The medicine composition is prepared into powder, granules, common tablets, capsules, chewable tablets, dispersible tablets, dry suspension and soft capsules.
The filler is selected from one or more of starch, lactose, sugar powder, mannitol, microcrystalline cellulose, pregelatinized starch and sorbitol.
The disintegrant is selected from one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium.
The lubricant is selected from one or more of superfine silica gel powder, talcum powder and magnesium stearate.
The oil phase is selected from one or more of medium chain triglyceride, fish oil, squalene, soybean oil, and hydrogenated soybean oil. The oil phase can be effectively dissolved with vitamin D3, and does not cause adverse reaction clinically.
The binder can be selected from one or more of starch, hypromellose, polyvidone K30, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyethylene glycol, and gelatin.
A preparation method of a pharmaceutical composition containing calcium carbonate, vitamin D3, vitamin K2, vitamin K2 and vitamin K2 comprises the following steps:
1) mixing calcium carbonate and a disintegrating agent to obtain a calcium-containing mixed material;
2) dissolving vitamin D3 in oil phase, adding binder, stirring to dissolve to obtain solution, and spray drying;
3) granulating the powder obtained in the step 1) and the step 2) with vitamin D3 microcapsules and vitamin K2 microcapsules by using a centrifugal granulator to obtain calcium carbonate composite powder;
4) and mixing and tabletting the calcium carbonate composite powder obtained in the step, the filler, the disintegrating agent and the lubricant.
Compared with the prior art, the invention has the following advantages and positive effects:
1. the vitamin D3 in the product is stable, the distribution is uniform, the calcium carbonate content is high, and the tabletting quality is good.
2. The product of the invention has simple and easy production operation and is suitable for industrial production.
Vitamin D3 can participate in calcium metabolism, convert calcium-binding protein precursor existing in small intestine into calcium-binding protein, and enhance renal tubule absorption of calcium, so vitamin D3 has important effect in promoting calcium absorption and bone formation. However, in the calcium carbonate, vitamin D3 and vitamin K2 preparations, the content of vitamin D3 is usually very low, and the calcium carbonate, the vitamin D3 and the vitamin K2 are difficult to be mixed uniformly, so that the problem that the content uniformity is unqualified easily occurs. And vitamin D3 is extremely unstable, is relatively sensitive to temperature, light and air, and is easily converted into precursor substances in polar solution. Therefore, how to stabilize vitamin D3 and to mix it homogeneously is a technical problem to be overcome in calcium preparations.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention. Moreover, in the following description, descriptions of well-known structures and techniques are omitted so as to not unnecessarily obscure the concepts of the present invention.
The Light Calcium Carbonate (Light Calcium Carbonate), also called Precipitated Calcium Carbonate (PCC for short), is prepared by a chemical processing method, and the sedimentation volume is 2.4-2.8 mL/g.
The Heavy Calcium Carbonate (Heavy Calcium Carbonate) is formed by grinding natural Carbonate minerals such as calcite, marble and limestone, and the sedimentation volume is 1.2-1.9 mL/g.
The vitamin K2 is microcapsule powder prepared by fermentation.
The vitamin D3 was a microencapsulated powder prepared according to the method of ZL201210174763.9 example 2.
Table 1 recipe composition
The preparation method comprises the following steps:
1) sieving light calcium carbonate, heavy calcium carbonate and 1g of crospovidone, and mixing uniformly;
2) dissolving vitamin D3 in 5g hydrogenated soybean oil, adding 6g polyvidone K30, stirring to dissolve to obtain a first solution, and spray drying the first solution with a spray dryer at 170 deg.C and 70 deg.C;
3) granulating the powder obtained in the step 1) and the step 2) and vitamin D3 microcapsules and vitamin K2 microcapsules by using a centrifugal granulator, wherein the rotation speed of the granulator is 350rpm, the inlet temperature is 70 ℃, and the outlet temperature is 45 ℃ to obtain calcium carbonate composite powder;
4) 420g of calcium carbonate composite powder obtained in the steps, 136g of lactose, 6.3g of sodium carboxymethyl starch, 4.2g of hydroxypropyl cellulose and 5.05g of magnesium stearate are uniformly mixed, and the mixture is pressed into 1000 tablets by a tablet press to obtain calcium carbonate, vitamin D3 and vitamin K2 tablets.
And (4) relevant performance test:
1. calcium carbonate, vitamin D3 and vitamin K2 tablets accelerated stability test
The calcium carbonate, vitamin D3, and vitamin K2 tablets prepared in examples 1 to 5 were packaged in a high density polyethylene bottle, left to stand at 40 ± 2 ℃/75% ± 5% RH for 6 months, sampled periodically at 0, 1, 2, 3, and 6 months, and subjected to stability test using the appearance of the tablet, disintegration time, calcium carbonate content, and vitamin D3 content as test indicators, and the results are shown in table 2.
Testing the disintegration time limit: the determination is carried out according to a disintegration time limit inspection method (a second method hanging basket method of a second disintegration time limit inspection method in 2010 edition of Chinese pharmacopoeia).
And (3) calcium carbonate content determination: taking 20 tablets of the product, precisely weighing, grinding, precisely weighing a proper amount (about equivalent to 80mg of calcium), placing the mixture in a 250ml conical flask, adding 15ml of 1mol/L hydrochloric acid solution, heating on a steam bath for 5-10 minutes until the reaction is completely stopped, cooling, adding 100ml of water, 20ml of 1mol/L sodium hydroxide test solution and 0.3g of hydroxynaphthol blue indicator solution, shaking and mixing uniformly, and titrating by using ethylene diamine tetraacetic acid disodium titrate solution (0.05mol/L) until the solution is changed from pink to blue. Each 1ml of disodium EDTA titrant (0.05mol/L) corresponds to 2.004mg of Ca.
Determination of vitamin D3 content: the procedure was performed in the dark and the measurement was performed by high performance liquid chromatography (appendix V D of the second part of the 2015 version of Chinese pharmacopoeia).
Chromatographic conditions and system applicability test: silica gel is used as filler (recommended chromatographic column: Supelcosil-LC-SI, 4.6mm × 250mm, 5 μm or equivalent performance chromatographic column); gradient elution was performed according to the following table using a n-hexane solution containing 0.45% (V/V) isopropanol as mobile phase a and a n-hexane solution containing 20% (V/V) isopropanol as mobile phase B, with a detection wavelength of 265nm and a flow rate of 1.0 ml/min. The tailing factor of vitamin D3 should not be greater than 2.0, and the relative standard deviation of vitamin D3 peak area should not be greater than 3.0% by repeating sample injection 6 times; and heating a proper amount of the reference substance stock solution II in a water bath at 55 ℃ for 1 hour, cooling, and injecting 40 mu l of the solution into a liquid chromatograph, wherein the separation degree between a vitamin D3 precursor peak and a vitamin D3 peak is more than 3.0.
TABLE 2 mobile phase
The determination method comprises the following steps: 20 tablets of the product are precisely weighed and ground, a proper amount (about equivalent to vitamin D3250 IU) is precisely weighed and placed in a 50ml centrifuge tube, about 20ml of 75% dimethyl sulfoxide aqueous solution is added, and the mixture is tightly plugged and uniformly shaken. The centrifuge tube was placed in a 45 ℃. + -. 5 ℃ water bath for 15 minutes with sonication, shaken without delay, and allowed to cool. Precisely adding 15ml of n-hexane (mixed at a ratio of 1: 20, and then collecting n-hexane layer) treated with 75% dimethyl sulfoxide aqueous solution, shaking for 90 min, centrifuging at 3000rpm for 10 min, and collecting supernatant as sample solution; and precisely weighing about 25mg of a vitamin D3 reference substance (40000IU/mg), placing into a 100ml measuring flask, adding the n-hexane treated by the 75% dimethyl sulfoxide aqueous solution, dissolving, diluting to scale, and shaking up to obtain a reference substance stock solution I. Precisely measuring 5ml of the reference substance stock solution I, placing the reference substance stock solution I into a 100ml measuring flask, adding the n-hexane treated by the 75% dimethyl sulfoxide aqueous solution for dissolving, diluting to a scale, and shaking up to obtain a reference substance stock solution II. Precisely measuring 5ml of the reference substance stock solution II, placing the reference substance stock solution II in a 100ml measuring flask, adding the n-hexane treated by the 75% dimethyl sulfoxide aqueous solution for dissolving, diluting to scale, and shaking up to obtain a reference substance solution. Precisely measuring 40 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram; taking the n-hexane treated by the 75% dimethyl sulfoxide aqueous solution as a blank solution, and injecting the blank solution by the same method to eliminate the interference on content measurement. The total amount of vitamin D3 was calculated as follows:
the total amount of vitamin D3, vitamin D3 content, vitamin D3 precursor content, vitamin D3 content × 1.09
＝Au×Ws×5.0×5.0×15.0×ATW/As/100/100/100/Wu×1.09
In the formula:
area of peak of vitamin D3 in Au-sample solution
Peak area of As-vitamin D3 in control solution
Wu is the sample volume of the sample, g
Ws is the sample weight of the reference substance mg × 40000IU/mg × purity
ATW-average tablet weight, g
Correction factors for conversion of 1.09-vitamin D3 and vitamin D3 precursors to vitamin D3
Determination of vitamin K2 content: the procedure was performed in the dark and the measurement was performed by high performance liquid chromatography (appendix V D of the second part of the 2015 version of Chinese pharmacopoeia).
Chromatographic conditions and system applicability test: octadecylsilane bonded silica gel was used as a filler (recommended column: AgilentZORBAX eclipseXDB-C18, 4.6 mm. times.150 mm, 5 μm or equivalent performance column); eluting with methanol as mobile phase, detecting wavelength of 270nm, flow rate of 1.0ml/min, theoretical plate number calculated by vitamin K2(20) no less than 20000, and separation degree of main component peak and impurity peak greater than 10.
Determination method A proper amount of vitamin K2 reference substance is precisely weighed, added with isopropanol to dissolve and quantitatively diluted to prepare solution containing vitamin K20.1mg/mL. Precisely weighing about 10.0mg of sample, placing the sample in a 100mL brown volumetric flask, adding isopropanol to dissolve and dilute the sample to a scale, shaking the solution evenly, filtering the solution by using a microporous filter membrane, and taking a subsequent filtrate to obtain the product. Precisely measuring 5ml of the solution and 1ml of the internal standard solution, placing the solution and the internal standard solution into a 10ml measuring flask, diluting the solution to a scale by using a mobile phase, shaking the solution uniformly, injecting 10 mu l of the solution into a liquid chromatograph, recording a chromatogram, and calculating the mass fraction of the vitamin K2 according to an external standard method to obtain the vitamin K2.
TABLE 3 accelerated stability test results for calcium carbonate, vitamin D3, and vitamin K2 tablets
The results in table 3 show that the calcium carbonate, vitamin D3 and vitamin K2 tablets of examples 1-5 have no obvious change in appearance after being accelerated for 6 months, the disintegration time conforms to the pharmacopoeia regulations, and the contents of calcium carbonate, vitamin D3 and vitamin K2 are basically unchanged, which indicates that the products prepared by the invention can keep good stability.
2. Long-term stability study of calcium carbonate, vitamin D3 and vitamin K2 tablets
Calcium carbonate, vitamin D3, and vitamin K2 tablets prepared in example 2, example 4, and example 5 were packaged in a high-density polyethylene bottle, left to stand for 36 months at 25 ± 2 ℃/60% ± 10% RH, and sampled periodically at 0, 3, 6, 9, 12, 18, 24, and 36 months, and stability was examined using the appearance of the tablet, disintegration time, calcium carbonate content, and vitamin D3 content as examination indices, and the results are shown in table 4.
TABLE 4 Long-term stability test results for calcium carbonate, vitamin D3, and vitamin K2 tablets
The results in table 4 show that the calcium carbonate, vitamin D3 and vitamin K2 tablets prepared in example 2, example 4 and example 5 have no obvious change in appearance after being placed for 36 months for a long time, the disintegration time conforms to the pharmacopoeia regulations, and the contents of calcium carbonate, vitamin D3 and vitamin K2 are basically unchanged, which indicates that the tablets of the present invention can maintain good stability.
3. Effect of vitamin D3 microcapsule on long-term stability of calcium carbonate, vitamin D3 and vitamin K2 tablets
The calcium carbonate, vitamin D3, and vitamin K2 tablets prepared in example 3 were packaged in a high density polyethylene bottle, left to stand at 25 ± 2 ℃/60% ± 10% RH for 36 months, sampled periodically at 0 th, 3 th, 6 th, 9 th, 12 th, 18 th, 24 th, and 36 th months, and subjected to stability tests using the appearance of the tablet, disintegration time, calcium carbonate content, and vitamin D3 content as test indices, and the results are shown in table 3.
In addition, calcium carbonate, vitamin D3 and vitamin K2 tablets are prepared by the following formula composition and preparation process, packaged by a high-density polyethylene bottle, placed for 36 months under the condition of 25 +/-2 ℃/60% +/-10% RH, sampled periodically at 0, 3, 6, 9, 12, 18, 24 and 36 months, and subjected to stability inspection by taking the appearance of the tablets, the disintegration time, the calcium carbonate content, the vitamin D3 and the vitamin K2 content as inspection indexes.
Comparative example 1 preparation method:
1) sieving 480g of heavy calcium carbonate, 120 g of light calcium carbonate and 1g of crospovidone, and uniformly mixing;
2) dissolving 0.005g of vitamin D3 in 5g of hydrogenated soybean oil, adding 6g of povidone K30, stirring to dissolve to form a first solution, and drying the first solution by using a spray dryer, wherein the inlet temperature of the dryer is 170 ℃ and the outlet temperature of the dryer is 70 ℃;
3) granulating the powder obtained in the step 1) and the step 2) and 0.08g of vitamin K2 microcapsules by using a centrifugal granulator, wherein the rotation speed of the granulator is 350rpm, the inlet temperature is 70 ℃, and the outlet temperature is 45 ℃ to obtain calcium carbonate composite powder;
4) 420g of calcium carbonate composite powder obtained in the steps, 136g of lactose, 6.3g of sodium carboxymethyl starch, 4.2g of hydroxypropyl cellulose and 5.05g of magnesium stearate are uniformly mixed, and the mixture is pressed into 1000 tablets by a tablet press to obtain calcium carbonate, vitamin D3 and vitamin K2 tablets.
TABLE 5 accelerated stability test results for calcium carbonate, vitamin D3, and vitamin K2 tablets
The results in table 5 show that the calcium carbonate, vitamin D3 and vitamin K2 tablets in example 3 have no obvious change in appearance after being placed for 36 months for a long time, the disintegration time conforms to the pharmacopoeia regulations, and the contents of calcium carbonate, vitamin D3 and vitamin K2 are basically unchanged, which indicates that the calcium carbonate, vitamin D3 and vitamin K2 can maintain good stability. And the content of the vitamin D3 in calcium carbonate, vitamin D3 and vitamin K2 tablets which do not adopt vitamin D3 microcapsules is lower than that in example 3 at month 0, which shows that the vitamin D3 is degraded to a certain extent in the production process. After being placed for 36 months for a long time, the appearance has no obvious change, the disintegration time accords with the regulation of pharmacopeia, but the content of the vitamin D3 is continuously reduced. The result shows that the preparation method of the preparation can obviously improve the stability of the vitamin D3.
4. Influence of light calcium carbonate on content uniformity of calcium carbonate, vitamin D3 and vitamin K2 tablets
The calcium carbonate, vitamin D3, and vitamin K2 tablets prepared in examples 1-5 and comparative example 2 were randomly sampled for 10 tablets per example, and the contents of calcium carbonate, vitamin D3, and vitamin K2 per tablet were measured and the Relative Standard Deviation (RSD) of the contents was calculated, and the results were shown in table 4.
Comparative example 2 preparation method:
1) sieving 600g of heavy calcium carbonate and 1g of crospovidone, and mixing uniformly;
2) dissolving 0.00125 vitamin D3 in 5g hydrogenated soybean oil, adding 6g polyvidone K30, stirring to dissolve to obtain a first solution, and spray drying the first solution with a spray dryer at an inlet temperature of 170 deg.C and an outlet temperature of 70 deg.C;
3) granulating the powder obtained in the step 1) and the step 2) with 0.00375g of vitamin D3 microcapsules and 0.08g of vitamin K2 microcapsules by using a centrifugal granulator, wherein the rotating speed of the granulator is 350rpm, the inlet temperature is 70 ℃, and the outlet temperature is 45 ℃ to obtain calcium carbonate composite powder;
4) 420g of calcium carbonate composite powder obtained in the steps, 136g of lactose, 6.3g of sodium carboxymethyl starch, 4.2g of hydroxypropyl cellulose and 5.05g of magnesium stearate are uniformly mixed, and the mixture is pressed into 1000 tablets by a tablet press to obtain calcium carbonate, vitamin D3 and vitamin K2 tablets.
TABLE 6 calcium carbonate, vitamin D3, vitamin K2 tablets content uniformity results
| Test example | Calcium carbonate content/RSD (%) | Vitamin D3 content/RSD (%) | Vitamin K2/RSD (%) |
| Example 1 | 106.00/1.02 | 108.80/1.19 | 100.32/0.98 |
| Example 2 | 108.60/1.09 | 108.70/1.09 | 100.42/0.99 |
| Example 3 | 107.80/1.08 | 109.20/1.17 | 100.41/1.01 |
| Example 4 | 107.10/1.09 | 109.60/1.23 | 100.38/1.01 |
| Example 5 | 100.12/1.08 | 109.93/1.03 | 100.28/0.99 |
| Comparative example 2 | 100.21/1.23 | 97.92/5.36 | 93.23/3.87 |
The results in table 6 show that the calcium carbonate, vitamin D3 and vitamin K2 tablets prepared by the method provided by the invention have RSD mean value of less than 5% of the contents of calcium carbonate, vitamin D3 and vitamin K2, and have good content uniformity. And only the preparation process method of the heavy calcium carbonate raw material (comparative example 2) is adopted, the content of the vitamin D3 and the vitamin K2 is obviously reduced, the content uniformity of the vitamin D3 and the vitamin K2 is poor, and the content and uniformity of the vitamin D3 and the vitamin K2 can be influenced by the proportional relation of the heavy calcium carbonate and the light calcium carbonate.
5. Determination of angle of repose, bulk density, tap density and Carr index of calcium carbonate, vitamin D3 and vitamin K2 tablets
The granules obtained by the second granulation and drying were subjected to 5 pilot scale productions according to the formulation composition and the preparation process of example 3 and comparative example 2, respectively, and the angle of repose, bulk density, tap density, and Carl index were measured, and the results are shown in Table 7.
TABLE 7 measurement results of angle of repose, bulk density, tap density, Carr index of calcium carbonate, vitamin D3, and vitamin K2 tablets
And (4) test conclusion: the results show that the angle of repose of the granules produced by the process of the invention is less than 18 ° and the carr index is less than 15%, indicating that the granules produced by the process of the invention have better flowability than comparative example 2, indicating that the flowability of the granules produced by the process is good.
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims.
Claims (5)
1. The pharmaceutical composition containing calcium carbonate, vitamin D3 and vitamin K2 is characterized by comprising the following components in parts by weight: 600 parts by weight of calcium carbonate, 0.005 part by weight of vitamin D3, 0.08 part by weight of vitamin K2; the calcium carbonate is a mixture consisting of light calcium carbonate and heavy calcium carbonate, and the weight ratio of the light calcium carbonate to the heavy calcium carbonate is (2-5): 1; the vitamin D3 is a mixture of vitamin D3 microcapsules and vitamin D3, wherein the weight ratio of vitamin D3 microcapsule powder to vitamin D3 in the vitamin D3 mixture is 1-4: 1; the vitamin K2 is microcapsule.
2. The composition according to claim 1, wherein the composition comprises the following components in parts by weight: 600 parts of calcium carbonate, 0.005 part of vitamin D3, 0.08 part of vitamin K2, 130-160 parts of filler, 5-10 parts of lubricant, 4-10 parts of disintegrant, 10-30 parts of adhesive and 1-5 parts of oil phase.
3. The composition according to claim 1 or 2, wherein the pharmaceutical composition is prepared into powder, granules, common tablets, capsules, chewable tablets, dispersible tablets, dry suspensions, soft capsules.
4. The composition according to claim 2, wherein the filler is selected from one or more of starch, lactose, powdered sugar, mannitol, microcrystalline cellulose, pregelatinized starch, and sorbitol; the disintegrating agent is selected from one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium; the lubricant is selected from one or more of superfine silica gel powder, talcum powder and magnesium stearate; the oil phase is selected from one or more of medium chain triglyceride, fish oil, squalene, soybean oil and hydrogenated soybean oil; the adhesive is selected from one or more of starch, hydroxypropyl methylcellulose, polyvidone K30, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyethylene glycol, and gelatin.
5. The pharmaceutical composition of claim 3, wherein the preparation method comprises the following steps:
1) mixing calcium carbonate and a disintegrating agent to obtain a calcium-containing mixed material;
2) dissolving vitamin D3 in oil phase, adding binder, stirring to dissolve to obtain solution, and spray drying;
3) granulating the powder obtained in the step 1) and the step 2) with vitamin D3 microcapsules and vitamin K2 microcapsules by using a centrifugal granulator to obtain calcium carbonate composite powder;
4) and mixing and tabletting the calcium carbonate composite powder obtained in the step, the filler, the disintegrating agent and the lubricant.
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| CN201810406815.8A CN108478595B (en) | 2018-05-01 | 2018-05-01 | A pharmaceutical composition containing calcium carbonate, vitamin D3, and vitamin K2 |
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| CN110151715B (en) * | 2019-05-28 | 2021-09-28 | 北京斯利安药业有限公司 | Calcium chewable tablet suitable for lactating women and preparation method thereof |
| CN110140969A (en) * | 2019-06-26 | 2019-08-20 | 北京诺康达医药科技股份有限公司 | A kind of preparation process thereof containing powder and the full nutrient formulation powder of tumour using its preparation |
| CN112370429A (en) * | 2019-10-21 | 2021-02-19 | 广州富诺营养科技有限公司 | Direct-compression type organic calcium vitamin D3 chewable tablet and preparation method thereof |
| CN112370430A (en) * | 2019-10-21 | 2021-02-19 | 广州富诺营养科技有限公司 | Calcium and vitamin K2 tablet and preparation method thereof |
| CN114088826A (en) * | 2021-10-27 | 2022-02-25 | 昆明源瑞制药有限公司 | Extraction method of vitamin D3 and method for detecting content of vitamin D3 |
| CN114767719B (en) * | 2022-05-30 | 2023-01-17 | 北京朗迪制药有限公司 | A pharmaceutical composition for preventing and treating rickets, and its preparation method |
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| CN1762386A (en) * | 2005-09-23 | 2006-04-26 | 上海百嘉营养保健品有限公司 | Bone density-increasing and senility-postponing capsule formulation |
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| BE1016895A6 (en) * | 2005-12-16 | 2007-09-04 | Psaltopoulos Emmanuel | Calcium composition, useful to prevent/treat osteoporosis and articular cartilage calcification, comprises optionally elementary calcium in the form e.g. of calcium carbonate or calcium citrate, and vitamins e.g. vitamin-D3, vitamin-K3 |
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| CN102716087A (en) * | 2012-05-31 | 2012-10-10 | 浙江中同科技有限公司 | Vitamin powder and preparation method thereof |
| CN103006693A (en) * | 2013-01-08 | 2013-04-03 | 昆明邦宇制药有限公司 | Double-vitamin calcium carbonate composition |
| CN106235063A (en) * | 2016-08-06 | 2016-12-21 | 阿坝州九寨生物科技有限公司 | A kind of compound recipe yak bone powder vitamin D calcium tablet and preparation method thereof |
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