CN112220775A - Preparation intermediate granule containing calcium carbonate and vitamin D3 and preparation method thereof - Google Patents

Preparation intermediate granule containing calcium carbonate and vitamin D3 and preparation method thereof Download PDF

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Publication number
CN112220775A
CN112220775A CN202011199130.4A CN202011199130A CN112220775A CN 112220775 A CN112220775 A CN 112220775A CN 202011199130 A CN202011199130 A CN 202011199130A CN 112220775 A CN112220775 A CN 112220775A
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vitamin
calcium carbonate
preparation
granules
granule
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张海龙
侯志远
潘登峰
乔佳
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Changsha Jingyi Medical Technology Co ltd
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Changsha Jingyi Medical Technology Co ltd
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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
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A61K9/5057—Gelatin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a calcium carbonate and vitamin D-containing food3The preparation intermediate granule and the preparation method thereof are based on the fluidized bed technology to prepare the intermediate granule with good stability and content uniformity, and the granule is used as calcium carbonate-vitamin D3Intermediate of compound solid preparation (granule, tablet, capsule, etc.) for improving calcium carbonate-vitamin D3Vitamin D in compound solid preparation3Poor stability and wide content limit. The invention takes the calcium carbonate particles with specific particle size after granulation as a substrate and utilizes the coating/medicine application technology to treat vitamin D3The protection is applied to delay the degradation rate, and the prepared particles have uniform shape, good stability and content uniformity. The preparation intermediate granule has simple and feasible production process, and can be prepared in batches in large production in a workshop.

Description

Preparation intermediate granule containing calcium carbonate and vitamin D3 and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to stable preparation intermediate granules containing calcium carbonate and vitamin D3 and a preparation method thereof.
Background
Osteoporosis is a systemic bone disease in which bone density and bone quality decrease, and bone microarchitecture is destroyed, resulting in increased bone fragility, thereby facilitating fracture. It is clinically manifested as pain and fracture, the pain can reduce the quality of life of the patient, and the fracture can cause disability and even the life can not be self-managed. The number of the osteoporosis patients in China reaches 9000 ten thousand, accounts for 7.1 percent of the population in China, and is estimated to reach 2.21 hundred million by 2050.
Calcium carbonate and vitamin D3The combination is an effective treatment means for preventing and treating osteoporosis and fracture and increasing bone density. Clinical studies have shown that exogenous calcium carbonate administration with vitamin D3The combined medication can reduce the relative risk ratio of the hip joint fracture and the non-spine fracture to different degrees.
And calcium carbonate-vitamin D3The research of compound solid preparations (including granules, tablets and the like) mainly faces the following technical difficulties: one is vitamin D3The stability of the composite is poor, and the composite can be degraded by heat, light, oxygen and acid; second, vitamin D3The specification of the vitamin D is generally extremely low, the preparation only contains 60-200 IU (1.5-5.0 mu g), the blending process is very difficult, and under the trend that the drug evaluation organization continuously stricts the content limit of the preparation product, the traditional preparation technology and the vitamin D3The preparation intermediates are difficult to meet the requirements, and a solution to the problem of vitamin D in the preparation is urgently needed3Stability and content uniformity problems orAnd (5) producing the product.
Disclosure of Invention
The invention aims to solve the problem of the prior calcium carbonate-vitamin D3The technical difficulty existing in the research of compound solid preparation provides a calcium carbonate and vitamin D-containing preparation based on fluidized bed coating/medicine application technology3The preparation intermediate granule has good stability and content uniformity, and the granule is used for feeding to solve the problem of calcium carbonate-vitamin D3Vitamin D in compound solid preparation3Poor stability, wide content limit, simple and feasible production process and capability of batch preparation in large-scale production in a workshop.
The technical scheme of the invention is as follows: the invention provides a calcium carbonate and vitamin D-containing food3The preparation intermediate granule of (1), is prepared from calcium carbonate and vitamin D3And pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials are selected from one or more than two of alpha-tocopherol, vitamin C, gelatin, hydroxypropyl methyl cellulose, sucrose, starch, superfine silica gel powder, mannitol, sorbitol, glucose and the like.
The dosage of calcium carbonate per gram of the preparation intermediate particles can be 200-500 mg, preferably 300 mg calculated as calcium; vitamin D3The amount of (B) may be 10-100. mu.g, preferably 20-50. mu.g.
The preparation method of the preparation intermediate granule comprises the following steps:
a) adding water or 20-80% ethanol into calcium carbonate, adhesive and pharmaceutically acceptable adjuvants, wet granulating, oven drying to water content of 0.5-3%, and sieving with 30-60 mesh sieve to obtain calcium carbonate granule;
b) sieving to obtain 40-100 mesh calcium carbonate particles; preferably, the particle size of the calcium carbonate particles is 80-100 meshes.
c) Spraying the medicine on the bottom of the fluidized bed by taking the sieved calcium carbonate particles as a substrate, and sequentially carrying out an isolation layer and vitamin D3Applying the medicinal materials to the medicinal layer, antioxidant protective layer and outermost protective layer, and drying to obtain calcium carbonate and vitamin D3The formulation intermediate granule of (1).
And for the isolating layer, a coating solution with the concentration of 3% -15% is adopted, and the coating solution is one or more of gelatin, polyethylene glycol, ethyl cellulose, hydroxypropyl methyl cellulose, talcum powder and cellulose acetate phthalate. The weight gain of the coating is 1-5%, the air inlet temperature is 50-80 ℃, and the liquid spraying speed is 2-8 g/min.
For vitamin D3A medicine layer, which is prepared from 0.01 to 0.20 weight percent of vitamin D3Adding into purified water, and spraying while stirring in dark condition, wherein the air inlet temperature is 40-70 deg.C, and the liquid spraying speed is 4-16 g/min.
For the antioxidant protective layer, the antioxidant is one or more of alpha-tocopherol, vitamin C, propyl gallate and di-tert-butyl-p-cresol, and is dissolved in solvent and sprayed, the air inlet temperature is 40-70 ℃, and the liquid spraying speed is 4-16 g/min.
For the outermost protective layer, a coating solution with the concentration of 3% -15% is adopted, the coating material is one or more of gelatin, polyethylene glycol, ethyl cellulose, hydroxypropyl methyl cellulose, talcum powder and cellulose acetate phthalate, and the weight of the coating is increased by 2% -15%. The air inlet temperature is 50-70 deg.C, and the liquid spraying speed is 6-16 g/min.
Preferably, the vitamin D is3Vitamin D may also be added into the medicine layer3Sodium ascorbate with the molar weight of 20-100% is used as an antioxidant.
Preferably, the air inlet humidity is controlled to be 12-25 g/m in the feeding process of the fluidized bed3。
As another object of the invention, the invention also provides a pharmaceutical preparation, such as oral solid preparations, for example granules, tablets, capsules and the like, which comprises the preparation intermediate granules.
The preparation process comprises the following steps: a) granules: mixing the preparation intermediate granules with common adjuvants or granules obtained by granulating common pharmaceutical adjuvants, and packaging to obtain calcium carbonate-vitamin D3And (4) granules.
b) And (3) capsule preparation: mixing the above intermediate granules with fillerPackaging with capsule shell to obtain calcium carbonate-vitamin D3And (4) capsules.
c) And (3) tablet preparation: mixing the above intermediate granules with filler or correctant and appropriate amount of lubricant, adding disintegrating agent to chewable tablet, and mixing to obtain calcium carbonate-vitamin D3And (4) tablets.
The oral solid preparation such as granules, capsules and tablets prepared from the preparation intermediate granules has excellent quality, and vitamin D3Has good stability and content uniformity.
Detailed Description
The present invention is further illustrated or described below in the following examples, which should not be construed as limiting the scope of the invention.
Example 1:
the materials are fed according to the following formula:
Figure DEST_PATH_IMAGE002AA
the preparation process comprises the following steps:
mixing calcium carbonate, sucrose and mannitol in a wet granulator, adding 20% ethanol solution containing polyvidone by spraying to obtain soft material, and sieving with 24 mesh sieve. Drying with fluidized bed at 60-70 deg.C until the water content is about 1%, and grading with 30 mesh sieve to obtain calcium carbonate granules. Coating/applying the calcium carbonate particles of 80-100 meshes as a substrate by adopting a fluidized bed technology, spraying 5% gelatin water solution on the substrate, wherein the spraying pressure is 1.0 bar, the liquid inlet speed is 2 g/min, the air inlet temperature is 65 ℃, and the coating weight gain is 2%; continuously bottom spraying vitamin D3Adding the aqueous solution while magnetically stirring, wherein the spraying pressure is 1.0 bar, the liquid inlet speed is 4 g/min, the air inlet temperature is 50 ℃, and the preparation and spraying processes are carried out under the condition of keeping out of the sun; continuously spraying alpha-tocopherol ethanol solution at the bottom, wherein the spraying pressure is 1.0 bar, the liquid inlet speed is 4 g/min, and the air inlet temperature is 50 ℃; finally spraying 5% gelatin water solution at bottom with spraying pressure of 1.0 bar, liquid inlet speed of 4 g/min, air inlet temperature of 65 deg.C, and packagingThe weight of the coating is increased by 5%, and the coating is continuously dried until the moisture is about 2%, thus obtaining the calcium carbonate and vitamin D3The preparation intermediate granule has good stability and content uniformity.
Wherein, before mixing, mannitol and sucrose are crushed and sieved by a 40-mesh sieve so as to ensure that the materials are uniformly mixed.
Example 2:
the materials are fed according to the following formula:
Figure DEST_PATH_IMAGE004AA
the preparation process comprises the following steps:
mixing calcium carbonate, maltodextrin and glucose in a wet granulator, adding 60% ethanol solution in a spraying manner to prepare a soft material, and grading with a 24-mesh sieve. Drying with fluidized bed at 55-65 deg.C until the water content is about 1%, and grading with 30 mesh sieve to obtain calcium carbonate granules. Coating/applying the calcium carbonate particles of 80-100 meshes as a substrate by adopting a fluidized bed technology, spraying 10% hydroxypropyl methyl cellulose aqueous solution on the substrate, wherein the spraying pressure is 1.0 bar, the liquid inlet speed is 2.5 g/min, the air inlet temperature is 65 ℃, and the coating weight gain is 1%; continuously bottom spraying vitamin D3Adding the L-sodium ascorbate aqueous solution while magnetically stirring, wherein the spraying pressure is 1.0 bar, the liquid inlet speed is 5 g/min, the air inlet temperature is 60 ℃, the preparation and spraying processes are carried out under the condition of keeping out of the sun, continuously spraying the alpha-tocopherol ethanol solution at the bottom, the spraying pressure is 1.5 bar, the liquid inlet speed is 6 g/min, and the air inlet temperature is 60 ℃; finally spraying 5% gelatin water solution at the bottom, with spraying pressure of 1.5 bar, liquid inlet speed of 7 g/min, air inlet temperature of 70 deg.C, coating weight gain of 4%, and continuously drying until water content is about 2%, to obtain calcium carbonate and vitamin D3The preparation intermediate granule has good stability and content uniformity.
Wherein, before mixing, the glucose is sieved by a 40-mesh sieve so as to ensure that the materials are uniformly mixed.
Example 3:
the materials are fed according to the following formula:
Figure DEST_PATH_IMAGE006A
the preparation process comprises the following steps:
taking the calcium carbonate particles described in example 1 and calcium carbonate-vitamin D3Adding sorbitol, essence, croscarmellose sodium and magnesium stearate into the intermediate granules, and mixing with calcium carbonate-vitamin D3The content uniformity of the intermediate particles is good, and vitamin D is directly added3Compared with the mixing of auxiliary materials, the risk of unqualified content uniformity of the intermediate particles and the auxiliary materials is lower, and the calcium carbonate D is obtained by tabletting after mixing3A chewable tablet is prepared.
Wherein, sorbitol and croscarmellose sodium are sieved by a 40-mesh sieve to ensure that the materials are uniformly mixed; the croscarmellose sodium may also be replaced with other disintegrants such as corn starch; the essence can be changed into different flavors according to market demands.
Example 4:
the materials are fed according to the following formula:
Figure DEST_PATH_IMAGE008
the preparation process comprises the following steps:
taking the calcium carbonate particles described in example 2 and calcium carbonate-vitamin D3Intermediate granules, mixing with sodium citrate due to calcium carbonate-vitamin D3The content uniformity of the intermediate particles is good, and vitamin D is directly added3Compared with the mixing of auxiliary materials, the risk of unqualified content uniformity of the intermediate particles and the auxiliary materials is lower, and the calcium carbonate D is obtained by bagging after mixing3And (4) granules.
Wherein, the vitamin D can be added into the preparation product3Dose modification of calcium carbonate particles: calcium carbonate-vitamin D3Ratio of intermediate particles.
The above embodiments are illustrative of the present invention, and are not intended to limit the present invention, and any simple modifications of the present invention are within the scope of the present invention.
The experimental effect of the invention is as follows:
the calcium carbonate-vitamin D prepared by the preparation method provided by the invention3The preparation intermediate has good granule stability.
Mixing the obtained calcium carbonate-vitamin D3Formulation intermediate granules with vitamin D from commercially available Dutch DSM group3The powder is synchronously tested for stability (60 ℃ at high temperature), and the stability of the powder are equivalent.
Conditions of standing DSM vitamin D3Powder Prescription composition 1 Prescription composition 2
Day 0 102.7 100.3 99.7
High temperature (60 ℃) for 20 hours 101.3 100.2 99.8
Elevated temperature (60 ℃) for 2 days 101.9 100.2 99.6
High temperature (60 ℃) for 3 days 101.0 100.0 99.6
High temperature (60 ℃) for 5 days 99.7 99.8 99.4
High temperature (60 ℃) for 7 days 99.5 99.3 99.2
High temperature (60 ℃) for 15 days 99.2 98.9 98.8
Elevated temperature (60 ℃) for 30 days 96.4 96.7 96.3
Secondly, the calcium carbonate-vitamin D prepared by the preparation method provided by the invention3Vitamin D formulation intermediate granules3The content uniformity is good.
Determination of vitamin D in 2 batches of self-made samples (using recipe compositions 1 and 2)3Content uniformity, results were as follows:
batches of Prescription composition 1 Prescription composition 2
1 100.00 100.05
2 100.05 102.00
3 100.02 101.50
4 99.40 101.40
5 99.80 100.90
6 99.90 100.50
7 101.30 100.60
8 100.80 99.90
9 100.60 99.80
10 100.20 100.40
Mean value 100.2 100.7
RSD（%） 0.55 0.74
Thirdly, the calcium carbonate-vitamin D provided by the invention is utilized3Calcium carbonate D prepared from formulation intermediate granules3Flakes, calcium carbonate D3The compound solid preparation such as the granules has good stability and content uniformity.
1. By adopting the technical process, 2 batches of homemade chewable tablet samples prepared by the prescription composition 3 and the Huishi calcium Erqi chewable tablet (II) are used, the content uniformity is measured according to the method of the content uniformity of Chinese pharmacopoeia, and the result is as follows:
batch number Huishi calcium erqi chewable tablet (II) Self-made sample-1 Self-made sample-2
1 157.21 99.81 99.67
2 110.14 98.45 106.54
3 145.19 100.36 111.78
4 99.53 116.23 93.25
5 128.38 99.65 116.31
6 107.46 108.22 97.23
7 108.06 93.45 99.80
8 113.09 92.40 103.24
9 126.60 103.10 95.72
10 122.99 104.26 96.55
Mean value 121.9 101.6 102.0
RSD（%） 15.0 6.9 7.4
The content uniformity of 3 batches of self-grinding chewable tablets is superior to calqi.
The stability of the two was compared and the results were as follows:
conditions of standing Huishi calcium erqi chewable tablet (II) Self-madeSample No. 1
Day 0 128.2 101.6
Accelerated conditions (40 ℃, 75% RH) for 1 month 123.5 101.4
Accelerated conditions (40 ℃, 75% RH) for 2 months 111.5 99.7
Accelerated conditions (40 ℃, 75% RH) for 3 months 106.8 95.5
Using calcium carbonate-vitamin D3Calcium carbonate D prepared from formulation intermediate granules3The tablet stability is comparable to calqi.
2. By adopting the technical process of the invention, the self-made sample prepared by the prescription composition 4 and the calcium carbonate D for the infant's Anshi3The content uniformity of the particles (disky) was determined according to the content uniformity method of the Chinese pharmacopoeia, and the results were as follows:
batch number Calcium carbonate D for the infant's Anshi3Granules Self-made sample-3
1 89.77 101.23
2 92.82 99.88
3 100.66 97.56
4 96.86 102.31
5 92.35 94.35
6 94.57 97.48
7 89.57 100.25
8 93.64 93.45
9 92.29 99.79
10 91.41 105.29
Mean value 93.4 99.2
RSD（%） 3.58 3.61
Content uniformity of self-ground granules and calcium carbonate D for children produced by American Anshi pharmacy3The particles (disky) were comparable.
The stability of the two was compared and the results were as follows:
conditions of standing Calcium carbonate D for the infant's Anshi3Granules Self-made sample-3
Day 0 108.4 98.6
Accelerated conditions (40 ℃, 75% RH) for 1 month 77.8 97.6
Accelerated conditions (40 ℃, 75% RH) for 2 months 69.6 96.1
Accelerated conditions (40 ℃, 75% RH) for 3 months 56.3 93.2
Accelerated conditions (40 ℃, 75% RH) for 6 months 40.5 88.7
Using calcium carbonate-vitamin D3Calcium carbonate D prepared from formulation intermediate granules3The stability of the granules is obviously superior to that of 'Diqiao' in an anshi medicine.

Claims (10)

1. Calcium carbonate and vitamin D-containing food3The preparation intermediate granule of (1), is prepared from calcium carbonate and vitamin D3And pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials are selected from one or more than two of alpha-tocopherol, vitamin C, gelatin, hydroxypropyl methyl cellulose, sucrose, starch, superfine silica gel powder, mannitol, sorbitol, glucose and the like.
2. The formulation intermediate granule of claim 1, wherein: each gram of the preparation intermediate granules contains calcium carbonate and vitamin D3The dosage of the calcium carbonate can be 200-500 mg, preferably 300 mg calculated by calcium; vitamin D3The amount of (B) may be 10-100. mu.g, preferably 20-50. mu.g.
3. A process for preparing the formulation intermediate granules of claim 1, wherein: comprises a calcium carbonate particle preparation process and a fluidized bed medicine application/coating process which takes the calcium carbonate particles as a substrate.
4. A method of formulating intermediate granules according to claim 3, characterized in that: the preparation process of the calcium carbonate particles comprises the following steps:
a) adding water or 20-80% ethanol into calcium carbonate, adhesive and pharmaceutically acceptable adjuvants, wet granulating, oven drying to water content of 0.5% -3%, and sieving with 30-60 mesh sieve;
b) sieving to obtain 40-100 mesh calcium carbonate particles; preferably, the particle size of the calcium carbonate particles is 80-100 meshes.
5. The method of formulating intermediate granules of claim 4, wherein: the calcium carbonate particles obtained after screening are used as substrates to carry out fluidized bed bottom spraying/coating process, which comprises the following steps: sequentially carrying out an isolation layer and vitamin D3Applying the medicinal materials to the medicinal layer, antioxidant protective layer and outermost protective layer, and drying to obtain calcium carbonate and vitamin D3The formulation intermediate granule of (1).
6. A method of formulating intermediate granules according to claim 5, characterized in that: the isolating layer adopts coating liquid with the concentration of 3% -15%, and the coating liquid is one or more of gelatin, polyethylene glycol, ethyl cellulose, hydroxypropyl methyl cellulose, talcum powder and cellulose acetate phthalate; the weight gain of the coating is 1-5%, the air inlet temperature is 50-80 ℃, and the liquid spraying speed is 2-8 g/min.
7. A method of formulating intermediate granules according to claim 5, characterized in that: the vitamin D3The medicine layer is prepared by adding 0.01-0.20 wt% of vitamin D3Adding into purified water, and spraying while stirring in dark condition, wherein the air inlet temperature is 40-70 deg.C, and the liquid spraying speed is 4-16 g/min; preferably, the vitamin D is3Vitamin D may also be added into the medicine layer3Sodium ascorbate with the molar weight of 20-100% is used as an antioxidant.
8. A method of formulating intermediate granules according to claim 5, characterized in that: the antioxidant used in the antioxidant protective layer is one or more of alpha-tocopherol, vitamin C, propyl gallate and di-tert-butyl-p-cresol, and the antioxidant is dissolved in a solvent and sprayed, wherein the air inlet temperature is 40-70 ℃, and the liquid spraying speed is 4-16 g/min.
9. A method of formulating intermediate granules according to claim 5, characterized in that: the outermost protective layer adopts coating liquid with the concentration of 3% -15%, and the coating material is one or more of gelatin, polyethylene glycol, ethyl cellulose, hydroxypropyl methyl cellulose, talcum powder and cellulose acetate phthalate; the weight gain of the coating is 2-15%, the air inlet temperature is 50-70 ℃, and the liquid spraying speed is 6-16 g/min.
10. Comprises pharmaceutical preparation based on the intermediate granules of the preparation of claim 1, such as oral solid preparation such as granules, tablets and capsules, wherein vitamin D3The stability is good, the content uniformity is good, and the preparation process is characterized as follows:
a) granules: mixing the preparation intermediate granules with common auxiliary materials or granules prepared by granulating the common medicinal auxiliary materials, and subpackaging to obtain the calcium carbonate-vitamin D3Granules;
b) and (3) capsule preparation: mixing the preparation intermediate particles with a filler, and encapsulating to obtain the calcium carbonate-vitamin D3Capsules;
c) and (3) tablet preparation: adding a filling agent or a flavoring agent and a proper amount of lubricant into the preparation intermediate granules, adding a disintegrating agent into chewable tablets, and mixing to obtain the calcium carbonate-vitamin D3And (4) tablets.
CN202011199130.4A 2020-11-01 2020-11-01 Preparation intermediate granule containing calcium carbonate and vitamin D3 and preparation method thereof Pending CN112220775A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114129521A (en) * 2021-11-05 2022-03-04 昆明源瑞制药有限公司 Calcium carbonate D3Granule and preparation method thereof
GB2615103A (en) * 2022-01-27 2023-08-02 Anabio Tech Limited A method of forming a composition comprising a probiotic micro-encapsulated in a denatured plant protein matrix

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114129521A (en) * 2021-11-05 2022-03-04 昆明源瑞制药有限公司 Calcium carbonate D3Granule and preparation method thereof
GB2615103A (en) * 2022-01-27 2023-08-02 Anabio Tech Limited A method of forming a composition comprising a probiotic micro-encapsulated in a denatured plant protein matrix

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