CN117503708A - A special calcium supplement for children with rickets and its preparation method - Google Patents
A special calcium supplement for children with rickets and its preparation method Download PDFInfo
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- CN117503708A CN117503708A CN202311257143.6A CN202311257143A CN117503708A CN 117503708 A CN117503708 A CN 117503708A CN 202311257143 A CN202311257143 A CN 202311257143A CN 117503708 A CN117503708 A CN 117503708A
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- vitamin
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- calcium
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- mannitol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 208000007442 rickets Diseases 0.000 title claims abstract description 14
- 229940069978 calcium supplement Drugs 0.000 title claims abstract description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 58
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Chemical group C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims abstract description 48
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical group C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims abstract description 41
- 239000011647 vitamin D3 Chemical group 0.000 claims abstract description 39
- 235000005282 vitamin D3 Nutrition 0.000 claims abstract description 39
- 229940021056 vitamin d3 Drugs 0.000 claims abstract description 39
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 29
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000011575 calcium Substances 0.000 claims abstract description 26
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 26
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 25
- 229930195725 Mannitol Chemical group 0.000 claims abstract description 25
- 239000000594 mannitol Chemical group 0.000 claims abstract description 25
- 235000010355 mannitol Nutrition 0.000 claims abstract description 25
- 229930006000 Sucrose Chemical group 0.000 claims abstract description 24
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical group O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 24
- 239000005720 sucrose Chemical group 0.000 claims abstract description 24
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Chemical group OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 18
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical group OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims abstract description 18
- 238000002156 mixing Methods 0.000 claims abstract description 17
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 13
- 235000010378 sodium ascorbate Nutrition 0.000 claims abstract description 13
- 229960005055 sodium ascorbate Drugs 0.000 claims abstract description 13
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 12
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011732 tocopherol Chemical group 0.000 claims abstract description 10
- 235000010384 tocopherol Nutrition 0.000 claims abstract description 10
- 229930003799 tocopherol Chemical group 0.000 claims abstract description 10
- 229960001295 tocopherol Drugs 0.000 claims abstract description 10
- 239000007779 soft material Substances 0.000 claims abstract description 7
- 229920003081 Povidone K 30 Chemical group 0.000 claims abstract description 6
- 241000220479 Acacia Species 0.000 claims abstract description 5
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims abstract description 5
- 238000004806 packaging method and process Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 238000003756 stirring Methods 0.000 claims description 45
- 239000002245 particle Substances 0.000 claims description 23
- 238000010008 shearing Methods 0.000 claims description 20
- 235000010489 acacia gum Nutrition 0.000 claims description 18
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 13
- 239000000839 emulsion Substances 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 11
- 238000007873 sieving Methods 0.000 claims description 11
- 238000005303 weighing Methods 0.000 claims description 11
- 238000007599 discharging Methods 0.000 claims description 10
- 229930003316 Vitamin D Natural products 0.000 claims description 9
- 235000019166 vitamin D Nutrition 0.000 claims description 9
- 239000011710 vitamin D Substances 0.000 claims description 9
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 9
- 229940046008 vitamin d Drugs 0.000 claims description 9
- 239000000080 wetting agent Substances 0.000 claims description 9
- 239000011627 DL-alpha-tocopherol Substances 0.000 claims description 8
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- 229960000984 tocofersolan Drugs 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 239000007921 spray Substances 0.000 claims description 6
- 238000000889 atomisation Methods 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 4
- 230000002572 peristaltic effect Effects 0.000 claims description 4
- 238000010298 pulverizing process Methods 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 abstract description 8
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 230000001502 supplementing effect Effects 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 3
- 235000010216 calcium carbonate Nutrition 0.000 abstract description 2
- 229960003563 calcium carbonate Drugs 0.000 abstract 1
- 229960001855 mannitol Drugs 0.000 abstract 1
- 229960004793 sucrose Drugs 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 30
- 239000003921 oil Substances 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- 230000000052 comparative effect Effects 0.000 description 11
- 229920000084 Gum arabic Polymers 0.000 description 5
- 239000000205 acacia gum Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 206010006956 Calcium deficiency Diseases 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 229940057917 medium chain triglycerides Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 241001456553 Chanodichthys dabryi Species 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010034203 Pectus Carinatum Diseases 0.000 description 1
- 208000030695 Sparse hair Diseases 0.000 description 1
- 208000003217 Tetany Diseases 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002366 mineral element Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 210000003205 muscle Anatomy 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 206010039722 scoliosis Diseases 0.000 description 1
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- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- General Health & Medical Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Hematology (AREA)
- Diabetes (AREA)
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Abstract
The invention relates to a calcium supplement special for rickets, and a preparation method thereof, wherein the calcium supplement special for rickets comprises the following components: calcium carbonate, vitamin D3, mannitol, sucrose, povidone K30, essence, tocopherol, medium chain triglyceride, acacia, and sodium ascorbate. The preparation method comprises the following steps: preparing a vitamin D3 intermediate; pre-treating auxiliary materials; preparing a soft material; granulating, drying, grading, mixing, and packaging. Compared with the calcium supplementing preparation prepared by the prior art, the preparation not only furthest promotes the absorption and utilization of calcium in human bodies, but also has better quality level such as content uniformity, dissolution rate, stability and the like than the calcium supplementing commercial products in the current market.
Description
Technical Field
The invention relates to a pharmaceutical preparation technology, in particular to a special calcium supplement for rickets children patients and a preparation method thereof, belonging to the technical field of medicines.
Background
Calcium is the mineral element with the highest content in the human body, 99% of calcium in the human body exists in bones and teeth, and the bones are the brackets for forming the human body and are the basic storage pool of calcium in the human body; another 1% of the calcium is present in soft tissues, extracellular fluids and blood, collectively referred to as miscible calcium pools, and is necessary to maintain a dynamic balance with bone calcium to maintain the normal state of all cells. Calcium plays an extremely important physiological regulation role in physiological processes such as nerve, muscle stress, nerve impulse conduction, heart rhythm maintenance, blood coagulation, cell adhesion and the like. Vitamin D3 belongs to an endogenous substance of a human body, is an important vitamin necessary for the human body, can participate in the metabolism of calcium and promote the absorption of the calcium. The calcium carbonate is a calcium preparation with relatively highest calcium content, is scientifically and reasonably matched with vitamin D3, can fully promote the absorption of calcium by human bodies, and is used for supplementing calcium for children, pregnant women, women in lactation period, the elderly and the like.
Calcium deficiency of infants and children is often manifested by sparse hair, alopecia, night convulsion, long teeth, late learning to walk, and weak and multiple diseases. Susceptible to foot and hand tetany, common cold, tracheitis, eczema, myopia, caries, bone pain, enterospasm, abdominal pain, hyperkinetic syndrome and other diseases; bone diseases such as rickets, such as rickets bone deformation, beaded rib, chicken breast, humpback, scoliosis, X-shaped leg, O-shaped leg, etc. caused by calcium deficiency of children can be caused when serious calcium deficiency occurs. The oral calcium supplement preparation in the current market has poor absorption in human body and lower bioavailability due to the prior art.
In order to overcome the above problems, although individual related studies have been made, the effect is not ideal:
for example, patent publication No. CN 106420808 discloses a preparation containing vitamin D3 and calcium carbonate and a preparation method thereof, wherein the vitamin D3 is coated by using Opadry to achieve the effects of stability and content uniformity, and indirectly promote the absorption of calcium by human body.
Disclosure of Invention
In order to remarkably improve the bioavailability and benefit children suffering from rickets at home and abroad, the invention provides a calcium carbonate D3 particle and a preparation method thereof, and the technical point of the invention is as follows: (1) Vitamin D3 belongs to endogenous fat-soluble vitamin, vitamin D3 is dissolved in an oil solvent, then is mixed with an aqueous phase containing Arabic gum, sucrose and vitamin C sodium, emulsion is prepared by a high-speed homogenizer, and vitamin D3 intermediate particles in the form of oil-in-water are prepared by adopting a low-spray technology. (2) In the research process of technicians, the calcium carbonate/vitamin D3 ratio with the highest calcium bioavailability is unexpectedly discovered, and the ratio can enable the vitamin D3 to promote the absorption and utilization of calcium in human bodies to the maximum extent. The technology of the invention not only obviously improves the bioavailability of calcium, but also has better quality level of the preparation such as content uniformity, dissolution rate, stability and the like than the calcium supplementing commercial products in the current market.
The invention is realized by the following technical scheme:
the special calcium carbonate D3 particles for rickets patients comprise the following raw and auxiliary materials in parts by weight: 800 to 1500 parts of calcium carbonate, 0.001 to 0.02 part of vitamin D, 500 to 750 parts of mannitol, 800 to 1100 parts of sucrose, 30 to 300 parts of povidone K, 10 to 30 parts of essence, 0.001 to 0.02 part of tocopherol, 0.1 to 0.3 part of medium chain triglyceride, 0.5 to 3 parts of acacia and 0.02 to 0.1 part of sodium ascorbate.
Preferably, the calcium carbonate D3 particles comprise the following raw and auxiliary materials in parts by weight: 1393 parts of calcium carbonate, 0.01 part of vitamin D, 510 parts of mannitol, 651 parts of sucrose, 30 parts of povidone K, 15 parts of essence, 0.01 part of tocopherol, 0.12 part of medium chain triglyceride, 1 part of acacia, and 0.058 part of sodium ascorbate.
A preparation method of special calcium carbonate D3 particles for rickets patients comprises the following steps:
1) Vitamin D3 intermediate granule preparation
(1) Heating the purified water with the prescription amount to 70 ℃ in a water bath, setting the stirring rotation speed to 300rpm, stirring the purified water, slowly adding the Arabic gum with the prescription amount, continuously stirring until the Arabic gum is completely dissolved, then adding the sucrose with the prescription amount and the sodium ascorbate, and stirring until the Arabic gum is completely dissolved to obtain a water phase;
(2) weighing prescribed amount of oil solvent, adding DL-alpha-tocopherol into beaker, adding prescribed amount of vitamin D 3 Heating at constant temperature in water bath of 50deg.C, stirring to dissolve to obtain oil phase;
(3) placing the oil phase in a water bath at 70 ℃, slowly adding the water phase into the oil phase while stirring, and shearing for 10-5 min by adopting a high-speed homogenizer at a rotating speed of 5000-9000 rpm after the water phase is added to obtain vitamin D3 emulsion;
(4) taking mannitol with a prescription amount, placing the mannitol into a fluidized bed, setting the frequency of an induced draft fan to be 14-18 HZ, the air inlet temperature to be 85 ℃, starting the fluidized bed, setting the rotating speed of a peristaltic pump to be 9rpm when the temperature of materials is increased to 60 ℃, setting the atomization pressure to be 0.2Mpa, starting to spray emulsion, setting the air inlet temperature to be 50 ℃ after spraying, continuing to dry for 10min (controlling the moisture to be less than 1%), and discharging. Sieving with 40 mesh sieve, and granulating to obtain vitamin D3 intermediate granule;
2) Pretreatment of auxiliary materials: pulverizing sucrose and mannitol, sieving, and sieving with 80 mesh and 60 mesh sieve respectively;
3) Preparing a wetting agent: weighing ethanol and purified water according to the prescription, and stirring uniformly to obtain an ethanol water solution to obtain a wetting agent;
4) Preparing a soft material: placing calcium carbonate, vitamin D3 intermediate particles, sucrose, mannitol and povidone K30 into a high-speed mixing granulator, setting stirring at 200rpm, shearing at 600rpm, premixing, and setting mixing for 5min; stirring at 200rpm, shearing at 600rpm, adding 50% ethanol water solution (stirring and shearing are started), adding wetting agent, stirring and shearing for 2min, stopping, and discharging to obtain soft material;
5) Granulating: granulating with a 10 mesh screen using a swing type granulator;
6) And (3) drying: drying the fluidized bed, wherein the air inlet temperature is 50 ℃, the fan frequency is 20-35 HZ, drying is carried out until the moisture is less than or equal to 2.0%, and discharging is carried out after the drying is finished;
7) Finishing: finishing grains by using a 10-mesh screen of a swinging grain machine;
8) Total mixing: placing the calcium intermediate particles in a hopper mixer, adding the essence with the prescription amount, setting the mixing rotating speed to be 10rpm, mixing for 10min, and sub-packaging.
Preferably, the oil solvent in item (2) below is a medium chain triglyceride.
Preferably, the method comprises the steps of, 1) the shearing condition of the medium-high speed homogenizer in the oil solvent in the step (2) is that the shearing condition is that the rotating speed is 9000rpm for 7min.
Description of the embodiments
The following are specific embodiments of the present invention, which are described in order to further illustrate the invention, not to limit the invention.
Example 1:
1. the composition comprises the following components in percentage by mass:
41.79% of calcium carbonate
Vitamin D3 0.00017%
Mannitol 20.83%
Sucrose 30.15%
Povidone K30.69%
Essence 0.5%
Tocopherol 0.00017%
Olive oil 0.004%
Acacia gum 0.033%
Sodium ascorbate 0.0019%
2. The preparation method comprises the following steps:
1) Vitamin D3 intermediate granule preparation
(1) Heating the purified water with the prescription amount to 70 ℃ in a water bath, setting the stirring rotation speed to 300rpm, stirring the purified water, slowly adding the Arabic gum with the prescription amount, continuously stirring until the Arabic gum is completely dissolved, then adding the sucrose and the sodium ascorbate with the prescription amount of 0.2%, and stirring until the Arabic gum is completely dissolved to obtain a water phase;
(2) weighing the prescription amount of olive oil and DL-alpha-tocopherol into a beaker, and adding the prescription amount of vitamin D 3 Heating at constant temperature in water bath of 50deg.C, stirring to dissolve to obtain oil phase;
(3) placing the oil phase in a water bath at 70 ℃, slowly adding the water phase into the oil phase while stirring, and shearing for 10min by adopting a high-speed homogenizer at 8000rpm after the water phase is added to obtain vitamin D3 emulsion;
(4) taking mannitol with a prescription amount of 1/10, placing the mannitol into a fluidized bed, setting the frequency of an induced draft fan to be 14-18 HZ, the air inlet temperature to be 85 ℃, starting the fluidized bed, setting the rotating speed of a peristaltic pump to be 9rpm when the temperature of materials is increased to 60 ℃, setting the atomization pressure to be 0.2Mpa, starting to spray emulsion, setting the air inlet temperature to be 50 ℃ after the spraying, continuing to dry for 10min (controlling the moisture to be less than 1%), and discharging. Sieving with 40 mesh sieve, and granulating to obtain vitamin D3 intermediate granule;
2) Pretreatment of auxiliary materials: pulverizing and sieving the rest sucrose and mannitol, and sieving with 80 mesh and 60 mesh sieve respectively;
3) Preparing a wetting agent: weighing ethanol and purified water according to the prescription, and stirring uniformly to obtain an ethanol water solution to obtain a wetting agent;
4) Preparing a soft material: placing calcium carbonate, vitamin D3 intermediate particles, 80-mesh sucrose, 60-mesh mannitol and povidone K30 into a high-speed mixer-granulator, stirring at 200rpm, shearing at 600rpm, premixing, and mixing for 5min; stirring at 200rpm, shearing at 600rpm, adding 50% ethanol water solution (stirring and shearing are started), adding wetting agent, stirring and shearing for 2min, stopping, and discharging to obtain soft material;
5) Granulating: granulating with a 10 mesh screen using a swing type granulator;
6) And (3) drying: drying the fluidized bed, wherein the air inlet temperature is 50 ℃, the fan frequency is 20-35 HZ, drying is carried out until the moisture is less than or equal to 2.0%, and discharging is carried out after the drying is finished;
7) Finishing: finishing grains by using a 10-mesh screen of a swinging grain machine;
8) Total mixing: placing the calcium intermediate particles in a hopper mixer, adding the essence with the prescription amount, setting the mixing rotating speed to be 10rpm, mixing for 10min, and sub-packaging.
Example 2:
1. the composition comprises the following components in percentage by mass:
41.79% of calcium carbonate
Vitamin D3 0.00017%
Mannitol 20.83%
Sucrose 30.15%
Povidone K30.69%
Essence 0.5%
Tocopherol 0.00017%
Medium chain triglycerides 0.004%
Acacia gum 0.033%
Sodium ascorbate 0.0019%
2. The preparation method comprises the following steps:
referring to example 1, except 1) the following (2) is: weighing prescribed amount of medium chain triglyceride and DL-alpha-tocopherol, adding the prescribed amount of vitamin D into a beaker 3 Heating in 50deg.C water bath at constant temperature, stirring to dissolve to obtain oil phase.
Example 3:
1. the composition comprises the following components in percentage by mass:
41.79% of calcium carbonate
Vitamin D3 0.00017%
Mannitol 20.83%
Sucrose 30.15%
Povidone K30.69%
Essence 0.5%
Tocopherol 0.00017%
Soybean oil 0.004%
Acacia gum 0.033%
Sodium ascorbate 0.0019%
2. The preparation method comprises the following steps:
referring to example 1, except 1) the following (2) is: weighing soybean oil with prescription amount, adding DL-alpha-tocopherol into beaker, adding vitamin D with prescription amount 3 Heating in 50deg.C water bath at constant temperature, stirring to dissolve to obtain oil phase.
Example 4:
1. the composition comprises the following components in percentage by mass:
41.79% of calcium carbonate
Vitamin D3 0.0003%
Mannitol 17.05%
Sucrose 21.79%
Povidone K30.34%
Essence 0.50%
Tocopherol 0.0003%
Medium chain triglycerides 0.004%
Acacia gum 0.033%
Vitamin C sodium 0.002%
2. The preparation method comprises the following steps:
referring to example 1, except 1) the following (2) is: weighing prescribed amount of medium chain triglyceride and DL-alpha-tocopherol, adding the prescribed amount of vitamin D into a beaker 3 Heating in 50deg.C water bath at constant temperature, stirring to dissolve to obtain oil phase. (3) In order to place the oil phase in a water bath at 70 ℃, slowly adding the water phase into the oil phase while stirring, and shearing for 5min by adopting a high-speed homogenizer at 9000rpm after the water phase is added to obtain the vitamin D3 emulsion.
Example 5:
1. the composition comprises the following components in percentage by mass:
41.79% of calcium carbonate
Vitamin D3 0.0003%
Mannitol 17.05%
Sucrose 21.79%
Povidone K30.34%
Essence 0.50%
Tocopherol 0.0003%
Medium chain triglycerides 0.004%
Acacia gum 0.033%
Vitamin C sodium 0.002%
2. The preparation method comprises the following steps:
referring to example 1, except 1) the following (2) is: weighing prescribed amount of medium chain triglyceride and DL-alpha-tocopherol, adding the prescribed amount of vitamin D into a beaker 3 Heating in 50deg.C water bath at constant temperature, stirring to dissolve to obtain oil phase. (3) In order to place the oil phase in a water bath at 70 ℃, slowly adding the water phase into the oil phase while stirring, and shearing for 7min by adopting a high-speed homogenizer at 9000rpm after the water phase is added to obtain the vitamin D3 emulsion.
Comparative example 1:
1. prescription: same as in example 5
2. The preparation method comprises the following steps: referring to example 5, vitamin D3 and tocopherol were directly dissolved in medium chain triglyceride, and vitamin D3 intermediate particles were directly prepared with mannitol and sodium ascorbate without emulsification.
1. Prescription: same as in example 5
2. The preparation method comprises the following steps:
1) Vitamin D3 emulsion preparation
(1) Heating the purified water with the prescription amount to 70 ℃ in a water bath, setting the stirring rotation speed to 300rpm, stirring the purified water, slowly adding the Arabic gum with the prescription amount, continuously stirring until the Arabic gum is completely dissolved, then adding the sucrose with the prescription amount and the sodium ascorbate, and stirring until the Arabic gum is completely dissolved to obtain a water phase;
(2) weighing prescribed amount of medium chain triglyceride and DL-alpha-tocopherol, adding the prescribed amount of vitamin D into a beaker 3 Heating at constant temperature in water bath of 50deg.C, stirring to dissolve to obtain oil phase;
(3) placing the oil phase in a water bath at 70 ℃, slowly adding the water phase into the oil phase while stirring, and shearing for 10min by adopting a high-speed homogenizer at 8000rpm after the water phase is added to obtain vitamin D3 emulsion;
2) Pretreatment of auxiliary materials: pulverizing sucrose and mannitol, sieving, and sieving with 80 mesh and 60 mesh sieve respectively;
3) Taking mannitol, calcium carbonate, povidone K30 and sucrose with prescribed amounts, placing the mannitol, the calcium carbonate, the povidone K30 and the sucrose into a fluidized bed, setting the frequency of an induced draft fan to be 14-18 HZ, the air inlet temperature to be 85 ℃, starting the fluidized bed, setting the rotating speed of a peristaltic pump to be 9rpm when the temperature of materials is increased to 60 ℃, enabling the atomization pressure to be 0.2Mpa, starting to spray emulsion, setting the air inlet temperature to be 50 ℃ after the spraying of the liquid is finished, continuing to dry for 10min (controlling the moisture to be less than 1%), and discharging;
4) Finishing: finishing grains by using a 10-mesh screen of a swinging grain machine;
5) Total mixing: placing the calcium intermediate particles in a hopper mixer, adding the essence with the prescription amount, setting the mixing rotating speed to be 10rpm, mixing for 10min, and sub-packaging.
The same number of calcium carbonate D3 particles prepared in examples 1 to 5 and comparative examples 1 to 2 were randomly selected, and quality and relative bioavailability were compared. The results are shown in the table.
Table 1: content uniformity comparison results
| Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Comparative example 1 | Comparative example 2 | |
| 1 st bag | 101.6 | 97.7 | 99.3 | 98.2 | 97.5 | 97.5 | 103.5 |
| Bag 2 | 99.1 | 99.3 | 97.4 | 107.1 | 99.3 | 112.8 | 99.1 |
| 3 rd bag | 98.7 | 96.8 | 101.6 | 97.1 | 99.8 | 89.0 | 110.7 |
| 4 th bag | 98.2 | 107.5 | 107.3 | 102.5 | 98.1 | 97.3 | 91.5 |
| 5 th bag | 97.9 | 103.1 | 98.6 | 96.8 | 103.7 | 96.7 | 92.7 |
| 6 th bag | 110.5 | 99.6 | 95.2 | 97.8 | 98.4 | 108.2 | 107.4 |
| 7 th bag | 96.4 | 97.3 | 97.8 | 103.5 | 99.7 | 95.5 | 101.4 |
| 8 th bag | 95.8 | 98.7 | 96.3 | 95.7 | 102.9 | 99.4 | 92.2 |
| 9 th bag | 99.1 | 111.4 | 101.8 | 98.9 | 106.3 | 95.1 | 107.3 |
| 10 th bag | 104.6 | 97.9 | 98.1 | 99.7 | 99.6 | 97.8 | 94.6 |
| A+2.2S | 9.90 | 11.7 | 8.32 | 8.12 | 6.76 | 16.00 | 15.65 |
Table 2: dissolution comparative results
| 6-bag dissolution (30 min%) | Average dissolution (%) | |
| Example 1 | 90.7、95.5、91.8、90.4、88.7、90.3 | 91.2 |
| Example 2 | 92.8、93.7、91.8、94.1、94.6、95.5 | 93.8 |
| Example 3 | 89.7、91.4、90.3、92.4、95.2、89.2 | 91.4 |
| Example 4 | 91.1、90.8、93.7、92.6、90.4、93.5 | 92.0 |
| Example 5 | 95.2、94.7、96.0、93.9、94.5、92.7 | 94.5 |
| Comparative example 1 | 90.4、96.1、87.4、88.7、90.2、83.6 | 87.7 |
| Comparative example 2 | 88.5、92.1、83.7、90.0、84.6、82.2 | 86.8 |
Table 3: quality comparison results
Table 4: stability investigation results of commercial calcium carbonate D3 particles
Table 5: example 5 stability investigation results
Table 6: comparative example 1 stability investigation results
Table 7: comparison of in vitro dissolution and in vivo bioavailability
| Commercial calcium carbonate D3 particles | Example 5 | Comparative example 1 | |
| Dissolution (30 min,%) | 86.2 | 94.5 | 87.7 |
| Compared with blank group, the urine calcium quantity is increased (mg) | 21.55±10 | 39.42±12 | 37.32±10 |
By comparing the results of the examples, the comparative examples and the commercial calcium carbonate D3 particles, it can be seen that the content uniformity and the dissolution rate of examples 1 to 5 are satisfactory, no significant difference exists, and the quality level is higher than that of the commercial calcium carbonate D3 particles, especially the quality level of example 5 is optimal. The stability and bioavailability of example 5 are significantly better than the commercial calcium carbonate D3 particles and comparative example 1. Compared with the existing similar products, the quality level and bioavailability of the calcium carbonate D3 particles prepared by the invention are obviously improved. The above examples only represent a few embodiments of the present invention, which are described in more detail. It will be apparent to those skilled in the art that modifications can be made to the present invention without departing from the spirit of the invention.
Claims (4)
1. The special calcium supplement for the rickets patients is characterized by comprising vitamin D3 intermediate particles in an oil-in-water form, and the special calcium supplement comprises the following raw and auxiliary materials in parts by weight: 800 to 1500 parts of calcium carbonate, 0.001 to 0.02 part of vitamin D, 500 to 750 parts of mannitol, 800 to 1100 parts of sucrose, 30 to 300 parts of povidone K, 10 to 30 parts of essence, 0.001 to 0.02 part of tocopherol, 0.1 to 0.3 part of medium chain triglyceride, 0.5 to 3 parts of acacia and 0.02 to 0.1 part of sodium ascorbate.
2. The calcium supplement for children of rickets patients according to claim 1, wherein the vitamin D3 intermediate particles are prepared by preparing vitamin D3 into an oil phase, then preparing an emulsion with a water phase prepared from acacia, sucrose and sodium ascorbate, and then preparing the vitamin D3 intermediate particles in an oil-in-water form by adopting a low-spray technology.
3. The special calcium supplement for rickets children patients according to claim 1, wherein the optimal weight ratio of the calcium carbonate to the vitamin D3 is 1393:0.01.
4. A method for preparing the special calcium supplement for rickets patients according to any one of claims 1-3, which is characterized by comprising the following steps:
1) Vitamin D3 intermediate granule preparation
(1) Heating the purified water with the prescription amount to 70 ℃ in a water bath, setting the stirring rotation speed to 300rpm, stirring the purified water, slowly adding the Arabic gum with the prescription amount, continuously stirring until the Arabic gum is completely dissolved, then adding the sucrose and the sodium ascorbate with the prescription amount of 0.2%, and stirring until the Arabic gum is completely dissolved to obtain a water phase;
(2) weighing prescribed amount of medium chain triglyceride and DL-alpha-tocopherol, adding the prescribed amount of vitamin D into a beaker 3 Heating at constant temperature in water bath of 50deg.C, stirring to dissolve to obtain oil phase;
(3) placing the oil phase in a water bath at 70 ℃, slowly adding the water phase into the oil phase while stirring, and shearing for 7min by adopting a high-speed homogenizer at 9000rpm after the water phase is added to obtain vitamin D3 emulsion;
(4) taking mannitol with a prescription amount of 1/10, placing the mannitol into a fluidized bed, setting the frequency of an induced draft fan to be 14-18 HZ, the air inlet temperature to be 85 ℃, starting the fluidized bed, setting the rotating speed of a peristaltic pump to be 9rpm when the temperature of materials is increased to 60 ℃, setting the atomization pressure to be 0.2Mpa, starting to spray emulsion, setting the air inlet temperature to be 50 ℃ after the spraying, continuing to dry for 10min (controlling the moisture to be less than 1%), and discharging. Sieving with 40 mesh sieve, and granulating to obtain vitamin D3 intermediate granule;
2) Pretreatment of auxiliary materials: pulverizing and sieving the rest sucrose and mannitol, and sieving with 80 mesh and 60 mesh sieve respectively;
3) Preparing a wetting agent: weighing ethanol and purified water according to the prescription, and stirring uniformly to obtain an ethanol water solution to obtain a wetting agent;
4) Preparing a soft material: placing calcium carbonate, vitamin D3 intermediate particles, 80-mesh sucrose, 60-mesh mannitol and povidone K30 into a high-speed mixer-granulator, stirring at 200rpm, shearing at 600rpm, premixing, and mixing for 5min; stirring at 200rpm, shearing at 600rpm, adding 50% ethanol water solution (stirring and shearing are started), adding wetting agent, stirring and shearing for 2min, stopping, and discharging to obtain soft material;
5) Granulating: granulating with a 10 mesh screen using a swing type granulator;
6) And (3) drying: drying the fluidized bed, wherein the air inlet temperature is 50 ℃, the fan frequency is 20-35 HZ, drying is carried out until the moisture is less than or equal to 2.0%, and discharging is carried out after the drying is finished;
7) Finishing: finishing grains by using a 10-mesh screen of a swinging grain machine;
8) Total mixing: placing the calcium intermediate particles in a hopper mixer, adding the essence with the prescription amount, setting the mixing rotating speed to be 10rpm, mixing for 10min, and sub-packaging.
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