AU2021106183A4 - Vitamin d3 complex and preparation method and application thereof - Google Patents
Vitamin d3 complex and preparation method and application thereof Download PDFInfo
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- AU2021106183A4 AU2021106183A4 AU2021106183A AU2021106183A AU2021106183A4 AU 2021106183 A4 AU2021106183 A4 AU 2021106183A4 AU 2021106183 A AU2021106183 A AU 2021106183A AU 2021106183 A AU2021106183 A AU 2021106183A AU 2021106183 A4 AU2021106183 A4 AU 2021106183A4
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- vitamin
- complex
- antioxidant
- porous carrier
- carrier material
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- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound 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 title claims abstract description 119
- 229940021056 vitamin d3 Drugs 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 238000010668 complexation reaction Methods 0.000 title 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products 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 117
- 235000005282 vitamin D3 Nutrition 0.000 claims abstract description 116
- 239000011647 vitamin D3 Substances 0.000 claims abstract description 116
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 51
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 48
- 239000012876 carrier material Substances 0.000 claims abstract description 29
- 235000006708 antioxidants Nutrition 0.000 claims description 47
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 20
- 239000011148 porous material Substances 0.000 claims description 17
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 239000000377 silicon dioxide Substances 0.000 claims description 11
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 10
- 229930003268 Vitamin C Natural products 0.000 claims description 10
- 235000019154 vitamin C Nutrition 0.000 claims description 10
- 239000011718 vitamin C Substances 0.000 claims description 10
- 229930003427 Vitamin E Natural products 0.000 claims description 8
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 8
- 235000019165 vitamin E Nutrition 0.000 claims description 8
- 229940046009 vitamin E Drugs 0.000 claims description 8
- 239000011709 vitamin E Substances 0.000 claims description 8
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 6
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 5
- 239000000378 calcium silicate Substances 0.000 claims description 4
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 4
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 4
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 4
- OVYMWJFNQQOJBU-UHFFFAOYSA-N 1-octanoyloxypropan-2-yl octanoate Chemical compound CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC OVYMWJFNQQOJBU-UHFFFAOYSA-N 0.000 claims description 3
- NFIHXTUNNGIYRF-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate Chemical compound CCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCC NFIHXTUNNGIYRF-UHFFFAOYSA-N 0.000 claims description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 3
- 229930064664 L-arginine Natural products 0.000 claims description 3
- 235000014852 L-arginine Nutrition 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 3
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 3
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 229940001474 sodium thiosulfate Drugs 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 239000007910 chewable tablet Substances 0.000 abstract description 10
- 239000008187 granular material Substances 0.000 abstract description 7
- 239000003826 tablet Substances 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 28
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 16
- 230000007774 longterm Effects 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229940088594 vitamin Drugs 0.000 description 11
- 229930003231 vitamin Natural products 0.000 description 11
- 235000013343 vitamin Nutrition 0.000 description 11
- 239000011782 vitamin Substances 0.000 description 11
- 150000003722 vitamin derivatives Chemical class 0.000 description 11
- 229910000019 calcium carbonate Inorganic materials 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- XQFJZHAVTPYDIQ-LETJEVNCSA-N (1s)-3-[(e)-2-[(1r,3ar,7ar)-1-[(e,2r,5r)-5,6-dimethylhept-3-en-2-yl]-7a-methyl-1,2,3,3a,6,7-hexahydroinden-4-yl]ethenyl]-4-methylcyclohex-3-en-1-ol Chemical compound C=1([C@@H]2CC[C@@H]([C@]2(CCC=1)C)[C@H](C)/C=C/[C@H](C)C(C)C)\C=C\C1=C(C)CC[C@H](O)C1 XQFJZHAVTPYDIQ-LETJEVNCSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- BUNBVCKYYMRTNS-UHFFFAOYSA-N tachysterol Natural products C=1CCC2(C)C(C(C)CCC(C)C(C)C)CCC2C=1C=CC1=C(C)CCC(O)C1 BUNBVCKYYMRTNS-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Ceramic Engineering (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
OF THE DISCLOSURE
Disclosed are a vitamin D3 complex and a preparation method and application
thereof, belonging to the technical field of pharmaceutical preparations. The vitamin D3
complex of the present disclosure includes vitamin D3, a porous carrier material and an
antioxidant; the antioxidant and vitamin D3 are loaded inside the porous carrier material,
which can effectively improve the stability of vitamin D3 and prevent vitamin D3 from
being degraded during the preparation process and product storage. The present
disclosure provides the composition and the preparation method of the above vitamin
D3 complex. The vitamin D3 complex can be further prepared into granules, tablets and
chewable tablets, and the content of vitamin D3 in the complex can be adjusted as
required to meet the requirements of the content uniformity of the vitamin D3 in the
preparation product.
Description
VITAMIN D3 COMPLEX AND PREPARATION METHOD AND APPLICATION THEREOF
[01] The present disclosure relates to the technical field of pharmaceutical preparations, in particular to a vitamin D3 complex and a preparation method and application thereof.
[02] Vitamin D3, also known as cholecalciferol, is the most important form of the vitamin D family. It can regulate calcium and phosphorus metabolism in the body and has a wide range of biological functions, including improving the body's absorption of calcium and phosphorus, promoting bone growth, and exerting immune regulation, etc.
[03] Vitamin D3 is unstable, the unsaturated double bond in the structure is easily degraded under conditions such as light, oxidation and high temperature; the content of vitamin D3 in the preparation product is extremely low (as low as a few parts per million), and the content uniformity has huge challenges; therefore, due to stability and content uniformity, it is impossible to use a single vitamin D3 component to produce vitamin D3 solid preparations. It needs to be developed as a stable complex. The vitamin D3 complex in the prior art has the problem of poor stability.
[04] In view of this, the purpose of the present disclosure is to provide a vitamin D3 complex and a preparation method and application thereof. The vitamin D3 complex provided by the present disclosure has good stability.
[05] In order to achieve the above purpose of the present disclosure, the present disclosure provides the following technical schemes:
[06] The present disclosure provides a vitamin D3 complex, comprising the following components in mass percentage: 0.1-1.0% of vitamin D3, 0.5-6.0% of an antioxidant, and the balance of a porous carrier material, the antioxidant and the vitamin D3 are loaded in the pores of the porous carrier material.
[07] Preferably, it further comprises a solvent-based excipient, the mass percentage of the solvent-based excipient in the vitamin D3 complex is less than or equal to 45%, and the solvent-based excipient is loaded in the pores of the porous carrier material; the solvent-based excipient includes one or more of polyethylene glycol 400, soybean oil, medium-chain triglycerides, and propylene glycol dicaprylate/dicaprate.
[08] Preferably, the porous carrier material comprises one or more of gel silica, calcium silicate and magnesium aluminum silicate; the antioxidant comprises a water-soluble antioxidant and/or a fat-soluble antioxidant, the water-soluble antioxidant includes one or more of sodium bisulfite, disodium edetate, sodium thiosulfate, vitamin C and L-arginine, and the fat-soluble antioxidant includes one or more of vitamin E, butylated hydroxyanisole and butylated hydroxytoluene.
[09] The present disclosure also provides a preparation method of the vitamin D3 complex including the following steps:
[10] Mixing a vitamin D3 solution, an antioxidant solution and the porous carrier material to make the vitamin D3 solution and the antioxidant solution adsorbed into the pores of the porous carrier material to obtain the vitamin D3 complex.
[11] The present disclosure also provides the application of the vitamin D3 complex described in the above technical scheme or the vitamin D3 complex prepared by the preparation method described in the above technical scheme in the preparation of granules, tablets or chewable tablets.
[12] The present disclosure provides a vitamin D3 complex, comprising the following components in mass percentage: 0.1-1.0% of vitamin D3, 0.5-6.0% of an antioxidant, and the balance of a porous carrier material, the antioxidant and the vitamin D3 are loaded in the pores of the porous carrier material. In the present disclosure, the porous carrier material is an amorphous particle with very strong liquid absorption capacity. The present disclosure utilizes the excellent liquid absorption capacity of the porous carrier material to prepare a vitamin D3 complex containing antioxidants, which can effectively improve the stability of vitamin D3, and prevent vitamin D3 from degrading during storage or preparation production and storage; and according to the needs of preparation prescription and process development, the content of vitamin D3 in the complex and the particle size of the complex can be adjusted to meet the requirements of the mixing uniformity of vitamin D3 and the content uniformity of vitamin D3 in the preparations.
[13] Further, the porous carrier material used in the present disclosure includes one or more of gel silica, calcium silicate and magnesium aluminum silicate. These porous carrier material particles have an abundant pore structure, a high specific surface area and a large porosity.
[14] The present disclosure also provides a preparation method of the vitamin D3 complex described in the above technical scheme. In the present disclosure, the preparation method of the present disclosure is simple, easy to operate, and has low dependence on equipment.
[15] The vitamin D3 complex of the present disclosure can be further prepared into calcium carbonate D3 preparations (such as granules, tablets or chewable tablets) with good stability and vitamin D3 content uniformity meeting the requirements.
[16] FIG.1 is a scanning electron micrograph of the vitamin D3 complex prepared in Example 1.
[17] The present disclosure provides a vitamin D3 complex, comprising the following components in mass percentage: 0.1-1.0% of vitamin D3, 0.5-6.0% of an antioxidant, and the balance of a porous carrier material, the antioxidant and the vitamin D3 are loaded in the pores of the porous carrier material.
[18] In the present disclosure, the vitamin D3 complex preferably further comprises a solvent-based excipient, the mass percentage of the solvent-based excipient in the vitamin D3 complex is less than or equal to 45%, and the solvent-based excipient is loaded in the pores of the porous carrier material.
[19] In the present disclosure, the solvent-based excipient preferably further includes one or more of polyethylene glycol 400, soybean oil, medium-chain triglycerides, and propylene glycol dicaprylate/dicaprate.
[20] In the present disclosure, the porous carrier material preferably comprises one or more of gel silica, calcium silicate and magnesium aluminum silicate.
[21] In the present disclosure, the antioxidant preferably includes a water-soluble antioxidant and/or a fat-soluble antioxidant, the water-soluble antioxidant includes one or more of sodium bisulfite, disodium edetate, sodium thiosulfate, vitamin C and L-arginine, and the fat-soluble antioxidant includes one or more of vitamin E, butylated hydroxyanisole and butylated hydroxytoluene.
[22] The present disclosure also provides a preparation method of the vitamin D3 complex including the following steps:
[23] Mixing a vitamin D3 solution, an antioxidant solution and the porous carrier material to make the vitamin D3 solution and the antioxidant solution adsorbed into the pores of the porous carrier material to obtain the vitamin D3 complex.
[24] When the antioxidant is preferably only a water-soluble antioxidant, the preparation method of the vitamin D3 complex preferably includes the following steps:
[25] Dissolving the water-soluble antioxidant in water to obtain a water-soluble antioxidant solution;
[26] Adding the water-soluble antioxidant solution to the pores of the porous carrier material to obtain a moist water-soluble antioxidant-porous carrier complex;
[27] Placing the moist antioxidant-porous carrier complex in an oven and drying at -60°C to obtain a dry water-soluble antioxidant-porous carrier complex;
[28] Mixing the vitamin D3 and ethanol to obtain a vitamin D3 solution;
[29] Adding the vitamin D3 solution to the pores of the dry water-soluble antioxidant-porous carrier complex to obtain a moist vitamin D3 complex;
[30] Placing the moist vitamin D3 complex in an oven and drying at 40-60°C to obtain the vitamin D3 complex.
[31] When the antioxidant is preferably only a fat-soluble antioxidant, the preparation method of the vitamin D3 complex preferably includes the following steps:
[32] Mixing the vitamin D3, fat-soluble antioxidant and ethanol to obtain a vitamin D3-antioxidant solution;
[33] Adding the vitamin D3-antioxidant solution into the pores of the porous carrier material to obtain a moist vitamin D3 complex;
[34] Placing the moist vitamin D3 complex in an oven and drying at 40-60°C to obtain the vitamin D3 complex.
[35] When the antioxidant preferably contains both a water-soluble antioxidant and a fat-soluble antioxidant, the preparation method of the vitamin D3 complex preferably includes the following steps:
[36] Dissolving the water-soluble antioxidant in water to obtain a water-soluble antioxidant solution;
[37] Adding the water-soluble antioxidant solution to the pores of the porous carrier material to obtain a moist water-soluble antioxidant-porous carrier complex;
[38] Placing the moist antioxidant-porous carrier complex in an oven and drying at -60°C to obtain a dry water-soluble antioxidant-porous carrier complex;
[39] Mixing the vitamin D3, fat-soluble antioxidant and ethanol to obtain a vitamin D3-fat-soluble antioxidant solution;
[40] Adding the vitamin D3-fat-soluble antioxidant solution into the pores of the dry water-soluble antioxidant-porous carrier complex to obtain a moist vitamin D3 complex;
[41] Placing the moist vitamin D3 complex in an oven and drying at 40-60°C to obtain the vitamin D3 complex.
[42] When the vitamin D3 complex preferably contains solvent-based excipients, the preparation method of the vitamin D3 complex is consistent with that of the above scheme, except that the ethanol is replaced with the solvent-based excipients, and the drying step at 40-60°C is omitted.
[43] The present disclosure also provides the application of the vitamin D3 complex described in the above technical scheme or the vitamin D3 complex prepared by the preparation method described in the above technical scheme in the preparation of granules, tablets or chewable tablets.
[44] In order to further illustrate the present disclosure, the vitamin D3 complex provided by the present disclosure and the preparation method and application thereof will be described in detail below in conjunction with examples, but they should not be understood as limiting the protection scope of the present disclosure.
[45] Example 1:
[46] The preparation materials of the vitamin D3 complex are shown in Table 1.
[47] Table 1 Preparation materials of the vitamin D3 complex in Example 1
[48] vitamin D3 0.3 g gel silica 50 g vitamin C 3.0 g vitamin E 1.2 g purified water * 35.0 g ethanol* 35.0 g note: *removed during the preparation process
[49] Preparation method:
[50] 1) Vitamin C was added to purified water and stirred to dissolve to obtain an aqueous solution of vitamin C;
[51] 2) The aqueous solution of vitamin C was added to the gel silica powder, the powder was stirred while adding the solution to make the gel silica quickly and effectively adsorb the aqueous solution to obtain a moist vitamin C-gel silica complex;
[52] 3) The complex prepared in 2) was passed through a No. 4 sieve, the sieved complex was placed in an oven and dried at 50°C for 2 h, and the dried complex was passed through a No. 4 sieve to obtain a dried vitamin C-gel silica complex;
[53] 4) Vitamin D3 and vitamin E were added to ethanol, stirred to dissolve to obtain a solution; the above solution was added to the vitamin C-gel silica complex powder obtained in 3), and the powder was stirred while adding the solution to make the complex quickly and effectively adsorb the solution to obtain a moist vitamin D3 complex;
[54] 5) The vitamin D3 complex prepared in 4) was pass through a No. 4 sieve, the sieved vitamin D3 complex was placed in an oven and dried at 50°C for 2 h, and then the dried complex was passed through a No. 4 sieve to obtain the vitamin D3 complex.
[55] The morphology of the complex was observed with a scanning electron microscope, and the results are shown in FIG. 1. It can be seen that vitamin D3, vitamin C and vitamin E are all loaded in the pores of the gel silica.
[56] Example 2:
[57] The raw materials for the preparation of vitamin D3 complex are shown in Table 2.
[58] Table 2 Raw materials for the preparation of vitamin D3 complex in Example 2
[59] vitamin D3 0.25 g magnesium 50 g aluminum silicate vitamin C 2.0 g disodium edetate 0.8 g vitamin E 1.0 g pure water* 35.0 g medium chain 20.0 g triglycerides note: *removed during the preparation process
[60] Preparation method:
[61] 1) Vitamin C and disodium edetate were added to purified water and stirred to dissolve to obtain an aqueous solution;
[62] 2) The aqueous solution was added to the magnesium aluminum silicate powder, the powder was stirred while adding the solution to make the magnesium aluminum silicate quickly and effectively adsorb the aqueous solution to obtain a moist vitamin C-disodium edetate-magnesium aluminum silicate complex;
[63] 3) The complex prepared in 2) was passed through a No. 4 sieve, the sieved complex was placed in an oven and dried at 50°C for 2 h, and the dried complex was passed through a No. 4 sieve to obtain a dried vitamin C-disodium edetate-magnesium aluminum silicate complex;
[64] 4) Vitamin D3 and vitamin E were added to the medium chain triglycerides, stirred to dissolve to obtain a solution; the above solution was added to the vitamin C-disodium edetate-magnesium aluminum silicate complex powder obtained in 3), and the powder was stirred while adding the solution to make the complex quickly and effectively adsorb the solution, the complex prepared was pass through a No. 4 sieve to obtain the vitamin D3 complex.
[65] Example 3: Comparative study of stability
[66] The vitamin D3 complex prepared in Examples 1-2 and the commercially available vitamin D3 inclusion complex were subjected to a stability test. The results are shown in Table 3. Comparing the contents of the three and the changes of related substances, the results show that the content changes uniformly and significantly. The vitamin D3 complexes prepared in Examples 1-2 have significantly lower levels of related substances than the commercially available inclusion complex.
[67] Table 3 Comparison of the stability of the vitamin D3 complex prepared in Examples 1-2 and the commercially available vitamin D3 inclusion complex vitamin D3 related substances commerciallyavailable Example Example (wt%) vitamin D3 inclusion 1 2 complex 0 days f 0.10 0.03 0.03 trans vitamin logtr D3 long-term of 0.16 0.05 0.04 12 months not not 0 days not detectednont EP impurity detected detected B long-term of not detected not not 12 months detected detected not detected not not 0 days EP impurity detected detected C long-term of not detected not not 12 months detected detected not detected not not 0 days EP impurity detected detected D long-term of not detected not not 12 months detected detected 0 days 0.44 0.09 0.10 tachysterol long-term of 0.78 0.27 0.25 12 months 0 days 0.54 0.12 0.13 total long-term of impurities months 0.94 0.32 0.29 12 months 0 days f 101.2 100.6 100.9 vitamin D3 logtr content long-term of 100.6 100.4 100.7 12 months
[68] Example 4: Calcium carbonate D3 chewable tablets prepared based on vitamin D3 complex
[69] The vitamin D3 complex prepared in Example 2 was prepared into calcium carbonate D3 chewable tablets (batch: 15,000 tablets/batch), three batches of products (201101, 201102 and 201103) were prepared, and the commercially available products were used as a comparison to study the content uniformity and stability. Calcium carbonate and excipients of mannitol and povidone were granulated by wet granulation, the wet granules were passed through a 24 mesh sieve, and the dried granules were passed through a 20 mesh sieve for sizing. The obtained calcium carbonate granules were mixed with the vitamin D3 complex prepared in Example 2, flavor, and magnesium stearate, and the mixture was compressed.
[70] Content uniformity
[71] According to the General Rule 0941 of Chinese Pharmacopoeia (2020 Edition), the content uniformity was tested. The results are shown in Table 4, which shows that the calcium carbonate D3 chewable tablets prepared by the present disclosure have good content uniformity of vitamin D3 (better than commercially available products), meet the requirement that the value of A + 2.2S is less than or equal to 15, and conform to the provisions of Chinese Pharmacopoeia.
[72] Table 4 Comparison of content uniformity
[73] batch No. commercially 201101 201102 201103 available product average 108.5 101.6 100.2 102.5 content (%) A 8.5 1.6 0.2 2.5 S 14.6 3.1 3.5 2.7 A+ 2.2S 40.62 8.42 7.90 8.44
[74] Stability
[75] The stability study of the vitamin D3 chewable tablets prepared by the present disclosure and commercially available products was carried out. The results are shown in Table 5, which shows that the vitamin D3 content of the calcium carbonate D3 chewable tablets prepared by the present disclosure and commercially available products does not change significantly, but the levels of vitamin D3 related substances in the self-made preparations are significantly lower than that of commercially available products.
[76] Table 5 Comparison of stability
[771 commercially calcium carbonate D3 chewable vitamin D3 related available calcium tablets prepared by the present substances (wt%) carbonate D3 disclosure chewable tablets 201101 201102 201103 0 days f 0.26 0.06 0.07 0.06 trans logtr vitamin D3 long-term of 0.46 0.09 0.11 0.10 12 months not detected not not not 0 days EP impurity detected detected detected B long-term of not detected not not not 12 months detected detected detected not detected not not not 0 days EP impurity detected detected detected C long-term of not detected not not not 12 months detected detected detected EP impurity 0days not detected not not not D detected detected detected long-term of not detected not not not 12 months detected detected detected 0 days 0.75 0.12 0.13 0.11 tachysterol long-term of 1.22 0.28 0.29 0.28 12 months 0 days 1.01 0.18 0.20 0.17 total impurities long-term of 1.68 0.37 0.40 0.38 12 months 0 days 108.5 101.6 100.2 102.5 vitaminD3 content long-term of 107.6 101.2 99.7 101.9 12 months
[78] The above results indicate that the vitamin D3 complex provided by the present disclosure is of good quality and can meet the requirements for the content uniformity of vitamin D3 and stability of the preparation product.
[79] The above are only the preferred embodiments of the present disclosure, and do not limit the present disclosure in any form. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present disclosure, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present disclosure.
Claims (3)
1. A vitamin D3 complex, wherein comprising the following components in mass percentage: 0.1-1.0% of vitamin D3, 0.5-6.0% of an antioxidant, and the balance of a porous carrier material, the antioxidant and the vitamin D3 are loaded in the pores of the porous carrier material.
2. The vitamin D3 complex according to claim 1, wherein further comprising a solvent-based excipient, the mass percentage of the solvent-based excipient in the vitamin D3 complex is less than or equal to 45%, and the solvent-based excipient is loaded in the pores of the porous carrier material; the solvent-based excipient includes one or more of polyethylene glycol 400, soybean oil, medium-chain triglycerides, and propylene glycol dicaprylate/dicaprate; a preparation method of the vitamin D3 complex includes the following steps: mixing a vitamin D3 solution, an antioxidant solution and the porous carrier material to make the vitamin D3 solution and the antioxidant solution adsorbed into the pores of the porous carrier material to obtain the vitamin D3 complex.
3. The vitamin D3 complex according to claim 1 or 2, wherein the porous carrier material comprises one or more of gel silica, calcium silicate and magnesium aluminum silicate; The antioxidant includes a water-soluble antioxidant and/or a fat-soluble antioxidant, the water-soluble antioxidant includes one or more of sodium bisulfite, disodium edetate, sodium thiosulfate, vitamin C and L-arginine, and the fat-soluble antioxidant includes one or more of vitamin E, butylated hydroxyanisole and butylated hydroxytoluene.
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