CN107397760B - Iron-based hydroxide-low molecular weight sugar phosphorus binder, preparation method and application thereof - Google Patents
Iron-based hydroxide-low molecular weight sugar phosphorus binder, preparation method and application thereof Download PDFInfo
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- CN107397760B CN107397760B CN201610341394.6A CN201610341394A CN107397760B CN 107397760 B CN107397760 B CN 107397760B CN 201610341394 A CN201610341394 A CN 201610341394A CN 107397760 B CN107397760 B CN 107397760B
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- Prior art keywords
- phosphorus
- low molecular
- binding agent
- molecular weight
- iron
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title claims abstract description 101
- 239000011574 phosphorus Substances 0.000 title claims abstract description 101
- 229910052698 phosphorus Inorganic materials 0.000 title claims abstract description 101
- 239000011230 binding agent Substances 0.000 title claims abstract description 84
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 235000000346 sugar Nutrition 0.000 title claims abstract description 48
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 235000014413 iron hydroxide Nutrition 0.000 claims abstract description 19
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 claims abstract description 19
- 239000008280 blood Substances 0.000 claims abstract description 9
- 210000004369 blood Anatomy 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 50
- 229920001542 oligosaccharide Polymers 0.000 claims description 23
- 239000002585 base Substances 0.000 claims description 16
- 239000001509 sodium citrate Substances 0.000 claims description 15
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical group O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 15
- 150000002482 oligosaccharides Chemical class 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 12
- 150000002505 iron Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 150000001720 carbohydrates Chemical class 0.000 claims description 11
- 150000002772 monosaccharides Chemical group 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001179 sorption measurement Methods 0.000 claims description 6
- 235000021255 galacto-oligosaccharides Nutrition 0.000 claims description 5
- 150000003271 galactooligosaccharides Chemical class 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- 201000005991 hyperphosphatemia Diseases 0.000 claims description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 208000030159 metabolic disease Diseases 0.000 claims description 3
- 239000001508 potassium citrate Substances 0.000 claims description 3
- 229960002635 potassium citrate Drugs 0.000 claims description 3
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 3
- 235000011082 potassium citrates Nutrition 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 150000008163 sugars Chemical class 0.000 claims description 3
- 208000020084 Bone disease Diseases 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical class OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 201000002980 Hyperparathyroidism Diseases 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 229930003316 Vitamin D Natural products 0.000 claims description 2
- 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 description 2
- MWKXCSMICWVRGW-UHFFFAOYSA-N calcium;phosphane Chemical compound P.[Ca] MWKXCSMICWVRGW-UHFFFAOYSA-N 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 230000002708 enhancing effect Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 230000036039 immunity Effects 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 235000019166 vitamin D Nutrition 0.000 claims description 2
- 239000011710 vitamin D Substances 0.000 claims description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 2
- 229940046008 vitamin d Drugs 0.000 claims description 2
- 229960004887 ferric hydroxide Drugs 0.000 claims 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 5
- 125000001483 monosaccharide substituent group Chemical group 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- 239000000047 product Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 11
- 241000282414 Homo sapiens Species 0.000 description 9
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- 238000010521 absorption reaction Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
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- 239000006041 probiotic Substances 0.000 description 7
- 235000018291 probiotics Nutrition 0.000 description 7
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 6
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 6
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 6
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- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 4
- 235000013325 dietary fiber Nutrition 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- FTSSQIKWUOOEGC-RULYVFMPSA-N fructooligosaccharide Chemical compound OC[C@H]1O[C@@](CO)(OC[C@@]2(OC[C@@]3(OC[C@@]4(OC[C@@]5(OC[C@@]6(OC[C@@]7(OC[C@@]8(OC[C@@]9(OC[C@@]%10(OC[C@@]%11(O[C@H]%12O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%12O)O[C@H](CO)[C@@H](O)[C@@H]%11O)O[C@H](CO)[C@@H](O)[C@@H]%10O)O[C@H](CO)[C@@H](O)[C@@H]9O)O[C@H](CO)[C@@H](O)[C@@H]8O)O[C@H](CO)[C@@H](O)[C@@H]7O)O[C@H](CO)[C@@H](O)[C@@H]6O)O[C@H](CO)[C@@H](O)[C@@H]5O)O[C@H](CO)[C@@H](O)[C@@H]4O)O[C@H](CO)[C@@H](O)[C@@H]3O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O FTSSQIKWUOOEGC-RULYVFMPSA-N 0.000 description 4
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- 230000010438 iron metabolism Effects 0.000 description 4
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- 239000006188 syrup Substances 0.000 description 4
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- 238000005406 washing Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000607142 Salmonella Species 0.000 description 3
- CUPCBVUMRUSXIU-UHFFFAOYSA-N [Fe].OOO Chemical compound [Fe].OOO CUPCBVUMRUSXIU-UHFFFAOYSA-N 0.000 description 3
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- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 3
- 229910021519 iron(III) oxide-hydroxide Inorganic materials 0.000 description 3
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- 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 description 1
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- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- 239000012669 liquid formulation Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
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- 239000011707 mineral Substances 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
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- DPTATFGPDCLUTF-UHFFFAOYSA-N phosphanylidyneiron Chemical compound [Fe]#P DPTATFGPDCLUTF-UHFFFAOYSA-N 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
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- 239000012266 salt solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
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- 230000000153 supplemental effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
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Classifications
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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
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention provides a phosphorus binder based on iron hydroxide-low molecular weight sugar, a preparation method and application thereof, and particularly provides a phosphorus binder comprising iron hydroxide and low molecular weight sugar, wherein the number of monosaccharide units of the low molecular weight sugar is 3-20, and the mass ratio of iron is 2-45 wt% based on the total weight of the phosphorus binder. Experiments show that the phosphorus binding agent has the effect of remarkably reducing the concentration of the blood phosphorus, thereby having wide application prospect.
Description
Technical Field
The invention relates to a phosphorus binding agent, in particular to a phosphorus binding agent based on ferric salt-low molecular weight sugar, a preparation method and application thereof.
Background
Hyperphosphatemia is one of the major complications of chronic renal insufficiency (CKD), increased blood phosphorus levels are closely associated with mortality in CKD patients, and increased blood phosphorus levels can lead to further decline of renal function, secondary thyroid function resistance, vascular calcification and mineral, bone metabolic disorders. It is widely accepted in the modern times that regulation of phosphorus metabolism is the key to reducing cardiovascular complications, improving the quality of life of dialysis patients, and reducing disability rate and mortality rate.
In recent years, new phosphorus binders have been developed. Among them, the iron-phosphorus-containing binder was confirmed to be a highly efficient phosphorus binder, and did not cause ectopic calcification and could improve thyroid function resistance. Meanwhile, the compound preparation is beneficial to correcting the anemia state of CKD patients, and has no obvious influence on the iron metabolism in vivo.
Because the daily diet of the patient contains a large amount of phosphorus, and the phosphorus adsorption capacity of the existing phosphorus binders is too low, the patient needs to use a large amount of the phosphorus binders every day in order to control the blood phosphorus concentration to a normal level, and excessive administration of the phosphorus binders brings other side effects to the patient.
Therefore, there is an urgent need in the art to develop a phosphorus binder that can greatly improve the phosphorus adsorption capacity and reduce side effects.
Disclosure of Invention
The invention aims to provide a phosphorus binding agent which can greatly improve the phosphorus adsorption capacity and reduce side effects.
In a first aspect, the present invention provides a phosphorus binding agent comprising:
a hydroxide of iron; and
low molecular weight sugars;
wherein the number of monosaccharide units of the low molecular weight sugar is 3-20, and the mass ratio of iron is 2-45 wt% based on the total weight of the phosphorus binder.
In another preferred embodiment, the mass ratio of the iron is 10 to 35 wt%, preferably 25 to 33wt%, based on the total weight of the phosphorus binder.
In another preferred embodiment, the number of monosaccharide units of the low molecular weight saccharide is 3 to 10, preferably 4 to 9, more preferably 4 to 7.
In another preferred embodiment, the low molecular weight sugar comprises an oligosaccharide.
In another preferred embodiment, the oligosaccharide is selected from the group consisting of: fructo-oligosaccharide, galacto-oligosaccharide, lacto-lactose, gluco-oligosaccharide, mannose-oligosaccharide, xylo-oligosaccharide, trehalose, lactosucrose, malto-oligosaccharide, isomalto-oligosaccharide, cyclodextrin, chitin oligosaccharide, soy oligosaccharide, gentio-oligosaccharide, agarose-oligosaccharide, stachyose, pectin-oligosaccharide, lactulose, raffinose, palatino oligosaccharide, or a combination thereof.
In another preferred embodiment, the weight ratio of the iron hydroxide to the low molecular weight sugar is 1:0.25-4, preferably 1:0.5-1, more preferably 1: 0.6-0.7.
In another preferred embodiment, the hydroxide of iron is selected from the group consisting of: iron hydroxide, iron oxyhydroxide, iron oxide, or a combination thereof.
In another preferred embodiment, the hydroxide of iron forms a stable structure with the low molecular weight sugar by hydrogen bonding or adsorption.
In another preferred embodiment, the residual amount of citrate in the phosphorous binder is < 1%, preferably < 0.5%, more preferably < 0.1%.
In a second aspect, the invention provides the use of a phosphorus-binding agent according to the first aspect of the invention for the preparation of a composition for inhibiting elevated blood phosphorus concentrations.
In another preferred embodiment, the composition is also used for (i) enhancing immunity; and/or (ii) treating or preventing hyperphosphatemia, hyperparathyroidism, calcium phosphorus product changes, vitamin D metabolic disorders, renal bone disease, and cardiovascular complications related diseases.
In another preferred embodiment, the composition comprises a pharmaceutical composition, a nutraceutical composition, a food composition, or a combination thereof.
In another preferred embodiment, the composition comprises a safe and effective amount of (i) a hydroxide of iron; (ii) a low molecular sugar;
in another preferred embodiment, the composition is an oral preparation.
In another preferred embodiment, the composition is a formulation selected from the group consisting of: powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets.
In another preferred embodiment, the composition comprises a therapeutically effective amount of an iron salt, a carbohydrate, and an additive selected from the group consisting of: a flavoring agent, a preservative, a dispersant, a colorant, a flavorant, a capsule shell, a cosolvent, a disintegrant, a lubricant, a glidant, or a combination thereof.
In a third aspect, the present invention provides a method for preparing the phosphorous binder of the first aspect of the present invention, comprising the steps of:
(a) providing a low molecular weight sugar and a weak base;
(b) mixing the low molecular weight sugar and the weak base with iron hydroxide to obtain the phosphorus binder of the first aspect of the invention.
In another preferred embodiment, the iron hydroxide is prepared or prepared in situ.
In another preferred embodiment, the weak base is sodium citrate, potassium citrate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a mixture thereof.
In another preferred embodiment, the weak base comprises sodium citrate.
In another preferred embodiment, in the step (b), the mass ratio of the low molecular weight saccharide to the weak base is 1:0.01-1, preferably 1:0.1-0.5, more preferably 1: 0.2-0.3.
In another preferred embodiment, in the step (b), the mass ratio of the low molecular weight sugar to the hydroxide of iron is 1:0.2-4, preferably 1:0.5-1, more preferably 1: 0.6-0.7.
In another preferred example, in the step (b), the step (b1) is included: mixing the low molecular weight sugar, sodium citrate and alkali in water, adding iron salt and alkali to obtain a product, and separating and purifying to obtain the phosphorus binder of the first aspect of the invention.
In another preferred embodiment, the step (b1) has one or more of the following features:
(i) the temperature of the solution is 20-100 deg.C, preferably 60-95 deg.C, more preferably 80-90 deg.C;
(ii) the reaction time is 1-48h, preferably 1-24h, more preferably 4-16 h;
(iii) the cooling temperature is 0-40 ℃;
(iv) the pH is adjusted to 6-12, preferably 7-10.
In another preferred example, in the step (b1), the purification is performed with ethanol.
In another preferred embodiment, the ethanol contains 5-20% water.
In another preferred embodiment, the ethanol is absolute ethanol or 90-95% ethanol.
In another preferred embodiment, the ratio of ethanol to water (v/v) is 1: 0.05-1: 10.
In another preferred example, the step (b1) further comprises stirring and cooling steps.
In another preferred embodiment, in step (b1), the iron salt is selected from the group consisting of: a ferrous salt, a ferric salt, or a combination thereof.
In another preferred example, in step (b1), the iron salt is a trivalent iron salt selected from the group consisting of: ferric chloride, ferric nitrate, ferric sulfate, ferric citrate, or a combination thereof.
In another preferred embodiment, in step (b1), the base is selected from the group consisting of: from sodium hydroxide, potassium hydroxide, ammonia, or combinations thereof.
In another preferred embodiment, the mass ratio of the base to the low molecular weight sugar is 1:1 to 5, preferably 1:2 to 4.
In another preferred embodiment, the method further comprises a step (c) of isolating the product by drying to obtain the phosphorus binder in the form of a dry powder.
In another preferred embodiment, the drying comprises product air drying, heat drying, spray drying or fluidized spray drying.
In another preferred embodiment, the method further comprises a step (d) of formulating the phosphorus binder in dry powder form obtained in step (c).
In a fourth aspect, the present invention provides a composition comprising: a phosphorus binding agent according to the first aspect of the invention; and
a pharmaceutically acceptable carrier.
In another preferred embodiment, the composition comprises a pharmaceutical composition, a nutraceutical composition, a food composition, or a combination thereof.
In another preferred embodiment, the composition is an oral preparation.
In another preferred embodiment, the composition is a formulation selected from the group consisting of: powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets.
In another preferred embodiment, the composition comprises a therapeutically effective amount of an iron salt, a carbohydrate, and an additive selected from the group consisting of: a flavoring agent, a preservative, a dispersant, a colorant, a flavorant, a capsule shell, a cosolvent, a disintegrant, a lubricant, a glidant, or a combination thereof.
In another preferred embodiment, said phosphorus binder is contained in said composition in an amount of 0.1 to 99 wt.%, preferably 10 to 90 wt.%, based on the total weight of said composition.
In another preferred embodiment, the composition is in unit dosage form (tablet, capsule or vial), and the mass of the composition in each unit dosage form is 0.05-5g, preferably 0.5-2 g.
In a fifth aspect, the invention provides a method of inhibiting elevated blood phosphorus concentrations by administering to a subject in need thereof an effective amount of a phosphorus-binding agent according to the first aspect of the invention, or a composition according to the fourth aspect of the invention.
In another preferred embodiment, the subject comprises a human or non-human mammal.
In another preferred embodiment, the non-human mammal includes a rodent, such as a mouse, a rat.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors of the present invention have conducted extensive and intensive studies for a long time, and have unexpectedly found that a significant effect of reducing the blood phosphorus concentration can be obtained by mixing an iron salt and a low molecular weight sugar at a certain ratio in the presence of a sodium citrate catalyst. On this basis, the present inventors have completed the present invention.
Hydroxide of iron
The iron hydroxide of the present invention is not particularly limited, and one preferred iron hydroxide is iron hydroxide, iron oxyhydroxide, or iron oxide.
In the present invention, the mass ratio of iron in the phosphorus binder is not particularly limited, and a preferable mass ratio is 10 wt% to 45 wt%, preferably 20 wt% to 40 wt%; more preferably, from 25 wt% to 32 wt%.
Monosaccharide units
In the present invention, the low molecular weight saccharides each comprise on average 3 to 20 (preferably 3 to 10, more preferably 4 to 9, more preferably 4 to 7) monosaccharide units, and generally the size of the low molecular weight saccharides (i.e. the number of monosaccharide units) may be reduced by pretreatment (e.g. using acid and/or heat or an enzyme such as α -amylase), and the low molecular weight saccharides may be linear chains of (1 → 4) glycosidically linked monosaccharide units; or may be branched by forming a (1 → 6) glycosidic bond.
Low molecular sugar
In the present invention, the low molecular weight sugar means a low molecular weight sugar having a monosaccharide unit number of 3 to 20, preferably 3 to 10, more preferably 4 to 9, still more preferably 4 to 7, preferably a dietary fiber.
The low molecular weight saccharide of the present invention is not particularly limited, and a typical low molecular weight saccharide includes an oligosaccharide. Wherein the oligosaccharide is selected from the group consisting of: fructo-oligosaccharide, galacto-oligosaccharide, lacto-lactose, gluco-oligosaccharide, mannose-oligosaccharide, xylo-oligosaccharide, trehalose, lactosucrose, malto-oligosaccharide, isomalto-oligosaccharide, cyclodextrin, chitin oligosaccharide, soy oligosaccharide, gentio-oligosaccharide, agarose-oligosaccharide, stachyose, pectin-oligosaccharide, lactulose, raffinose, palatino oligosaccharide, or a combination thereof; the monosaccharide is selected from the group consisting of: glucose, xylose, arabinose, galactose, mannose, fructose, rhamnose, glucuronic acid, or a combination thereof, preferably xylose and arabinose.
Part of the low molecular weight sugar in the invention belongs to water-soluble dietary fiber, is not easy to be absorbed by human body, and can directly reach the large intestine. In the large intestine, the feed additive can be glycolyzed by probiotics in the field, is beneficial to the growth of the probiotics, can inhibit the growth of harmful bacteria such as salmonella and the like, reduces the generation and accumulation of carcinogens and harmful metabolites in the intestinal tract, really plays a role in clearing away intestinal garbage, and cannot interfere the iron metabolism in the body.
The phosphorus binder of the invention and the preparation thereof
In general, in order to obtain iron hydroxides with good phosphate binding capacity, which can be used as drugs, it is necessary to obtain stable iron-based compounds. It is known that iron hydroxides, especially ferric hydroxides, are very unstable and age over time, causing the initially randomly distributed molecules to recombine and form a roughly regular crystal lattice. Aging can also lead to iron release from iron-based phosphorus binders, and iron release from iron-containing drugs can cause safety concerns because excess iron is toxic to body organs. The daily iron intake of human body should not exceed 20mg, and due to inappropriate increase of iron absorption in intestinal tract, excessive iron is stored in parenchymal cells such as liver, heart and pancreas, and results in tissue organ degeneration and diffuse fibrosis, metabolism and dysfunction.
One typical class of phosphorus binders is the use of low molecular sugars and sodium citrate (catalyst) to prevent aging of iron hydroxides.
In the present invention, "the phosphorus binder of the present invention" includes iron hydroxide and low molecular weight sugar, and a weak base such as sodium citrate catalyzes the stable binding of the low molecular weight sugar and iron during the preparation process.
The low molecular sugar of the present invention is not particularly limited, and a typical low molecular sugar includes oligosaccharides. The low molecular sugar of the invention belongs to water-soluble dietary fiber, is not easy to be absorbed by human body, and can directly reach the large intestine. In the large intestine, the feed additive can be glycolyzed by probiotics in the field, is beneficial to the growth of the probiotics, can inhibit the growth of harmful bacteria such as salmonella and the like, reduces the generation and accumulation of carcinogens and harmful metabolites in the intestinal tract, really plays a role in clearing away intestinal garbage, and cannot interfere the iron metabolism in the body.
The iron hydroxide of the present invention is not particularly limited, and one preferred iron hydroxide is iron hydroxide, iron oxyhydroxide, or iron oxide.
In the present invention, the mass ratio of iron in the phosphorus binder is not particularly limited, and a preferable mass ratio is 2 to 45 wt%, preferably 10 to 35 wt%; more preferably, 25-33 wt%, based on the total weight of the phosphorus binder.
The phosphorus binding agent of the invention has high phosphorus binding capacity. In the present invention, the weight ratio of the hydroxide of iron to the low molecular sugar is 1:0.25 to 4, preferably 1:0.5 to 1, more preferably 1:0.6 to 0.7.
And when the mass ratio of the iron is 25-30%, the phosphorus binding agent has remarkably excellent phosphorus binding capacity (the phosphorus absorption amount is 200-300 mg/g).
The phosphorus binder of the present invention can be prepared by a conventional method, and in the present invention, the phosphorus binder of the present invention is prepared by the following method:
(a) providing low molecular sugar and sodium citrate;
(b) the low molecular sugar and sodium citrate are mixed with the hydroxide of iron to obtain the phosphorus binder of the first aspect of the invention.
In a preferred embodiment, the process further comprises a step (c) of isolating the product by drying to obtain the phosphorus binding agent in the form of a dry powder.
In a preferred embodiment, the method further comprises a step (d) of formulating the phosphorus binder in dry powder form obtained in step (c).
A preferred method for preparing a phosphorus binding agent comprises the steps of:
i, dissolving: dissolving sugar and weak base in water at 30-100 deg.C;
II, complexing: dropwise adding an iron salt aqueous solution into the solution at the temperature of 30-100 ℃, simultaneously dropwise adding an alkali solution to control the pH of the reaction solution, stopping dropwise adding after dropwise adding a certain amount of iron salt solution and alkali solution, and continuously stirring for 1-48h to obtain a product solution;
III, separation: cooling to room temperature, centrifuging or filtering to obtain reddish brown liquid, adding 1-5 times volume of ethanol, completely precipitating, centrifuging or filtering to separate, and washing with ethanol or diethyl ether;
IV, powder collection: drying and separating the product obtained in the step III;
v, preparation: and (4) preparing the powder obtained in the step (IV).
In the present invention, the iron salt is not particularly limited, and one preferable iron salt is iron chloride.
Composition and application thereof
The invention also provides a composition, preferably a pharmaceutical composition. The composition includes an effective amount of a phosphorus binding agent. In a preferred embodiment, the composition is a liquid preparation, a solid preparation or a semisolid preparation. In a preferred embodiment, the liquid formulation is selected from the group consisting of: solution preparations or suspension preparations.
In a preferred embodiment, the dosage form of the composition is selected from the group consisting of: powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, and sublingual tablets.
The pharmaceutical composition of the present invention may be administered in any form of pharmaceutical tablets, injections or capsules, which includes excipients, pharmaceutically acceptable vehicles and carriers, which may be selected according to the administration route. The pharmaceutical preparation of the present invention may further comprise auxiliary active ingredients.
Lactose, glucose, sucrose, sorbitol, mannose, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone (PVP), cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, or the like can be used as the carrier, excipient, diluent, or the like of the pharmaceutical composition of the present invention.
In addition, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, emulsifiers, suspension stabilizers, preservatives, sweeteners, flavors, and the like. The pharmaceutical compositions of the present invention may be manufactured in enteric-coated formulations by a variety of well-known methods so that the active ingredient of the pharmaceutical composition passes smoothly through the stomach without being destroyed by stomach acid.
The term "pharmaceutically effective amount" as used herein refers to an amount that is functional or active in humans and/or animals and is acceptable to humans and/or animals. For example, in the present invention, formulations containing 1% to 99% (specifically, 30% to 90%, more specifically, 50% to 80%) of the phosphorus binder may be prepared.
When used to prepare pharmaceutical compositions, the effective dose of the phosphorus-binding agent employed may vary with the mode of administration and the severity of the condition to be treated. Dosage forms suitable for oral administration comprise a phosphorus binder in an amount of about 1% to about 99% (specifically, 30% to about 90%, and more specifically, 50% to about 80%) intimately admixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the best therapeutic response. For example, divided doses may be administered several times per day, or the dose may be proportionally reduced, as may be required by the urgency of the condition being treated.
The phosphorus binding agent can be administered by oral administration or the like. The solid support comprises: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid carriers include: culture medium, polyethylene glycol, nonionic surfactant, and edible oil (such as corn oil, peanut oil, and sesame oil), as appropriate for the characteristics of the phosphorus-binding agent and the particular mode of administration desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, for example flavouring agents, colouring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
Preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules, from the standpoint of ease of preparation and administration. Oral administration is preferred.
The composition of the present invention is administered to the subject 1 or more times per day. Dosage units for administration represent dosages which can be divided formally and which are suitable for human beings or all other mammalian subjects. Each unit containing a pharmaceutically acceptable carrier and a therapeutically effective amount of a phosphorus binding agent of the invention. The amount administered will vary with the patient's blood phosphorus level, the supplemental active ingredient included, and the phosphorus binder used. Furthermore, the administration can be divided, if possible, and can be continued, if desired. Therefore, the amount to be administered is not a limitation of the present invention. Further, the "composition" in the present invention means not only a pharmaceutical but also a functional food and a health supplement food. In a preferred embodiment, the composition comprises: food, health product, medicine, etc. In a preferred embodiment of the present invention, there is also provided a food composition comprising an effective amount of a phosphorus binding agent, and the balance a food acceptable carrier, said food composition being in a form selected from the group consisting of a solid, a dairy product, a solution product, a powder product, and a suspension product.
In a preferred embodiment, the formulation of the composition is as follows:
0.1-90 wt% of a phosphorus binding agent; and a food-acceptable or pharmaceutically acceptable carrier, and/or an excipient.
In another preferred embodiment, the formulation of the composition is as follows:
10-80 wt% of a phosphorus binder; and a food-acceptable or pharmaceutically acceptable carrier, and/or an excipient.
The composition containing the phosphorus-binding agent of the present invention has significantly excellent phosphorus-binding ability, and thus can be used for the treatment and/or prevention of hyperphosphatemia in mammals. The mammal of the present invention may be a human or a warm-blooded animal, particularly a cat, a dog, or the like.
The main advantages of the invention include:
(1) the invention develops a phosphorus binding agent consisting of iron and low molecular weight sugar, and uses weak base such as sodium citrate to catalyze the reaction, so that the invention can obviously improve the iron binding capacity, the phosphorus absorption amount of unit iron and the like, and greatly reduce the dosage of patients.
(2) The low molecular weight sugar belongs to water-soluble dietary fiber, is not easy to be absorbed by human body, and can directly reach the large intestine. In the large intestine, the probiotic bacteria can be glycolyzed by the probiotics in the field, which is beneficial to the growth of the probiotic bacteria, can inhibit the growth of harmful bacteria such as salmonella and the like, reduce the generation and accumulation of carcinogens and harmful metabolites in the intestinal tract, really play a role in clearing away intestinal tract garbage, and can not interfere the iron metabolism in the body, thereby being beneficial to the diet control of patients with chronic renal insufficiency.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
The general method comprises the following steps:
the method for testing the absorption capacity of the phosphoric acid comprises the following steps: preparing a phosphoric acid solution with the concentration of 2 mu g/mL, adjusting the pH to 3.0 by using sodium hydroxide hydrochloride, and sampling to obtain a standard solution Control A. And adding 100 +/-5 mg (marked as B) of the prepared phosphorus binding agent into 25mL of Control A, and reacting for 24h at 37 ℃ under low-speed stirring. After 24 hours, the reaction mixture was centrifuged (14000rpm), and the supernatant was collected to obtain C. The concentrations of a and C were measured separately using an ultraviolet spectrophotometer. The phosphate binding capacity is calculated according to the following formula:
the adsorption activity (mg/g) is defined as the Phosphate (PO) adsorbed per gram of API4 3-) Mass of
The iron content was measured with an ICP inductively coupled plasma emission spectrometer.
The molecular weight was determined by GFC gel filtration chromatography.
Example 1
The experimental method comprises the following steps:
dissolving 20g of galacto-oligosaccharide in 200g of water, adding 4g of sodium citrate, raising the temperature to 80 ℃, and stirring until the galacto-oligosaccharide is fully dissolved; dropwise adding 250g of 20% by mass of ferric chloride hexahydrate aqueous solution into the solution at the temperature of 80 ℃, simultaneously dropwise adding 20% by mass of NaOH aqueous solution to control the pH of the reaction solution to be 7.5-8.5, and stirring for 4 hours at the temperature of 90 ℃ after dropwise adding is finished to obtain a reddish brown solution; cooling to room temperature, adding 95% ethanol with 3 times volume, completely precipitating, centrifuging, and washing the solid with 80% ethanol twice; the obtained product is heated and dried, and 28.6g of product is obtained in total, and the product is dark black brown.
The experimental results are as follows:
after the product was ground and pulverized, it was found that the iron content was 32.4% and the phosphorus absorption was 271.9 mg/g.
Example 2
The experimental method comprises the following steps:
dissolving 300g of fructo-oligosaccharide in 2000g of water, adding 40g of sodium citrate and 20g of sodium carbonate, raising the temperature to 90 ℃, and stirring until the fructo-oligosaccharide is fully dissolved; dropping 2500g of 30 mass percent ferric chloride hexahydrate aqueous solution into the solution at the temperature of 90 ℃, simultaneously dropping 20 mass percent NaOH aqueous solution to control the pH of the reaction solution to be 7.0-8.5, and stirring for 8 hours at the temperature of 90 ℃ after dropping is finished to obtain a reddish brown suspension; cooling to room temperature, adding 95% ethanol with 4 times volume, completely precipitating, centrifuging, and washing the solid with 80% ethanol twice; the obtained product is heated and dried, and 402.4g of product is obtained in total, and the product is black brown.
The experimental results are as follows:
after the product was ground and pulverized, it was found that the iron content was 32.4% and the phosphorus absorption was 342.1 mg/g.
Comparative example 1
The experimental method comprises the following steps:
dissolving 200g of arabinose in 2000g of water, adding 40g of sodium citrate, raising the temperature to 90 ℃, and stirring until the arabinose is fully dissolved; dropping 2500g of 30 mass percent ferric chloride hexahydrate aqueous solution into the solution at the temperature of 90 ℃, simultaneously dropping 20 mass percent NaOH aqueous solution to control the pH of the reaction solution to be 8.0-9.0, and stirring for 4 hours at the temperature of 90 ℃ after dropping is finished to obtain a reddish brown suspension; cooling to room temperature, adding 95% ethanol with 4 times volume, completely precipitating, centrifuging, and washing the solid twice with 70% ethanol and 80% ethanol respectively; the obtained product was dried by heating to obtain 372.4g of product in total, which was dark black brown.
The experimental results are as follows:
after the product was ground and pulverized, the iron content was found to be 31.2% and the phosphorus absorption was found to be 195.6 mg/g.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (19)
1. A phosphorus binding agent, comprising:
a hydroxide of iron; and
low molecular weight sugars;
wherein the number of monosaccharide units of the low molecular weight sugar is 3-10, the mass ratio of iron is 25-33 wt% based on the total weight of the phosphorus binding agent, and the low molecular weight sugar is oligosaccharide;
and the phosphorus binder is prepared by the following method:
(a) providing a low molecular weight sugar and a weak base;
(b) mixing the low molecular weight sugar with the weak base and the hydroxide of iron to obtain the phosphorus binder, wherein the weak base is sodium citrate, potassium citrate or the mixture of the sodium citrate and the potassium citrate;
the oligosaccharide is selected from the group consisting of: fructooligosaccharides, galactooligosaccharides, or combinations thereof;
the hydroxide of iron is selected from the group consisting of: ferric hydroxide;
in the step (b), the mass ratio of the low molecular weight sugar to the weak base is 1: 0.01-1;
in step (b), comprising step (b 1): mixing the low molecular weight sugar, sodium citrate and alkali obtained in the step (a) in water, adding iron salt and alkali to obtain a product, and separating and purifying to obtain the phosphorus binding agent; the ferric salt is ferric salt and is ferric chloride.
2. The phosphorus binding agent of claim 1, wherein the low molecular weight saccharide has a number of monosaccharide units ranging from 4 to 9.
3. The phosphorus binding agent of claim 2, wherein the low molecular weight saccharide has a number of monosaccharide units ranging from 4 to 7.
4. The phosphorus binding agent of claim 1, wherein the weight ratio of the iron hydroxide to the low molecular weight sugar is 1: 0.6-0.7.
5. The phosphorus binder of claim 1, wherein the hydroxide of iron forms a stable structure with the low molecular weight sugar through hydrogen bonding or adsorption.
6. The phosphorus-binding agent of claim 1, wherein the residual amount of citrate in the phosphorus-binding agent is < 1%.
7. The phosphorus-binding agent of claim 6, wherein the residual amount of citrate in the phosphorus-binding agent is < 0.5%.
8. The phosphorus-binding agent of claim 7, wherein the residual amount of citrate in the phosphorus-binding agent is < 0.1%.
9. The use of the phosphorus-binding agent of claim 1, in the preparation of a composition for inhibiting elevation of blood phosphorus concentration.
10. The use of claim 9, wherein the composition is further used for (i) enhancing immunity; and/or (ii) treating or preventing hyperphosphatemia, hyperparathyroidism, calcium phosphorus product changes, vitamin D metabolic disorders, renal bone disease, and cardiovascular complications related diseases.
11. The phosphorus binding agent of claim 1, wherein in step (b), the mass ratio of the low molecular weight sugar to the weak base is from 1:0.1 to 0.5.
12. The phosphorus binding agent of claim 11, wherein in step (b), the mass ratio of the low molecular weight sugar to the weak base is from 1:0.2 to 0.3.
13. The phosphorus binder of claim 1, wherein in step (b), the mass ratio of the low molecular weight sugar to the iron hydroxide is from 1:0.2 to 4.
14. The phosphorus binder of claim 13, wherein in step (b), the mass ratio of the low molecular weight sugar to the iron hydroxide is from 1:0.5 to 1.
15. The phosphorus binder of claim 14, wherein in step (b), the mass ratio of the low molecular weight sugar to the iron hydroxide is from 1:0.6 to 0.7.
16. The phosphorus-binding agent of claim 1, wherein the process further comprises a step (c) of isolating the product by drying to obtain the phosphorus-binding agent in a dry powder form.
17. A composition, comprising: the phosphorus binding agent of claim 1; and
a pharmaceutically acceptable carrier.
18. The composition of claim 17, wherein said phosphorus binding agent is present in said composition in an amount of from 0.1 to 99 weight percent, based on the total weight of said composition.
19. The composition of claim 18, wherein the phosphorus-binding agent is present in an amount of 10 to 90 wt.%, based on the total weight of the composition.
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