CN107397760A - Phosphate binder, its preparation method and its application of hydroxide-low molecular weight sugar based on iron - Google Patents

Phosphate binder, its preparation method and its application of hydroxide-low molecular weight sugar based on iron Download PDF

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Publication number
CN107397760A
CN107397760A CN201610341394.6A CN201610341394A CN107397760A CN 107397760 A CN107397760 A CN 107397760A CN 201610341394 A CN201610341394 A CN 201610341394A CN 107397760 A CN107397760 A CN 107397760A
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phosphate binder
iron
molecular weight
low molecular
hydroxide
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CN107397760B (en
Inventor
梁星
崔洋洋
许婧
陆佳美
包丽霞
刘荣军
袁西伦
肖飞
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XINKAI MEDICAL CHEMICAL INTERMEDIATE (SHANGHAI) CO Ltd
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XINKAI MEDICAL CHEMICAL INTERMEDIATE (SHANGHAI) CO Ltd
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Priority to CN201610341394.6A priority Critical patent/CN107397760B/en
Priority to PCT/CN2017/084944 priority patent/WO2017198199A1/en
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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
    • 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

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  • Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

The invention provides phosphate binder, its preparation method and its application of hydroxide-low molecular weight sugar based on iron, specifically, the invention provides a kind of phosphate binder, hydroxide and low molecular weight sugar including iron, wherein, the monosaccharide unit number of the low molecular weight sugar is 3 20, and with total restatement of the phosphate binder, the mass ratio of iron is 2-45wt%.Experiment shows that the phosphate binder has the effect for being significantly reduced serium inorganic phosphorus concentration, thus is with a wide range of applications.

Description

Phosphate binder, its preparation method and its application of hydroxide-low molecular weight sugar based on iron
Technical field
The present invention relates to a kind of phosphate binder, in particular it relates to a kind of phosphorus based on molysite-low molecular weight sugar Bonding agent, its preparation method and its application.
Background technology
Hyperphosphatemia is one of major complications of chronic renal insufficiency (CKD), serium inorganic phosphorus concentration increase with CKD mortalities are closely related, and serium inorganic phosphorus concentration increases renal function can be caused further to fail, be secondary Property thyroid function resists into, angiosteosis and mineral matter, bone metabolism disturbance.Modern times generally believe regulation phosphorus generation It is the key for reducing cardiovascular complication, improving dialysis patient quality of life, reducing disability rate and the death rate to thank.
Constantly there is new phosphate binder to come out in recent years.Wherein, iron content phosphate binder is proved to be a kind of high Imitate phosphate binder, and heterotopic calcification will not be caused and can improve thyroid function resist into.Meanwhile have Help correct CKD anemia states, and internal iron metabolism is not influenceed significantly.
Due to containing substantial amounts of phosphorus in the daily diet of patient, and the phosphorus adsorption capacity mistake of existing phosphate binder It is low, therefore in order to control serium inorganic phosphorus concentration normal horizontal to one, patient needs to use substantial amounts of phosphoric acid daily Bonding agent, and excessive use can bring other side effects to patient.
Therefore, this area can increase substantially phosphorus adsorption capacity there is an urgent need to develop one kind, reduce side effect Phosphate binder.
The content of the invention
It is an object of the invention to provide one kind can increase substantially phosphorus adsorption capacity, reduce the phosphorus knot of side effect Mixture.
First aspect present invention provides a kind of phosphate binder, including：
The hydroxide of iron；With
Low molecular weight sugar；
Wherein, the monosaccharide unit number of the low molecular weight sugar is 3-20, and with total restatement of the phosphate binder, The mass ratio of iron is 2-45wt%.
In another preference, the mass ratio of the iron is 10-35wt%, it is preferred that 25-33wt%, with institute State the total restatement of phosphate binder.
In another preference, the monosaccharide unit number of the low molecular weight sugar is 3-10, it is preferred that 4-9, more preferably Ground, 4-7.
In another preference, shown low molecular weight sugar includes oligosaccharide.
In another preference, the oligosaccharide is selected from the group：FOS, galactooligosaccharide, oligomeric lactose, Glucose oligosaccharide, Oligomeric manna sugar, xylo-oligosaccharide, trehalose, lactosucrose, oligomeric maltose, different malt are oligomeric It is sugar, cyclodextrin, chitin oligosaccharide, soyabean oligosaccharides, oligomeric dragon gallbladder sugar, oligomeric agarose, stachyose, oligomeric Pectin, lactulose, gossypose, para gold oligosaccharide or its combination.
In another preference, the weight ratio of the hydroxide of the iron and the low molecular weight sugar is 1:0.25-4, It is preferred that 1:0.5-1, more preferably, 1:0.6-0.7.
In another preference, the hydroxide of the iron is selected from the group：Iron hydroxide, FeOOH, The oxide of iron or its combination.
In another preference, the hydroxide of the iron passes through hydrogen bond or suction-operated and the low molecule amount Sugar forms stable structure.
In another preference, the residual quantity ＜ 1% of citrate in the phosphate binder, it is preferred that ＜ 0.5%, more preferably, ＜ 0.1%.
Second aspect of the present invention provides the purposes of phosphate binder described in first aspect present invention, presses down for preparing The elevated composition of serium inorganic phosphorus concentration processed.
In another preference, the composition is additionally operable to (i) and improves immunity of organisms；And/or (ii) Treatment or prevention hyperphosphatemia, hyperparathyroidism, calcium-phosphorus product change, vitamin D metabolism barrier Hinder, the disease that renal osteodystrophy and cardiovascular complication are related.
In another preference, the composition include pharmaceutical composition, health composition, food compositions, Or its combination.
In another preference, the composition includes the hydroxide of (i) iron of safe and effective amount；(ii) Low molecular sugar；
In another preference, described composition is oral formulations.
In another preference, described composition is the preparation being selected from the group：Last agent, powder, tablet, Sugar-coat agent, capsule, granule, suspending agent, solution, syrup, drops, sublingual lozenge.
In another preference, described composition contain the molysite of therapeutically effective amount, carbohydrate, with And the additive being selected from the group：Flavouring, preservative, dispersant, colouring agent, spices, capsule shells, help Solvent, disintegrant, lubricant, glidant, or its combination.
Third aspect present invention provides the preparation method of phosphate binder described in first aspect present invention, including step：
(a) low molecular weight sugar and weak base are provided；
(b) low molecular weight sugar and the weak base are mixed with the hydroxide of iron, obtains the present invention the Phosphate binder described in one side.
In another preference, the hydroxide of the iron has been prepared or now matched somebody with somebody.
In another preference, the weak base is sodium citrate, potassium citrate, sodium carbonate, potassium carbonate, carbon Sour hydrogen sodium, saleratus or their mixture.
In another preference, the weak base includes sodium citrate.
In another preference, in the step (b), the quality of the low molecular weight sugar and the weak base Than for 1:0.01-1, it is preferred that 1:0.1-0.5, more preferably, 1:0.2-0.3.
In another preference, in the step (b), the hydroxide of the low molecular weight sugar and the iron The mass ratio of thing is 1:0.2-4, it is preferred that 1:0.5-1, more preferably, 1:0.6-0.7.
In another preference, in step (b), including step (b1)：By low point of step (a) Son amount sugar, sodium citrate and alkali mix in water, add molysite and alkali, obtain product, isolate and purify, obtain Phosphate binder described in first aspect present invention.
In another preference, the step (b1) has one or more following characteristics：
(i) solution temperature is 20-100 DEG C, it is preferred that 60-95 DEG C, more preferably, 80-90 DEG C；
(ii) reaction time is 1-48h, it is preferred that 1-24h, more preferably, 4-16h；
(iii) chilling temperature is 0-40 DEG C；
(iv) pH is adjusted to 6-12, it is preferred that 7-10.
In another preference, in the step (b1), purified with ethanol.
In another preference, the ethanol contains 5-20% water.
In another preference, the ethanol is absolute ethyl alcohol or 90-95% ethanol.
In another preference, the ethanol is 1 with water (v/v):0.05-1:10.
In another preference, the step (b1) also includes stirring and cooling step.
In another preference, in step (b1), the molysite is selected from the group：Divalent iron salt, trivalent Molysite or its combination.
In another preference, in step (b1), the molysite is trivalent iron salt, is selected from the group：Chlorine Change iron, ferric nitrate, ferric sulfate, ironic citrate or its combination.
In another preference, in step (b1), the alkali is selected from the group：From sodium hydroxide, hydrogen-oxygen Change potassium, ammoniacal liquor or its combination.
In another preference, the mass ratio of the alkali and low molecular weight sugar is 1:1-5, preferably 1:2-4.
In another preference, methods described also includes step (c), by drying separation product, with To the phosphate binder of dry powder form.
In another preference, the drying is dried including product, heating, drying, spray drying or fluidisation spray Mist is dried.
In another preference, methods described also includes step (d), step (c) is obtained described dry The phosphate binder of powder form carries out preparation.
Fourth aspect present invention provides a kind of composition, including：Phosphorus described in first aspect present invention combines Agent；With
Pharmaceutically acceptable carrier.
In another preference, the composition include pharmaceutical composition, health composition, food compositions, Or its combination.
In another preference, described composition is oral formulations.
In another preference, described composition is the preparation being selected from the group：Last agent, powder, tablet, Sugar-coat agent, capsule, granule, suspending agent, solution, syrup, drops, sublingual lozenge.
In another preference, described composition contain the molysite of therapeutically effective amount, carbohydrate, with And the additive being selected from the group：Flavouring, preservative, dispersant, colouring agent, spices, capsule shells, help Solvent, disintegrant, lubricant, glidant, or its combination.
In another preference, in the composition, containing 0.1-99wt%, preferably 10-90wt% Described phosphate binder, with the gross weight meter of the composition.
In another preference, described composition is unit dosage form (an a piece of, capsule or a bottle), often The quality of composition described in individual unit dosage form is 0.05-5g, preferably 0.5-2g.
Fifth aspect present invention provides a kind of suppression elevated method of serium inorganic phosphorus concentration, has to suppressing object administration Phosphate binder described in the first aspect present invention of effect amount, or the composition described in fourth aspect present invention.
In another preference, the object includes people or non-human mammal.
In another preference, the non-human mammal includes rodent, such as mouse, rat.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and below (such as implementation Example) in specifically describe each technical characteristic between can be combined with each other, so as to form new or preferable skill Art scheme.As space is limited, no longer tire out one by one herein and state.
Embodiment
The present inventor's in-depth study by long-term, it has unexpectedly been found that, will using sodium citrate as catalyst Molysite, low molecular weight sugar are mixed with certain proportion, and tool is significantly reduced the effect of serium inorganic phosphorus concentration. On this basis, the present inventor completes the present invention.
The hydroxide of iron
The hydroxide of the iron of the present invention is not particularly limited, and a kind of hydroxide of preferable iron is hydroxide Iron, FeOOH, the oxide of iron.
In the present invention, in phosphate binder, the mass ratio of iron is not particularly limited, a kind of preferable mass ratio For 10wt%-45wt%, it is preferred that 20wt%-40wt%；More preferably, 25wt%-32wt%.
Monosaccharide unit
In the present invention, each low molecular weight sugar averagely include 3-20 (it is preferred that 3-10, more preferably, 4-9, more preferably, 4-7) monosaccharide unit, the size (i.e. monosaccharide unit number) of usual low molecular weight sugar can pass through Pretreatment (for example, using acid and/or heating or enzyme, such as alpha-amylase) and reduces, and low molecular weight sugar can be with It is with the straight chain of the monosaccharide unit of (1 → 4) glucosides key connection；Or can be by forming (1 → 6) glycosidic bond and branched.
Low molecular sugar
In the present invention, it is 3-20 that the low molecular weight sugar, which refers to monosaccharide unit number, it is preferred that 3-10, more preferably, 4-9, more preferably, 4-7, preferably dietary fiber low molecular weight sugar.
The low molecular weight sugar of the present invention has no particular limits, and a kind of typical low molecular weight sugar includes oligosaccharide. Wherein, the oligosaccharide is selected from the group：It is FOS, galactooligosaccharide, oligomeric lactose, glucose oligosaccharide, low Poly- mannose, xylo-oligosaccharide, trehalose, lactosucrose, oligomeric maltose, isomalto-oligosaccharide, cyclodextrin, shell Matter oligosaccharide, soyabean oligosaccharides, oligomeric dragon gallbladder sugar, oligomeric agarose, stachyose, pecticoligosaccharide, lactulose, Gossypose, para gold oligosaccharide or its combination；The monose is selected from the group：Glucose, xylose, Arab Sugar, galactolipin, mannose, fructose, rhamnose, glucuronic acid or its combination, preferably xylose and Ah Draw uncle's sugar.
Part low molecular weight sugar in the present invention, belongs to water-soluble dietary fiber, is not easy to be absorbed by the body, energy Through large intestine.In big enteral, the growth of probiotics can be advantageous to, while can press down by probiotics glycolysis in field The growth of the harmful bacterias such as salmonella processed, reduce the generation of carcinogen and Toxic Metabolites and product in enteron aisle It is tired, really play a part of removing enteron aisle rubbish, and will not be to the iron metabolism in interfering bodies.
The phosphate binder of the present invention and its preparation
Generally, in order to obtain the hydroxide for the iron with good phosphate binding capacity that can be used as medicine Thing is, it is necessary to obtain the stable compound based on iron.The hydroxide of known iron, especially ferric hydrogen Oxide is very unstable, and aging can occur with the time, cause the molecule of initial random distribution to reconfigure, and Form substantially regular array of crystal lattice.Aging may also lead to the phosphate binder release iron based on iron, from iron content medicine Release iron may cause the worry to security in thing, because excessive iron is poisonous to organ. The iron that human body daily intakes should be no more than 20mg, due to the inappropriate increase that enteron aisle iron absorbs, cause excessive Iron be stored in the substantial cellulars such as liver, heart and pancreas, cause histoorgan retrogression and diffuse Property fibrosis, metabolism and malfunction.
A kind of typical phosphate binder is to prevent the hydrogen-oxygen of iron with low molecular sugar and sodium citrate (catalyst) The aging of compound.
In the present invention, " phosphate binder of the invention " includes the hydroxide and low molecular weight sugar of iron, prepares During, weak base such as sodium citrate plays the catalytic action for the stable bond for making low molecular weight sugar and iron.
The low molecular sugar of the present invention has no particular limits, and a kind of typical low molecular sugar includes oligosaccharide.This hair Bright low molecular sugar, belongs to water-soluble dietary fiber, is not easy to be absorbed by the body, and can go directly large intestine.In large intestine It is interior, the growth of probiotics can be advantageous to by probiotics glycolysis in field, while it is harmful to suppress salmonella etc. The growth of bacterium, the generation and accumulation of carcinogen and Toxic Metabolites in enteron aisle are reduced, really plays removing intestines The effect of road rubbish, and will not be to the iron metabolism in interfering bodies.
The hydroxide of the iron of the present invention is not particularly limited, and a kind of hydroxide of preferable iron is hydroxide Iron, FeOOH, the oxide of iron.
In the present invention, in phosphate binder, the mass ratio of iron is not particularly limited, a kind of preferable mass ratio For 2-45wt%, it is preferred that 10-35wt%；More preferably, 25-33wt%, with total restatement of phosphate binder.
The phosphate binder of the present invention has very high phosphorus binding ability.In the present invention, the hydroxide of the iron Weight ratio with low molecular sugar is 1:0.25-4, it is preferred that 1:0.5-1, more preferably, 1:0.6-0.7.
And the mass ratio of iron, when being 25-30%, phosphate binder of the invention has significantly excellent phosphorus binding ability, and (phosphorus is inhaled Receipts amount is 200-300mg/g).
The phosphate binder of the present invention can be prepared with conventional method, and in the present invention, phosphate binder of the invention is used It is prepared by following method：
(a) low molecular sugar and sodium citrate are provided；
(b) low molecular sugar and sodium citrate are mixed with the hydroxide of iron, obtains the present invention first Phosphate binder described in aspect.
In a preferred embodiment, methods described also includes step (c), by drying separation product, To obtain the phosphate binder of dry powder form.
In a preferred embodiment, methods described also includes step (d), and step (c) is obtained The phosphate binder of the dry powder form carries out preparation.
A kind of preparation method of preferable phosphate binder includes the following steps：
I dissolving：Sugar is soluble in water with weak base, and solution temperature is 30-100 DEG C；
II complexing：The aqueous solution of molysite is added dropwise into solution at a temperature of 30-100 DEG C, while alkali soluble is added dropwise The pH of hydraulic control reaction solution, after a certain amount of iron salt solutions and aqueous slkali are added dropwise, stop being added dropwise, and continue to stir 1-48h is mixed, obtains reaction mixture；
III separation：After being cooled to room temperature, centrifuge or be separated by filtration and take rufous liquid, add 1-5 times of body Long-pending ethanol, centrifuge or be separated by filtration after separating out precipitation completely, and cleaned with ethanol or ether；
IV receives powder：Dry the product obtained by separating step III；
V preparation：The powder that step IV is obtained carries out preparation.
In the present invention, molysite is not particularly limited, and a kind of preferable molysite is iron chloride.
Composition and its application
Present invention also offers a kind of composition, it is preferable that is pharmaceutical composition.The composition includes The phosphate binder of effect amount.In a preference, described composition is liquid formulation, solid formulation, partly consolidated State preparation.In a preference, described liquid formulation is selected from the group：Solution product or suspension product.
In a preference, the formulation of described composition is selected from the group：Powder agent, powder, tablet, sugar Clothing agent, capsule, granule, suspending agent, solution, syrup, drops and sublingual lozenge.
Pharmaceutical composition of the present invention can be described with medicinal tablet, any form administration of injection or capsule The medium and carrier that pharmaceutical preparation includes excipient, medicine allows, these materials can be carried out according to method of administration Selection.Pharmaceutical formulations of the present invention can further include the active constituent of auxiliary.
Lactose, glucose, sucrose, D-sorbite, mannose, starch, Arabic gum, calcium phosphate, algae Hydrochlorate, gelatin, calcium silicates, fine crystallization cellulose, polyvinylpyrrolidone (PVP), cellulose, water, Syrup, methylcellulose, methyl hydroxybenzoate, nipasol, talcum, magnesium stearate or ore deposit Thing oil etc. is used as the carrier of pharmaceutical composition, excipient or diluent etc. in the present invention.
In addition, the pharmaceutical composition of the present invention can further comprise lubricant, wetting agent, emulsifying agent, suspension Liquid stabilizer, preservative, sweetener and spices etc..The pharmaceutical composition of the present invention can be by a variety of known Method is produced with enteric-coated preparations, in order to which the active component of pharmaceutical composition can pass through stomach without by hydrochloric acid in gastric juice Destroyed.
In specification " medicine effective quantity " refer to that people and/or animal can be produced function or activity and can quilt The amount that people and/or animal are received.For example in the present invention, can prepare (particularly, can containing 1%-99% Contain 30% -90%；More particularly, contain 50% -80%) phosphate binder preparation.
When for preparing pharmaceutical composition, the effective dose of phosphate binder used can with administration pattern and treat The order of severity of the disease for the treatment of and change.Suitable for dosage form for oral administration, comprising with solid-state or liquid pharmacy Upper acceptable carrier is intimately mixed about (particularly, can to contain 30% -90% containing 1%-99%；Particularly Ground, contain 50% -80%) phosphate binder.This dosage be can adjust to provide optimal treatment response.Example Such as, by an urgent demand for the treatment of situation, dosage separated several times can be given daily, or by dosage pari passu Reduce.
Described phosphate binder can be given by the approach such as oral.Solid-state carrier includes：Starch, lactose, phosphorus Sour dicalcium, microcrystalline cellulose, sucrose and white bole, and liquid carrier includes：It is culture medium, polyethylene glycol, non- Ionic surfactant and edible oil (such as corn oil, peanut oil and sesame oil), as long as being adapted to phosphate binder special Property and required specific administration mode.Also can advantageously it be wrapped preparing adjuvant usually used in pharmaceutical composition Include, such as flavor enhancement, pigment, preservative and antioxidant such as vitamin E, vitamin C, BHT and BHA.
In terms of easily prepared and administration position, preferable pharmaceutical composition is solid-state composition, especially tablet The capsule filled with solid-filling or liquid.Oral administration is preferable.
The present composition is administered to the individual, is administered once daily or repeatedly.Dosage unit table Show that it can be separated and suitable for the mankind or the dosage of other all mammalian subjects in form.Per unit contains There are the carrier of medicine permission and the phosphate binder of the invention of effective therapeutic dose.Dosage with patient serium inorganic phosphorus water Flat, included supplement active constituent and used phosphate binder and change.In addition it is such as possible, it can separate Administration, and if desired for can successive administration.Therefore, the dosage will not cause to limit to the present invention.This Outside, " composition " in the present invention does not mean only that medicine and expression can be used as functional food and health Supplement.In a preference, the composition includes：Food, health products, medicine etc..At this In one preference of invention, a kind of food compositions are additionally provided, it contains the phosphate binder of effective dose, with And acceptable carrier on the food of surplus, the formulation of described food composition are selected from solid, dairy products, molten Liquid product, pulverulent product or suspension product.
In a preference, the formula of the composition is as follows：
0.1-90wt% phosphate binder；And on food or pharmaceutically acceptable carrier, and/or excipient.
In another preference, the formula of the composition is as follows：
10-80wt% phosphate binder；And on food or pharmaceutically acceptable carrier, and/or excipient.
The composition containing phosphate binder of the present invention has significantly excellent phosphorus binding ability, therefore can use Come the hyperphosphatemia treated and/or prevent mammal.The mammal of the present invention can refer to people, can also Refer to warm-blooded animal, especially cat, dog etc..
Main advantages of the present invention include：
(1) present invention develops a kind of by iron and the phosphate binder of low molecular weight sugar, has used sodium citrate Deng weak base catalytic reaction, the present invention can significantly improve it and combine the ability of iron, phosphorus uptake of unit iron etc. Deng the taking dose for reducing patient of high degree.
(2) low molecular weight sugar of the present invention belongs to water-soluble dietary fiber, is not easy to be absorbed by the body, Can through large intestine.In big enteral, the growth of probiotics, while energy can be advantageous to by probiotics glycolysis in field Suppress the growth of the harmful bacterias such as salmonella, reduce the generation of carcinogen and Toxic Metabolites and product in enteron aisle It is tired, really play a part of removing enteron aisle rubbish, and iron metabolism in interfering bodies will not be advantageous to slow The diet control of property potential renal insufficiency patient.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate The present invention rather than limitation the scope of the present invention.The experiment side of unreceipted actual conditions in the following example Method, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise Percentage and number are calculated by weight.
Universal method：
Phosphoric acid absorbability method of testing is：Configuration concentration is 2 μ g/mL phosphoric acid solution, with hydrochloric acid hydrogen-oxygen It is 3.0 to change sodium regulation pH, and samples and be set to standard liquid Control A.Control A 25mL are taken to add system 100 ± the 5mg of phosphate binder (being designated as B) got ready, 24h is reacted at 37 DEG C under stirring at low speed.After 24 hours, Reaction solution is centrifuged into (14000rpm), takes supernatant liquor, its concentration is C.Use ultraviolet spectrometry light Degree meter determines A and C concentration respectively.Phosphate binding capacity clicks formula calculating：
Adsorption activity (mg/g) is defined as every gram of adsorbable phosphate radical (PO of API institutes4 3-) quality
Iron content is determined with ICP inductive coupling plasma emission spectrographs.
The measure of molecular weight is determined with GFC gel filtration chromatographies.
Embodiment 1
Experimental method：
20g galactooligosaccharides are dissolved in 200g water, add 4g sodium citrates, rise temperature is 80 DEG C, stir to abundant dissolving；The ferric chloride hexahydrate of 20% mass ratio is added dropwise into solution at a temperature of 80 DEG C Aqueous solution 250g, while it is 7.5-8.5 that the NaOH aqueous solution that 20% mass ratio is added dropwise, which controls the pH of reaction solution, 4h is stirred at 90 DEG C after being added dropwise, obtains red tan solution；After being cooled to room temperature, 3 times of bodies are added 95% long-pending ethanol, centrifuged after separating out precipitation completely, and solid is washed twice with 80% ethanol；Gained Product heat drying, receives to obtain 28.6g products altogether, and product is in pitch black brown.
Experimental result：
After product is ground, it is 32.4% to measure iron content, and phosphorus is absorbed as 271.9mg/g.
Embodiment 2
Experimental method：
300g FOSs are dissolved in 2000g water, add 40g sodium citrates and 20g sodium carbonate, It is 90 DEG C to raise temperature, is stirred to abundant dissolving；30% mass ratio is added dropwise into solution at a temperature of 90 DEG C Ferric chloride hexahydrate aqueous solution 2500g, while the NaOH aqueous solution control reaction solution of 20% mass ratio is added dropwise PH is 7.0-8.5, and 8h is stirred at 90 DEG C after being added dropwise, and obtains rufous suspension；It is cooled to room Wen Hou, 95% ethanol of 4 times of volumes is added, is centrifuged after separating out precipitation completely, and washed with 80% ethanol Wash solid twice；Products obtained therefrom heat drying, receives to obtain 402.4g products altogether, and product is in dark brown.
Experimental result：
After product is ground, it is 32.4% to measure iron content, and phosphorus is absorbed as 342.1mg/g.
Comparative example 1
Experimental method：
200g arabinoses are dissolved in 2000g water, add 40g sodium citrates, rise temperature is 90 DEG C, stir to abundant dissolving；The ferric chloride hexahydrate of 30% mass ratio is added dropwise into solution at a temperature of 90 DEG C Aqueous solution 2500g, while it is 8.0-9.0 that the NaOH aqueous solution that 20% mass ratio is added dropwise, which controls the pH of reaction solution, 4h is stirred at 90 DEG C after being added dropwise, obtains rufous suspension；After being cooled to room temperature, 4 times are added 95% ethanol of volume, centrifuge after separating out precipitation completely, and washed respectively with 70% ethanol and 80% ethanol Wash solid twice；Products obtained therefrom heat drying, receives to obtain 372.4g products altogether, and product is in pitch black brown.
Experimental result：
After product is ground, it is 31.2% to measure iron content, and phosphorus is absorbed as 195.6mg/g.
All it is incorporated as referring in this application in all documents that the present invention refers to, just as each document It is individually recited as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, Those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within this Shen Please appended claims limited range.

Claims (10)

  1. A kind of 1. phosphate binder, it is characterised in that including：
    The hydroxide of iron；With
    Low molecular weight sugar；
    Wherein, the monosaccharide unit number of the low molecular weight sugar is 3-20, and with total restatement of the phosphate binder, The mass ratio of iron is 2-45wt%.
  2. 2. phosphate binder as claimed in claim 1, it is characterised in that the low molecular weight sugar includes oligosaccharide.
  3. 3. phosphate binder as claimed in claim 1, it is characterised in that the hydroxide of the iron with it is described low The weight ratio of molecular weight sugar is 1:0.25-4, it is preferred that 1:0.5-1, more preferably, 1:0.6-0.7.
  4. 4. the purposes of phosphate binder as claimed in claim 1, it is characterised in that suppress serium inorganic phosphorus for preparing The elevated composition of concentration.
  5. 5. the preparation method of phosphate binder as claimed in claim 1, it is characterised in that including step：
    (a) low molecular weight sugar and weak base are provided；
    (b) low molecular weight sugar and the weak base, the hydroxide of iron are mixed, obtains claim 1 Described phosphate binder.
  6. 6. preparation method as claimed in claim 5, it is characterised in that in the step (b), described low point Son amount is sugared and the mass ratio of the weak base is 1:0.01-1, it is preferred that 1:0.1-0.5, more preferably, 1:0.2-0.3。
  7. 7. preparation method as claimed in claim 5, it is characterised in that in the step (b), described low point Son amount is sugared and the mass ratio of the hydroxide of the iron is 1:0.2-4, it is preferred that 1:0.5-1, more preferably, 1:0.6-0.7。
  8. 8. preparation method as claimed in claim 5, it is characterised in that methods described also includes step (c), By drying separation product, to obtain the phosphate binder of dry powder form.
  9. A kind of 9. composition, it is characterised in that including：Phosphate binder described in claim 1；With
    Pharmaceutically acceptable carrier.
  10. 10. composition as claimed in claim 9, it is characterised in that in the composition, contain 0.1 - 99wt%, it is preferred that the phosphate binder described in 10-90wt%, with the gross weight meter of the composition.
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