CN106140109A - A kind of phosphate ion adsorbent and application thereof - Google Patents
A kind of phosphate ion adsorbent and application thereof Download PDFInfo
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- CN106140109A CN106140109A CN201510147539.4A CN201510147539A CN106140109A CN 106140109 A CN106140109 A CN 106140109A CN 201510147539 A CN201510147539 A CN 201510147539A CN 106140109 A CN106140109 A CN 106140109A
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Abstract
The invention discloses a kind of phosphate ion adsorbent and application thereof, this phosphate ion adsorbent is made up of the polymer or its salt with a metal complex group；It can exclusively adsorb phosphate ion in a live body, and is removed by phosphate ion from live body；Can use as the preventive of hyperphosphatemia and/or therapeutic agent；Also can use as blood purification medicament or device.It is an advantage of the invention that the phosphate ion that (1) phosphate adsorbent can exclusively adsorb in live body, and do not affect in live body that other is typically electrolysed composition；(2) phosphate adsorbent phosphate ion is had high adsorption, polymer or its salt dosage or usage amount relatively low time effect same notable；(3) from water or blood equal solvent, remove that to have adsorbed the method for the polymer of phosphate ion or its salt simple and easy to operate；(4) this polymer has unique phosphate anion adsorption and does not produce change in absorption post-consumer polymer itself, has no side effect.
Description
Technical field
The invention belongs to live body Medical Adsorbents technical field, be specifically related to a kind of phosphate ion adsorbent and application thereof.
Background technology
Hyperphosphatemia is the common complication of chronic kidney disease (CKD), it is to cause the change of secondary hyperparathyroidism, calcium phosphorus precipitation, vitamin D metabolism obstacle, the key factor of renal osteodystrophy, closely related with serious cardiovascular complication such as coronary insufficiency, atherosclerosis, valvular calcifications.Secondary hyperparathyroidism will cause serious complication, additionally, hyperparathyroidism also results in the generation of complication.
For improving hyperphosphatemia, generally adopt dietetic treatment as a kind of basic Therapeutic Method for treating secondary hyperparathyroidism, simultaneously by dialysing with phosphorus adsorbent to remove the phosphorus in blood further.For phosphorus adsorbent, can be the phosphorus adsorbent of gel aluminum hydroxide or calcic, such as winnofil.But, gel aluminum hydroxide has side effect, and it can cause this type of disease such as aluminum osteopathia, aluminum encephalopathy, and therefore, gel aluminum hydroxide is taboo to the patient needing dialysis.The phosphorus adsorbent of calcic has side effect equally, and it will cause the disease that hypercalcemia and heterotopic calcification etc. are like this.
In recent years, those skilled in the art study the method using anion exchange resin to make the phosphorus adsorbent without calcium.nullExample as anion exchange resin，It can be mentioned that to one have subsidiary couple a guanidine radicals polymer (see, for example，International publishing No.WO 94/19379)，With epoxychloropropane crosslinked polyallylamine hydrochlorate obtain polymer (see, for example，International publishing No.WO 95/05184)，The anion exchange resin that is made up of a MCI-196 or resin cholestyramine (see, for example，Japanese Unexamined Patent publishes No.Hei9-295941)，A kind of ferric ion be chelated to weak-base anion-exchange resin (see, for example，International publishing No.WO 98/03185)，The polymer that obtains with methacrylate or epoxychloropropane crosslinked polyethylenimine (see, for example，International publishing No.WO 01/66606 and 01/66607)，The weak-base anion-exchange resin that is made up of the Acrylate-divinylbenzene copolymer containing tertiary amine groups (see, for example，International publishing No.WO 01/68106)，The polymer that obtains with epoxychloropropane cross-linked polylysine (see, for example，Japanese Unexamined Patent publishes No.2003-33651)，The polymer that obtains with the vinyl monomer crosslinked polyethylene methacrylate with quaternary ammonium salt (see, for example，Japanese Unexamined Patent publishes No.2003-226648).But, these anion exchange resin are problematic, and it is relatively low to the adsorptivity of phosphorus and/or the specificity of Phosphate Sorption acid ion, therefore, in order to obtain preferably therapeutic effect, need to increase the usage amount of resin.
On the other hand, complex as zinc can capture the example of the material with a phosphate group, we it can be mentioned that have double-core zinc complex structure zinc complex crosslinking alkoxide (see, for example, international publishing No.WO 03/053932 and 04/078828), but, zinc complex is solvable, therefore in a solvent, even if zinc complex captures the material with phosphate group in a solvent, it is also very difficult for will removing this material from solvent.
Summary of the invention
In place of it is an object of the invention to according to above-mentioned the deficiencies in the prior art, a kind of phosphate ion adsorbent and application thereof are provided, this adsorbent is made up of polymer or its salt of a metal complex group, so that it can have the ability of absorption phosphate ion in live body.
The object of the invention realizes being completed by techniques below scheme:
A kind of phosphate ion adsorbent, it is characterised in that described phosphate ion adsorbent is made up of the polymer or its salt with a metal complex group, and its formula is as follows:
Wherein,
What M represented is the metallic atom that can form bivalent cation；
What R represented may is that a hydrogen atom；There is the alkyl of 1～16 carbon atom；A kind of acyl group, a kind of alkoxy carbonyl, a kind of acyl, a kind of alkoxy carbonyl alkyl; a kind of carbonylic alkyl, a kind of carbamyl alkyl, a kind of cyanoalkyl, a kind of hydroxy alkyl; a kind of aminoalkyl, a kind of halogenalkyl, the moieties in the most each group has 1～16 carbon atom；One carboxylic group；One carbamoyl group；One cyano group；One oh group, an amino group or a kind of halo group, can be bonded with described polymer or salt directly or by interval.
A kind of application relating to above-mentioned phosphate ion adsorbent, it is characterised in that be made up of preventive and/or the therapeutic agent of hyperphosphatemia described phosphate ion adsorbent, to adsorb the phosphate ion in blood.
A kind of application relating to above-mentioned phosphate ion adsorbent, it is characterised in that formed blood purification medicament by described phosphate ion adsorbent, to adsorb the phosphate ion in blood.
A kind of application relating to above-mentioned phosphate ion adsorbent, it is characterised in that use described phosphate ion adsorbent to make apparatus for purifying blood, to adsorb the phosphate ion in blood.
The invention have the advantage that
(1) phosphate adsorbent has specificity to the absorption of phosphate ion, and it is insoluble in water, blood or blood plasma, therefore, the phosphate ion in live body can be exclusively adsorbed in the use of polymer or its salt, and have no substantial effect in live body that other is typically electrolysed composition, such as, chloride ion, carbonate ion or sulfate ion；
(2) phosphate adsorbent has high adsorption to phosphate ion, and therefore, when polymer or its salt dosage or usage amount are relatively low, effect same is notable, can reduce dosage or usage amount accordingly；
(3) from water, blood or blood plasma equal solvent, remove that to have adsorbed the method for the polymer of phosphate ion or its salt simple and easy to operate, such as solid-liquid separation etc.；
(4) this polymer has unique phosphate anion adsorption and does not produce change, advantages of good adsorption effect in absorption post-consumer polymer itself, has no side effect.
Accompanying drawing explanation
Fig. 1 is the schematic diagram of the anion response rate in embodiment 6,7,9 in the present invention；
Fig. 2 is the schematic diagram of Anion-adsorption rate in embodiment 6,7,9 in the present invention.
Detailed description of the invention
Inventive feature and other correlated characteristic are described in further detail by embodiment below in conjunction with accompanying drawing, in order to the understanding of technical staff of the same trade:
Embodiment 1: the present embodiment is specifically related to a kind of phosphate ion adsorbent and application thereof, this adsorbent is not only in the distinctive ability in live body with absorption phosphate ion, and has higher absorbability to phosphate ion.
As following formula (I) show a kind of polymer being combined with metal complex group or its salt:
Wherein: m represents the metallic atom of a kind of bivalent cation formed, and m is not a zinc atom；
R occurs representing a hydrogen atom individually every time；There is the alkyl of 1 to 16 carbon atom；One acyl group, a kind of alkoxy carbonyl group, a kind of acyl, a kind of alkoxycarbonyl alkyl; a kind of carboxyalkyl, a kind of carbamoyl alkyl, a kind of cyanoalkyl, a kind of hydroxy alkyl; a kind of aminoalkyl or a kind of haloalkyl, wherein in each group, moieties has 1～16 carbon atom；One carboxylic group；One carbamyl group；One cyano group；One hydroxyl；One amino or a halogen group direct or through interval and are connected with moieties.
Phosphate ion adsorbent in the present embodiment is made up of polymer or its salt being combined with metal complex group, can represent such as following formula (II):
Wherein: M represents the metallic atom of a kind of bivalent cation formed, R occurs representing a hydrogen atom individually every time；There is the alkyl of 1 to 16 carbon atom；One acyl group, a kind of alkoxy carbonyl group, a kind of acyl, a kind of alkoxycarbonyl alkyl; a kind of carboxyalkyl, a kind of carbamoyl alkyl, a kind of cyanoalkyl, a kind of hydroxy alkyl; a kind of aminoalkyl or a kind of haloalkyl, wherein in each group, moieties has 1～16 carbon atom；One carboxylic group；One carbamyl group；One cyano group；One hydroxyl；One amino or a halogen group direct or through interval and are connected with moieties.
In the present embodiment, in the metal complex group represented by logical formula I or (II), for bivalent ions metallic atom can be formed, here there is no other special restriction, there is positive charge as long as it is one, bivalent ions typical metallic element or transition metal can be formed.The instantiation of metallic atom includes beryllium, magnesium, calcium, titanium, vanadium, chromium, manganese, ferrum, cobalt, nickel, copper, zinc, germanium, strontium, zirconium, niobium, molybdenum, ruthenium, rhodium, palladium, silver, cadmium, stannum, barium, tungsten, rhenium, osmium, iridium, platinum, hydrargyrum, lead, polonium and radium；Preferably example includes magnesium, calcium, chromium, manganese, ferrum, cobalt, nickel, copper, zinc and molybdenum；Most preferably example includes copper and zinc.
In the present embodiment, in the metal complex group represented by logical formula I or (II), the meaning of the alkyl with 1～16 carbon atom is to have the straight or branched alkyl of 1～16 carbon atom.
In this patent, in the metal complex group represented by logical formula I or (II), what the meaning of carboxyl groups was that R-CO-(R herein represents is the straight or branched alkyl with 1～16 carbon atom).
In this patent; in the metal complex group represented by logical formula I or (II), moieties and acyl moiety in carboxyl groups, alkoxycarbonyl group, acyl group, alkoxycarbonylalkyl groups, carboxyalkyl group, carbamoyl alkyl group, cyanoalkyl group, hydroxyalkyl groups, aminoalkyl groups or halogenalkyl are also by above-mentioned definition.
Additionally, refer to be attached to the polymer of above-mentioned group about the polymer with metal complex group represented by logical formula I or (II), and as a carrier or support, and have no particular limits.By one pharmaceutically acceptable polymer be first-selected.It addition, one phosphate ion is not had dysgenic polymer is also first-selected.The object lesson of polymer includes: polystyrene, polyethylene, polypropylene, polyacetylene, polrvinyl chloride, polyvinyl ester, polyvinylether, polyvinyl alcohol, polyacrylate, polyacrylic acid, polyacrylonitrile, polyacrylamide, polymethacrylates, polymethylacrylic acid, polymethacrylonitrile, PMAm, polyethers, polyacetals, polyester, polyethylene terephthalate, Merlon, polyamide, nylon, polyurethane, polyureas, polyimides, polyimidazole, poly-oxazole, polysulfides, polysulfones, polysulfonamide, polyether sulfone, polymer sulfone, polymer alloy, cellulose, cellulose acetate, glucosan, dextran sulfate, agarose, chitosan and silicone, polymer can also be its copolymer.
Polymer can be a polymer with cross-linked structure, and the instantiation of cross-linking reagent includes divinylbenzene, epoxychloropropane, N, N ＇-methylene-bisacrylamide and 4,4 ＇-'-diphenylmethane diisocyanate.
Polymer is directly or by an interval base indirect linkage to the metal complex group showed by logical formula I or (II), the importing of this interval base is to be used to produce a space between polymer and metal complex group, in order to metal complex group is to phosphatic absorption and increases swellbility.The example of interval base includes selecting an interval base from one group of group group being made up of alkyl or the alkylene group of straight or branched; this alkyl or alkylene group have 1～20 carbon atom, and (the interval base in this group group group can use carboxyl; carbamoyl; cyano group; hydroxyl; amino and/or halogeno-group arbitrarily replace) ,-O-,-C
(O)-,-N (O)-,-N (R ")-,-N+(R ")2-,-S (O)n-, ((wherein n is the integer of 0 to 2 to R "); R " is hydrogen with-N=C, one hydroxyl, or there is the straight or branched alkyl of 1 to 6 carbon atom) and it is spaced, by these, the interval base that basic body is combined into, but have no particular limits here, as long as above-mentioned purpose can be reached.The object lesson being bonded between metal complex group with polymer or spacer groups includes covalent bond such as carbon-carbon bond, ester bond, carbonyl bond, amido link, ehter bond, sulfide linkage, amino linkage and imine linkage.
The polymer being combined with metal complex group can also exist in a salt form, and the instantiation of salt includes all example hydrochloric acids of mineral acid, sulphuric acid, heavy carbonate, carbonic acid and nitric acid；Carboxylic organic acid includes such as oxalic acid, tartaric acid, benzoic acid, 4-methoxybenzoic acid, 4-HBA, valeric acid, citric acid, glyoxalic acid, glycolic, 1,3-propanedicarboxylic acid, monoxone, chloropropionic acid, cinnamic acid, succinic acid, acetic acid, lactic acid, acetone acid, fumaric acid, propanoic acid, 3-propanoic acid, malonic acid, butanoic acid, isopropylformic acid., aminoacid, imino-acetic acid, malic acid, hydroxyethylsulfonic acid., citraconic acid, adipic acid, itaconic acid, .beta.-methylacrylic acid, salicylic acid, gluconic acid, glucuronic acid, gallic acid and sorbic acid；The salt of the organic acid containing sulfonic acid group such as sulfoacetic acid, Loprazolam and ethane sulfonic acid, preferably pharmaceutical grade, such as halogenide；Inorganic salt such as hydrochlorate, sulfate, heavy carbonate and carbonate；Organic acid such as formic acid, acetic acid, propanoic acid, malonic acid, succinic acid, fumaric acid, ascorbic acid, glucuronic acid, aminoacid such as aspartic acid, glutamic acid and sulfonic acid.
As a logical formula I limited by the present embodiment, and represented by logical formula I, polymer or the instantiation of its salt with a metal complex group bonding, the polymer of one and copper complexation group bonding is it will be noted that such as Sepharose(trade mark) 4 quickly through an interval base and Cu2 + 2-N, N, N, ＇ N ＇-four [(2-pyridine radicals) methyl]-1,3-diaminourea-2-third aoxidizes base bonding.
As a logical formula II limited by the present embodiment, and represented by logical formula II, polymer or the instantiation of its salt with a metal complex group bonding, the polymer of one and zinc complexation group bonding is it will be noted that such as Sepharose(trade mark) 4 quickly through an interval base and Zn2 + 2-N, N, N, ＇ N ＇-four [(2-pyridine radicals) methyl]-1,3-diaminourea-2-third aoxidizes base bonding.
The metal complex group represented by logical formula II itself is usually dissolved in water or blood or blood plasma, but is to be insoluble in (the most insoluble) water or blood or blood plasma with the polymer of metal complex group complexation.Therefore, under the preferred conditions, the polymer with metal complex group or its salt that the logical formula II limited by the present embodiment represents have specificity and high adsorption to the phosphate ion in water or in blood or in blood plasma, and are practically insoluble in (the most insoluble) water or blood or blood plasma.Therefore, use a simple operations to remove, from water or in blood or in blood plasma, the phosphate ion adsorbed on polymer or its salt and be easily achieved, such as solid-liquid separation.The particularly polymer in the present embodiment or its salt has the most excellent and single-minded adsorptivity to phosphate ion, is a kind of high efficiency phosphate ion adsorbent.
Phosphate ion adsorbent in the present embodiment can be as the patient of the preventive of hyperphosphatemia and therapeutic agent, such as renal failure.Specifically, when by the polymer with metal complex group being limited by logical formula II and representing or its salt form phosphate ion adsorbent used as the medicine of a patient time, polymer or its salt in medicine pass through gastrointestinal tract and finally excrete external.In gastrointestinal course of conveying, polymer or its salt adsorb in the food that patient eats or capture phosphate ion, to prevent absorption or the accumulation of phosphorus in patient body.Therefore, it can make the concentration of reduction serium inorganic phosphorus be possibly realized.Polymer only has adsorption to phosphate ion and itself does not change, so the side effect that may be caused by tradition phosphorus adsorbent will not be caused.Such as, gel aluminum hydroxide or calcio phosphorus adsorbent, such as winnofil etc..
As medical phosphate adsorbent, especially as a preventive and/or therapeutic agent, it is a kind of effective ingredient by the polymer with metal complex group being limited by logical formula II and representing or its salt, it can be used, but, a kind of drug component being made up of polymer or its salt can use one general medicated premix by a kind of known method as a kind of effective ingredient and prepare.The Exemplary dosage forms of drug component includes tablet, capsule, granule, powder, pill, lozenge and liquid preparation, and these are all the application (including that sublingual administration is administered) being administered orally.
The drug component of oral administration can be prepared out with a kind of traditional known method, such as mixes, fills or tabletting.It addition, a kind of effective ingredient can use a kind of compound married operation to be distributed to utilize in the medicine composition of mass filler.Such as, oral tablet or capsule preferably provide the form of a unit dose, can comprise a kind of conventional medicament carrier such as binding agent, inserts, diluent, tablet agent, lubricant, disintegrating agent, coloring agent, perfume, wetting agent, or enteric coating agents.Presented in tablet can be the coated tablet prepared according to a kind of known method.Such as, a kind of coating materials (including enteric coatings agent) is used.
The preferred embodiment of implant includes that cellulose, mannitol, lactose etc. are like this.Disintegrating agent such as starch, polyvinylpyrrolidone or starch derivatives, such as carboxymethyl starch sodium；Lubricant such as sodium lauryl sulphate；Enteric coatings agent such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methyl cellulose acetic acid succinic acid, carboxymethylethylcellulose or methacrylic acid and the copolymer of methyl methacrylate, all can be used as medicated premix.
Oral liquid medicament component can provide by certain form, such as, aqueous solution or oil suspension, solution, emulsion, syrup, elixir, or a kind of dry drug component being soluble in before use in water or in suitable medium.In such liquid preparation, a known additive, such as, and a kind of precipitant, such as Sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats；A kind of emulsifying agent, such as lecithin, sorbitan monooleate or Radix Acaciae senegalis；A kind of oils and fats, such as almond oil, cochin oil or glyceride；A kind of nonaqueous solvent (including food oil), such as propylene glycol or ethanol；A kind of preservative, such as methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate or sorbic acid.If it is desired, a kind of known essence or coloring agent can use in the lump.
At one in the preparation of the drug component of oral administration, such as, tablet, capsule, granule, powder, be basis such as metal complex group portability by the effective dose of the polymer with metal complex group being limited by logical formula II and representing or its salt and the quantity that can accommodate determined.Based on renal function injury disease, the medical phosphate ion adsorbent in the present embodiment is extremely effective in prevention and/or treatment hyperphosphatemia.Especially prevention and/or treatment at hyperphosphatemia companion's renal function injury is the most effective.In the present embodiment, the preventive of hyperphosphatemia and/or the dosage of therapeutic agent can be determined according to the frequency of the age of patient, health condition and body weight, the order of severity of disease, type and treatment.
It is highly useful that phosphate ion adsorbent in the present embodiment is used for removing phosphate ion from blood or blood plasma as a kind of Blood purification material (i.e. medicament).Specifically, it is effective when being formed phosphate ion adsorbent as a Blood purification material (medicament) in a kind of Blood purification method by the polymer with metal complex group being limited by logical formula II and representing or its salt, such as hemodialysis, hemofiltration, hemodiafiltration, Blood index or plasma adsorption, polymer or its salt in blood purification material adsorb or capture the phosphate ion in blood or blood plasma, are possibly realized so that reducing the concentration of phosphorus in blood.Polymer shows only adsorption to phosphate ion, and polymer itself is not subject to change.Therefore, the scavenging material having adsorbed phosphate ion thereon can be processed together with phosphate ion.
When a phosphate adsorbent, especially as a kind of blood purification material, the polymer with metal complex group or its salt being limited by logical formula II and representing can be used as a kind of effective ingredient.Furthermore, it is understood that polymer or its salt are copolymerizable or be deposited in a kind of blood purification material that is a kind of for general blood purification material, that be made up of for effective ingredient polymer or its salt with formation, and use known method molding.The example of blood purification material forms includes hollow-fibre membrane, Flat Membrane, pearl, gel, and non-weaving cloth etc. is like this.
In the above-mentioned blood purification material being made up of as effective ingredient polymer or its salt, such as at hollow-fibre membrane, Flat Membrane, pearl, in gel and non-weaving cloth, the effective dose of the polymer with metal complex group being limited by logical formula II and representing or its salt it is basis such as metal complex group portability and the quantity that can accommodate is determined.In the present embodiment, the adsorbent of phosphate ion is useful at blood purification treatment because of the disease of renal function injury, particularly useful in the blood purification treatment of renal function injury.The form of the blood purification material in the present embodiment can determine according to the Therapeutic Method used, such as, and a kind of blood purification treatment method.
Arranging the blood purification material in the present embodiment in such as general apparatus for purifying blood, it is exceedingly useful as the apparatus for purifying blood that removes phosphate ion from blood and blood plasma.Such apparatus for purifying blood includes dialyser, hemofiltration, hemodiafiltration and absorbent-type device.
Apparatus for purifying blood is uses the most adaptive according to different blood purification methods, and apparatus for purifying blood can be classified according to concrete isolation technics, such as dialysis, ultrafiltration or absorption or presence or absence extracorporeal circulation of blood or durability etc..Phosphate ion adsorbent in the present embodiment can be used for the disease in terms for the treatment of renal function injury, especially particularly useful in the blood purification treatment of renal function injury.In the present embodiment, the type of apparatus for purifying blood depends on the body constitution of patient, the degree of Metabolism state and the degree of residual renal function.
Adsorbing the method for phosphate ion in the present embodiment is to utilize the metal complex group bonding represented by logical formula II to polymer or its salt and then the principle combining phosphate ion.The treatment of hyperphosphatemia and/or therapeutic agent, blood purification material or apparatus for purifying blood are that the method according to absorption phosphate ion selects, so that the absorption of phosphate ion is suitable for using every time.The method of absorption phosphate ion is included under such as neutral physiological condition and allows the phosphate ion adsorbent in the present invention to combine phosphate ion.
Embodiment 2:
Part synthesizes:
Weigh 33g DAP, 116g 2-pyridine carboxaldehyde and 50g sodium cyanoborohydride to be dissolved in the methanol of 500mL, be stirred at room temperature three days；The solution obtained is processed, then through column chromatography purification, output 34g synthetic intermediate；
Weigh the intermediate of 18g gained, and be dissolved in together with 14g potassium carbonate in 225mL DMF with 12g 6-bromomethyl methyl nicotinate, stir one hour at 50 DEG C；The solution obtained is processed, then through column chromatography purification, output 22g methyl ester derivative；
The methyl ester derivative and the 23g ethylenediamine that weigh 10g gained are dissolved in 100mL methanol, are stirred at room temperature three days；The solution obtained is processed, then through column chromatography purification, output N-{5-(2-amino) ethyl] carbamyl-2-pyridine radicals } methyl-N, N ＇, N ＇-three [(2-pyridine radicals) methyl]-DAP.
Embodiment 3:
One coordinating group is attached to the synthesis of polymer:
Measure 10mL and there is the Sepharose(trade mark of NHS-active group) 4 quick; add 10mL acetonitrile expanded gel; add the N-{5-(2-amino that concentration is 4.0mM obtained in 10mL embodiment 2) ethyl] carbamyl-2-pyridine radicals } methyl-N; N ＇; N ＇-three [(2-pyridine radicals) methyl]-1; the acetonitrile solution of 3-diaminourea-2-propanol, is stirred at room temperature four hours；Obtained reactant mixture is filtered and washing, wash with the mixed solution containing 0.1M sodium bicarbonate aqueous solution and the aqueous solution of 0.1M sodium carbonate again after washing, having of output 10mL connects N by interval, N, N ＇, Sepharose (trade mark) 4 of N ＇-four [(2-pyridine radicals) methyl]-DAP group is quick.
Embodiment 4:
Synthesis with the polymer of copper complexation group bonding:
Pipette that 0.1mL obtains in embodiment 3 by interval by N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-1, the Sepharose (trade mark) 4 of 3-diaminourea-2-propanol group bonding is quickly and 0.2mL is by 0.1M2-(N-morpholine) mixed liquor that ethane sulfonic acid (MES) buffer (pH6.0) and 0.1M copper acetate aqueous solution form, it is stirred at room temperature one hour.Being filtered by obtained reactant mixture and washing, wash with 20mM Tris-acetate buffer (pH7.4) after washing again, having of output 0.1mL connects Cu by interval2+ 2Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt is quick.
Embodiment 5:
Synthesis with the polymer of zinc complexation group bonding:
Pipette that 0.1mL obtains in embodiment 3 by interval by N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-1, the Sepharose (trade mark) 4 of 3-diaminourea-2-propanol group bonding is quickly and 0.2mL is by 0.1M2-(N-morpholine) mixed liquor that ethane sulfonic acid (MES) buffer (pH6.0) and 0.1M aqueous zinc acetate solution form, it is stirred at room temperature one hour；Being filtered by obtained reactant mixture and washing, wash with 20mM Tris-acetate buffer (pH7.4) after washing again, having of output 0.1mL connects Zn by interval2+ 2Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt is quick.
Embodiment 6:
There is the test of the Anion-adsorption of the polymer of copper complexation group bonding:
Pipette that 0.1mL obtains in example 4 connects Cu by interval2+ 2The Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt quickly, with milli-Q water, is subsequently adding 0.1mL and contains 103mM Cl-, 27.0mM HCO3 -, 2.26mM
HPO4 2-With 0.500nM SO4 2-Mixed aqueous solution (pH7.4), at 37 DEG C shake 5 minutes；The mixed aqueous solution of gained is filtered, collects filtrate, then with 0.1mL milli-Q water 9 times, collect all of filtrate；Ion chromatography is utilized each of to collect in the filtrate come the response rate of anion.As a result, following measurement data can be obtained: Cl:100%, HCO3 -: 100%, HPO4 2-: 52%, SO4 2-: 100%.The measurement of the response rate of anion, as shown in Figure 1.Additionally, from the determination of recovery rates of anion, connect Cu by interval2+ 2The Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt quickly uses, and the adsorption rate of each anion just will be determined.As result, obtain following measurement data: Cl:0%, HCO3 -: 0%, HPO4 2-: 48%, SO4 2-: 0%.The mensuration of the adsorption rate of anion, as shown in Figure 2.
Embodiment 7:
There is the test of the Anion-adsorption of the polymer of zinc complexation group bonding:
Pipette that 0.1mL obtains in embodiment 5 connects Zn by interval2+ 2The Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt quickly, with milli-Q water, is subsequently adding 0.1mL and contains 103mM Cl-, 27.0mM HCO3 -, 2.26mM
HPO4 2-With 0.500mM SO4 2-Mixed aqueous solution (pH7.4), at 37 DEG C shake 5 minutes；The mixed aqueous solution of gained is filtered, collects filtrate, then with 0.1mL milli-Q water 9 times, collect all of filtrate.Ion chromatography is utilized each of to collect in the filtrate come the response rate of anion.As a result, following measurement data can be obtained: Cl:100%, HCO3 -: 79%, HPO4 2-: 36%, SO4 2-: 100%.The measurement of the response rate of anion, as shown in Figure 1.Additionally, from the determination of recovery rates of anion, connect Zn by interval2+ 2The Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt quickly uses, and the adsorption rate of each anion just will be determined.As result, obtain following measurement data: Cl:0%, HCO3 -: 21%, HPO4 2-: 64%, SO4 2-: 0%.The mensuration of the adsorption rate of anion, as shown in Figure 2.
Embodiment 8:
There is the test of the serum phosphate ionic adsorption of the polymer of zinc complexation group bonding:
Pipette that 0.4mL obtains in example 5 connects Zn by interval2+ 2The Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt quickly, with milli-Q water, is subsequently adding 0.4mL hyclone (4.0mM HPO4 2-), then shake 5 minutes at 37 DEG C.The hyclone of gained is filtered, collects filtrate.The filtrate collected is used as testing liquid, through using trichloroacetic acid deproteinization, adds the aqueous sulfuric acid of ammonium molybdate in testing liquid, to form phosphomolybdic acid in testing liquid.Being reduced by the solution of gained 1-amino-2-naphthol-4-sulfonic acid, the molybdenum blue of formation can measure with colorimetric determination with ultraviolet-visible spectrophotometer.As a result, phosphate ion (HPO in testing liquid4 2-) it is found to be 4.5mM.Zn is connected by interval2+ 2The total amount of the quick stripped serum phosphate ion of Sepharose (trade mark) 4 of N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-DAP salt is 2.5mM.
Embodiment 9:
The mensuration of anion absorption rate in conjunction with the polymer of a coordinating group:
Pipette that 0.1mL obtains in example 3 by interval by N, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-1, the Sepharose (trade mark) 4 of 3-diaminourea-2-propanol group bonding quickly, with milli-Q water, is subsequently adding 0.1mL and contains 103mM Cl-, 27.0mM HCO3 -, 2.26mM
HPO4 2-With 0.500nM SO4 2-Mixed aqueous solution (pH7.4), at 37 DEG C shake 5 minutes.The mixed aqueous solution of gained is filtered, collects filtrate, then with 0.1mL milli-Q water 9 times, collect all of filtrate.Ion chromatography is utilized each of to collect in the filtrate come the response rate of anion.As a result, following measurement data can be obtained: Cl:100%, HCO3 -: 90%, HPO4 2-: 99%, SO4 2-: 98%.The measurement of the response rate of anion, as shown in Figure 1.Additionally, from the determination of recovery rates of anion, connect N by interval, N, N ＇, N ＇-four [(2-pyridine radicals) methyl]-1, the Sepharose (trade mark) 4 of 3-diaminourea-2-propanol quickly uses, and the adsorption rate of each anion just will be determined.As result, obtain following measurement data: Cl:0%, HCO3 -: 10%, HPO4 2-: 1%, SO4 2-: 2%.The mensuration of the adsorption rate of anion, as shown in Figure 2.
Claims (4)
1. a phosphate ion adsorbent, it is characterised in that described phosphate ion adsorbent is made up of the polymer or its salt with a metal complex group, and its formula is as follows:
Wherein,
What M represented is the metallic atom that can form bivalent cation；
What R represented may is that a hydrogen atom；There is the alkyl of 1～16 carbon atom；A kind of acyl group, a kind of alkoxy carbonyl, a kind of acyl, a kind of alkoxy carbonyl alkyl; a kind of carbonylic alkyl, a kind of carbamyl alkyl, a kind of cyanoalkyl, a kind of hydroxy alkyl; a kind of aminoalkyl, a kind of halogenalkyl, the moieties in the most each group has 1～16 carbon atom；One carboxylic group；One carbamoyl group；One cyano group；One oh group, an amino group or a kind of halo group, can be bonded with described polymer or salt directly or by interval.
2. the application relating to phosphate ion adsorbent described in claim 1, it is characterised in that be made up of preventive and/or the therapeutic agent of hyperphosphatemia described phosphate ion adsorbent, to adsorb the phosphate ion in blood.
3. the application relating to phosphate ion adsorbent described in claim 1, it is characterised in that formed blood purification medicament by described phosphate ion adsorbent, to adsorb the phosphate ion in blood.
4. the application relating to phosphate ion adsorbent described in claim 1, it is characterised in that use described phosphate ion adsorbent to make apparatus for purifying blood, to adsorb the phosphate ion in blood.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113019307A (en) * | 2021-03-03 | 2021-06-25 | 重庆三峡学院 | Magnesium-zirconium bimetallic oxide adsorbent and preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007018225A1 (en) * | 2005-08-09 | 2007-02-15 | Manac Inc. | Method of staining substance having phosphate group |
| EP1808452A1 (en) * | 2004-10-04 | 2007-07-18 | Manac Inc. | Phosphate ion adsorbent |
| CN102089075A (en) * | 2008-06-13 | 2011-06-08 | 诺瓦提斯公司 | Manufacture process for the preparation of an iron containing phosphate adsorbent |
| CN104258829A (en) * | 2014-09-24 | 2015-01-07 | 珠海健帆生物科技股份有限公司 | Serum phosphate adsorbing agent and preparation method thereof and adsorption column for blood perfusion |
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2015
- 2015-03-31 CN CN201510147539.4A patent/CN106140109A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1808452A1 (en) * | 2004-10-04 | 2007-07-18 | Manac Inc. | Phosphate ion adsorbent |
| WO2007018225A1 (en) * | 2005-08-09 | 2007-02-15 | Manac Inc. | Method of staining substance having phosphate group |
| CN102089075A (en) * | 2008-06-13 | 2011-06-08 | 诺瓦提斯公司 | Manufacture process for the preparation of an iron containing phosphate adsorbent |
| CN104258829A (en) * | 2014-09-24 | 2015-01-07 | 珠海健帆生物科技股份有限公司 | Serum phosphate adsorbing agent and preparation method thereof and adsorption column for blood perfusion |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113019307A (en) * | 2021-03-03 | 2021-06-25 | 重庆三峡学院 | Magnesium-zirconium bimetallic oxide adsorbent and preparation and application thereof |
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