WO2017198199A1 - Phosphate binder comprising hydroxide of ferrum and low-molecular-weight sugars, preparation method therefor, and applications thereof - Google Patents
Phosphate binder comprising hydroxide of ferrum and low-molecular-weight sugars, preparation method therefor, and applications thereof Download PDFInfo
- Publication number
- WO2017198199A1 WO2017198199A1 PCT/CN2017/084944 CN2017084944W WO2017198199A1 WO 2017198199 A1 WO2017198199 A1 WO 2017198199A1 CN 2017084944 W CN2017084944 W CN 2017084944W WO 2017198199 A1 WO2017198199 A1 WO 2017198199A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phosphorus
- iron
- low molecular
- molecular weight
- composition
- Prior art date
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 100
- 235000000346 sugar Nutrition 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims description 15
- 150000008163 sugars Chemical class 0.000 title abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 title abstract description 7
- 239000002694 phosphate binding agent Substances 0.000 title abstract description 5
- 239000011574 phosphorus Substances 0.000 claims description 102
- 229910052698 phosphorus Inorganic materials 0.000 claims description 102
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 101
- 239000011230 binding agent Substances 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 55
- 229910052742 iron Inorganic materials 0.000 claims description 48
- 235000014413 iron hydroxide Nutrition 0.000 claims description 21
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 claims description 21
- 229920001542 oligosaccharide Polymers 0.000 claims description 19
- 150000002482 oligosaccharides Chemical class 0.000 claims description 18
- 239000008280 blood Substances 0.000 claims description 17
- 210000004369 blood Anatomy 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000001483 monosaccharide substituent group Chemical group 0.000 claims 1
- 150000002772 monosaccharides Chemical group 0.000 abstract description 18
- 210000002966 serum Anatomy 0.000 abstract description 5
- 229910019142 PO4 Inorganic materials 0.000 abstract description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 2
- 239000010452 phosphate Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 70
- 239000000047 product Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 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 description 17
- 239000001509 sodium citrate Substances 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 13
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- 229920000084 Gum arabic Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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Classifications
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- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Definitions
- the present invention relates to a phosphorus binder, and in particular to an iron salt-low molecular weight sugar-based phosphorus binder, a preparation method thereof and use thereof.
- Hyperphosphatemia is one of the major complications of chronic renal insufficiency (CKD). Increased serum phosphorus concentration is closely related to mortality in CKD patients, and elevated blood phosphorus levels may lead to further decline in renal function and secondary thyroid function. , vascular calcification and minerals, bone metabolism disorders. It is widely believed that regulating phosphorus metabolism is the key to reducing cardiovascular complications, improving the quality of life of dialysis patients, and reducing morbidity and mortality.
- CKD chronic renal insufficiency
- the iron-phosphorus binder has been proven to be a high-efficiency phosphorus binder and does not cause ectopic calcification and can improve thyroid function. At the same time, it helps to correct the anemia of CKD patients and has no significant effect on iron metabolism in the body.
- a first aspect of the invention provides a phosphorus binder comprising:
- the number of monosaccharide units of the low molecular weight sugar is from 1 to 20, and the mass ratio of iron is from 2 to 45% by weight based on the total weight of the phosphorus binder.
- the low molecular weight sugar has a monosaccharide unit number of from 1 to 10, preferably from 3 to 9, more preferably from 4 to 7.
- the low molecular weight sugar has a number of monosaccharide units of from 3 to 20.
- the mass ratio of iron is from 10 to 35 wt%, preferably from 25 to 33 wt%, based on the total weight of the phosphorus binder.
- the low molecular weight sugar comprises a monosaccharide, an oligosaccharide, and/or a polysaccharide.
- the low molecular weight sugar comprises a monosaccharide and an oligosaccharide.
- the monosaccharide is selected from the group consisting of fructose, arabinose, glucuronic acid, glucose, galactose, or a combination thereof.
- the polysaccharide is selected from the group consisting of gum arabic, peach gum, guar gum, konjac gum, carrageenan, sodium alginate, pectin, dextran, or a combination thereof.
- the hydroxide of iron forms a stable structure with the low molecular weight sugar by hydrogen bonding or adsorption (coordination).
- the phosphorus binder has a citrate content of from 1 to 30%, preferably from 3 to 15%, more preferably from 5 to 11%.
- a second aspect of the invention provides the use of the phosphorus binder of the first aspect of the invention for the preparation of a composition for inhibiting an increase in blood phosphorus concentration.
- the composition is also used to (i) enhance immunity; and/or (ii) treat or prevent hyperphosphatemia, hyperparathyroidism, calcium-phosphorus product change, vitamin D metabolism Disorders, renal osteopathy, and diseases associated with cardiovascular complications.
- composition is also used to supplement iron.
- the composition comprises a pharmaceutical composition, a health care composition, a food composition, or a combination thereof.
- the composition comprises a safe and effective amount of (i) a hydroxide of iron; (ii) a low molecular weight sugar;
- the composition is an oral preparation.
- the composition is a preparation selected from the group consisting of a terminal preparation, a powder, a tablet, a sugar coating agent, a capsule, a granule, a suspension, a solution, a syrup, a drop, and a tongue. Under the tablet.
- the composition contains a therapeutically effective amount of an iron salt, a carbohydrate, and an additive selected from the group consisting of flavoring agents, preservatives, dispersing agents, coloring agents, perfumes, capsule shells, and helpers.
- an additive selected from the group consisting of flavoring agents, preservatives, dispersing agents, coloring agents, perfumes, capsule shells, and helpers.
- a third aspect of the invention provides a method for preparing a phosphorus binder according to the first aspect of the invention, comprising the steps of:
- the weak base is sodium citrate, potassium citrate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a mixture thereof.
- the weak base is citric acid, sodium citrate, and/or sodium citrate hydrate.
- the sodium citrate hydrate comprises trisodium citrate dihydrate.
- the weak base comprises sodium citrate.
- the mass ratio of the low molecular weight sugar to the weak base is 1:0.01-1, preferably 1:0.1-0.5, more preferably,1. : 0.2-0.3.
- the mass ratio of the low molecular weight sugar to the iron hydroxide is 1:0.2-4, preferably 1:0.5-1, more preferably Ground, 1:0.6-0.7.
- the step (b1) is included: mixing the low molecular weight sugar of the step (a), sodium citrate and a base in water, adding an iron salt and a base to obtain a product, and separating and purifying The phosphorus binder of the first aspect of the invention is obtained.
- said step (b1) has one or more of the following features:
- reaction time is 1-48 h, preferably 1-24 h, more preferably 4-16 h;
- the cooling temperature is 0-40 ° C;
- step (b1) purification is carried out with ethanol.
- the ethanol contains 5-20% water.
- the ethanol is anhydrous ethanol or 90-95% ethanol.
- the ethanol and water (v/v) are from 1:0.05 to 1:10.
- step (b1) further comprises a stirring and cooling step.
- the iron salt is selected from the group consisting of a divalent iron salt, a ferric salt, or a combination thereof.
- the iron salt is a ferric salt selected from the group consisting of ferric chloride, iron nitrate, iron sulfate, iron citrate, or a combination thereof.
- the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, aqueous ammonia, or a combination thereof.
- the method further comprises the step (c) of separating the product by drying to obtain the phosphorus binder in the form of a dry powder.
- the drying comprises product drying, heat drying, spray drying or fluidized spray drying.
- a fourth aspect of the invention provides a composition comprising: the phosphorus binder of the first aspect of the invention.
- a pharmaceutically acceptable carrier is selected from:
- the composition is an oral preparation.
- the composition is a preparation selected from the group consisting of a terminal preparation, a powder, a tablet, a sugar coating agent, a capsule, a granule, a suspension, a solution, a syrup, a drop, and a tongue. Under the tablet.
- the composition contains a therapeutically effective amount of an iron salt, a carbohydrate, and an additive selected from the group consisting of flavoring agents, preservatives, dispersing agents, coloring agents, perfumes, capsule shells, and helpers.
- an additive selected from the group consisting of flavoring agents, preservatives, dispersing agents, coloring agents, perfumes, capsule shells, and helpers.
- the composition contains from 0.1 to 99% by weight, preferably from 10 to 90% by weight, of the phosphorus binder, based on the total weight of the composition.
- the composition is a unit dosage form (one tablet, one capsule or one vial), and the mass of the composition in each unit dosage form is from 0.05 to 5 g, preferably from 0.5 to 2 g.
- the subject comprises a human or a non-human mammal.
- the non-human mammal comprises a rodent such as a mouse or a rat.
- the iron hydroxide of the present invention is not particularly limited, and a preferred iron hydroxide is iron hydroxide, iron oxyhydroxide, and iron oxide.
- each of the low molecular weight sugars comprises on average 1 to 20 (preferably, 1 to 10, more preferably, 3 to 9, more preferably 4 to 7) monosaccharide units or each of the above
- the low molecular weight sugars on average comprise from 3 to 20 (preferably, 3 to 10, more preferably, 4 to 9, more preferably 4 to 7) monosaccharide units, usually of small molecular weight (ie, monosaccharide singles)
- the number of elements may be reduced by pretreatment (for example, using an acid and/or heat or an enzyme such as an alpha-amylase), and the low molecular weight sugar may be a linear chain of monosaccharide units linked by a (1 ⁇ 4) glycosidic bond; Or it may be branched by forming a (1 ⁇ 6) glycosidic bond.
- a preferred method of preparing a phosphorus binder includes the following steps:
- a phosphorus binder 0.1-90 wt% of a phosphorus binder; and a food or pharmaceutically acceptable carrier, and/or an excipient.
- the phosphorus binder-containing composition of the present invention has remarkably excellent phosphorus binding ability, and thus can be used for treating and/or preventing hyperphosphatemia in a mammal.
- the mammal of the present invention may be referred to as a human, and may also be a warm-blooded animal, especially a cat, a dog or the like.
- the test method for the absorption capacity of phosphoric acid was as follows: a phosphoric acid solution having a concentration of 2 ⁇ g/mL was prepared, and the pH was adjusted to 3.0 with sodium hydroxide hydrochloride, and the sample was designated as Control A. Add 25 mL of Control A to the prepared phosphorus binder 100 ⁇ 5 mg (denoted as B), and react at 37 ° C for 24 h with low speed stirring. After 24 hours, the reaction solution was centrifuged (14,000 rpm), and the supernatant was taken at a concentration of C. The concentrations of A and C were determined using an ultraviolet spectrophotometer, respectively. The phosphate binding capacity is calculated by the formula:
- Adsorption activity (mg/g) is defined as the mass of phosphate (PO 4 3- ) adsorbed per gram of API
- the iron content was found to be 32.4%, and the phosphorus absorption was 342.1 mg/g.
- Ethanol was completely precipitated and centrifuged, and the solid was washed twice with 70% ethanol and 80% ethanol respectively.
- the obtained product was heated and dried to obtain 372.4 g of product.
- the product was dark brown and the particle size was 11.2 nm. Dissolved in water.
- the iron content was found to be 31.2%, and the phosphorus absorption was 195.6 mg/g.
- the iron content was found to be 32.4%, and the phosphorus absorption was 284.3 mg/g.
- the mixture was centrifuged, and the solid was washed twice with 70% ethanol and 80% ethanol respectively; the obtained product was dried by heating, and a total of 363 g of the product was obtained.
- the product was reddish brown with a particle size of 14.2 nm and was easily soluble in water.
- the experimental animals were fed freely without human intervention and continued for 2 weeks.
- the following indicators were observed and tested: animal survival (during the experiment), 24-hour food intake, body weight (once a week), blood phosphorus, blood calcium, iron, creatinine, BUN (1 day before administration, 2nd after administration) Week), urine volume (24 hours), urinary iron, urinary phosphorus (1 day before administration, 2 weeks after administration).
- the phosphorus-binding agent of the present invention has a significantly lower blood phosphorus-lowering effect than the positive drug, and has a very significant hypophosphatemic effect.
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Abstract
A phosphate binder comprising hydroxide of ferrum and low-molecular-weight sugars. The number of monosaccharide units of the low-molecular-weight sugars ranges from 1 to 20. On the basis of the total weight of the phosphate binder, the mass ratio of the ferrum ranges from 2 wt% to 45 wt%. The phosphate binder is used for reducing the serum phosphate concentration.
Description
本发明涉及一种磷结合剂,具体地,涉及一种基于铁盐-低分子量糖的磷结合剂、其制备方法及其应用。The present invention relates to a phosphorus binder, and in particular to an iron salt-low molecular weight sugar-based phosphorus binder, a preparation method thereof and use thereof.
高磷血症是慢性肾功能不全(CKD)的主要并发症之一,血磷浓度增高与CKD患者死亡率密切相关,并且血磷浓度增高会导致肾功能进一步衰退、继发性甲状腺功能抗进、血管钙化和矿物质,骨代谢紊乱。现代普遍认为调节磷代谢是减少心血管并发症、提高透析患者生活质量、降低病残率和死亡率的关键。Hyperphosphatemia is one of the major complications of chronic renal insufficiency (CKD). Increased serum phosphorus concentration is closely related to mortality in CKD patients, and elevated blood phosphorus levels may lead to further decline in renal function and secondary thyroid function. , vascular calcification and minerals, bone metabolism disorders. It is widely believed that regulating phosphorus metabolism is the key to reducing cardiovascular complications, improving the quality of life of dialysis patients, and reducing morbidity and mortality.
近年来不断有新型的磷结合剂问世。其中,含铁磷结合剂被证实是一种高效磷结合剂,并且不会导致异位钙化、并能够改善甲状腺功能抗进。同时,有助于纠正CKD患者贫血状态,并且对体内的铁代谢没有明显的影响。In recent years, new types of phosphorus binders have been introduced. Among them, the iron-phosphorus binder has been proven to be a high-efficiency phosphorus binder and does not cause ectopic calcification and can improve thyroid function. At the same time, it helps to correct the anemia of CKD patients and has no significant effect on iron metabolism in the body.
由于患者每天的饮食中含有大量的磷,而现有的磷结合剂的磷吸附能力过低,因此为了控制血磷浓度到一个正常的水平,患者每天需要使用大量的磷酸结合剂,而过量服用会给患者带来其他的副作用。Since the patient's daily diet contains a large amount of phosphorus, and the phosphorus adsorption capacity of the existing phosphorus binder is too low, in order to control the blood phosphorus concentration to a normal level, the patient needs to use a large amount of phosphate binder per day, and excessively take Will bring other side effects to the patient.
因此,本领域迫切需要开发一种能够大幅度提高磷吸附能力,减少副作用的磷结合剂。Therefore, there is an urgent need in the art to develop a phosphorus binder capable of greatly increasing the phosphorus adsorption capacity and reducing side effects.
发明内容Summary of the invention
本发明的目的是提供一种能够大幅度提高磷吸附能力,减少副作用的磷结合剂。An object of the present invention is to provide a phosphorus binder which can greatly improve phosphorus adsorption ability and reduce side effects.
本发明第一方面提供了一种磷结合剂,包括:A first aspect of the invention provides a phosphorus binder comprising:
铁的氢氧化物;和Iron hydroxide; and
低分子量糖;Low molecular weight sugar;
其中,所述低分子量糖的单糖单元数为1-20,并且以所述磷结合剂的总重计,铁的质量比为2-45wt%。Wherein the number of monosaccharide units of the low molecular weight sugar is from 1 to 20, and the mass ratio of iron is from 2 to 45% by weight based on the total weight of the phosphorus binder.
在另一优选例中,所述低分子量糖的单糖单元数为1-10,较佳地,3-9,更佳地,4-7。
In another preferred embodiment, the low molecular weight sugar has a monosaccharide unit number of from 1 to 10, preferably from 3 to 9, more preferably from 4 to 7.
在另一优选例中,所述低分子量糖的单糖单元数为3-20。In another preferred embodiment, the low molecular weight sugar has a number of monosaccharide units of from 3 to 20.
在另一优选例中,所述铁的质量比为10-35wt%,较佳地,25-33wt%,以所述磷结合剂总重计。In another preferred embodiment, the mass ratio of iron is from 10 to 35 wt%, preferably from 25 to 33 wt%, based on the total weight of the phosphorus binder.
在另一优选例中,所述低分子量糖的单糖单元数为3-10,较佳地,4-9,更佳地,4-7。In another preferred embodiment, the low molecular weight sugar has a number of monosaccharide units of from 3 to 10, preferably from 4 to 9, more preferably from 4 to 7.
在另一优选例中,所述低分子量糖包括单糖、低聚糖、和/或多聚糖。In another preferred embodiment, the low molecular weight sugar comprises a monosaccharide, an oligosaccharide, and/or a polysaccharide.
在另一优选例中,所述低分子量糖包括单糖和低聚糖。In another preferred embodiment, the low molecular weight sugar comprises a monosaccharide and an oligosaccharide.
在另一优选例中,所述低分子量糖包括低聚糖。In another preferred embodiment, the low molecular weight sugar comprises an oligosaccharide.
在另一优选例中,所述低聚糖选自下组:低聚果糖、低聚半乳糖、低聚乳糖、低聚葡萄糖、低聚甘露糖、低聚木糖、海藻糖、乳蔗糖、低聚麦芽糖、异麦芽低聚糖、环糊精、壳质低聚糖、大豆低聚糖、低聚龙胆糖、低聚琼脂糖、水苏糖、低聚果胶、乳果糖、棉子糖、帕拉金低聚糖、或其组合。In another preferred embodiment, the oligosaccharide is selected from the group consisting of oligofructose, galactooligosaccharide, oligosaccharide, oligoglucose, oligomannose, xylooligosaccharide, trehalose, lactose, Oligomeric maltose, isomalto-oligosaccharide, cyclodextrin, chitosan oligosaccharide, soybean oligosaccharide, oligosaccharide, oligomeric agarose, stachyose, oligo-pectin, lactulose, cottonseed Sugar, palatin oligosaccharide, or a combination thereof.
在另一优选例中,所述单糖选自下组:果糖、阿拉伯糖、葡萄糖醛酸、葡萄糖、半乳糖、或其组合。In another preferred embodiment, the monosaccharide is selected from the group consisting of fructose, arabinose, glucuronic acid, glucose, galactose, or a combination thereof.
在另一优选例中,所述多聚糖选自下组:阿拉伯胶、桃胶、瓜尔胶、魔芋胶、卡拉胶、海藻酸钠、果胶、葡聚糖、或其组合。In another preferred embodiment, the polysaccharide is selected from the group consisting of gum arabic, peach gum, guar gum, konjac gum, carrageenan, sodium alginate, pectin, dextran, or a combination thereof.
在另一优选例中,所述铁的氢氧化物与所述低分子量糖的重量比为1:0.25-4,较佳地,1:0.5-1,更佳地,1:0.6-0.7。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.
在另一优选例中,所述铁的氢氧化物选自下组:氢氧化铁、羟基氧化铁、铁的氧化物、或其组合。In another preferred embodiment, the hydroxide of iron is selected from the group consisting of iron hydroxide, iron oxyhydroxide, oxides of iron, or combinations thereof.
在另一优选例中,所述铁的氢氧化物通过氢键或吸附(配位)作用与所述低分子量糖形成稳定的结构。In another preferred embodiment, the hydroxide of iron forms a stable structure with the low molecular weight sugar by hydrogen bonding or adsorption (coordination).
在另一优选例中,所述磷结合剂中柠檬酸根的含量为1-30%,较佳地,3-15%,更佳地,5-11%。In another preferred embodiment, the phosphorus binder has a citrate content of from 1 to 30%, preferably from 3 to 15%, more preferably from 5 to 11%.
在另一优选例中,所述磷结合剂中柠檬酸根的残留量<1%,较佳地,<0.5%,更佳地,<0.1%。In another preferred embodiment, the residual amount of citrate in the phosphorus binder is <1%, preferably <0.5%, more preferably <0.1%.
本发明第二方面提供了本发明第一方面所述磷结合剂的用途,用于制备抑制血磷浓度升高的组合物。A second aspect of the invention provides the use of the phosphorus binder of the first aspect of the invention for the preparation of a composition for inhibiting an increase in blood phosphorus concentration.
在另一优选例中,所述组合物还用于(i)提高机体免疫力;和/或(ii)治疗或者预防高磷血症、甲状旁腺功能亢进、钙磷乘积变化、维生素D代谢障碍、肾性骨病以及心血管并发症相关的疾病。
In another preferred embodiment, the composition is also used to (i) enhance immunity; and/or (ii) treat or prevent hyperphosphatemia, hyperparathyroidism, calcium-phosphorus product change, vitamin D metabolism Disorders, renal osteopathy, and diseases associated with cardiovascular complications.
在另一优选例中,所述组合物还用于补铁。In another preferred embodiment, the composition is also used to supplement iron.
在另一优选例中,所述组合物包括药物组合物、保健组合物、食品组合物、或其组合。In another preferred embodiment, the composition comprises a pharmaceutical composition, a health care composition, a food composition, or a combination thereof.
在另一优选例中,所述组合物包括安全有效量的(i)铁的氢氧化物;(ii)低分子糖;In another preferred embodiment, the composition comprises a safe and effective amount of (i) a hydroxide of iron; (ii) a low molecular weight sugar;
在另一优选例中,所述的组合物为口服制剂。In another preferred embodiment, the composition is an oral preparation.
在另一优选例中,所述的组合物为选自下组的制剂:末剂、散剂、片剂、糖衣剂、胶囊剂、颗粒剂、悬浮剂、溶液剂、糖浆剂、滴剂、舌下含片。In another preferred embodiment, the composition is a preparation selected from the group consisting of a terminal preparation, a powder, a tablet, a sugar coating agent, a capsule, a granule, a suspension, a solution, a syrup, a drop, and a tongue. Under the tablet.
在另一优选例中,所述的组合物含有治疗有效量的铁盐、碳水化合物、以及选自下组的添加剂:矫味剂、防腐剂、分散剂、着色剂、香料、胶囊壳、助溶剂、崩解剂、润滑剂、助流剂,或其组合。In another preferred embodiment, the composition contains a therapeutically effective amount of an iron salt, a carbohydrate, and an additive selected from the group consisting of flavoring agents, preservatives, dispersing agents, coloring agents, perfumes, capsule shells, and helpers. A solvent, a disintegrant, a lubricant, a glidant, or a combination thereof.
本发明第三方面提供了本发明第一方面所述磷结合剂的制法,包括步骤:A third aspect of the invention provides a method for preparing a phosphorus binder according to the first aspect of the invention, comprising the steps of:
(a)提供一低分子量糖和弱碱;(a) providing a low molecular weight sugar and a weak base;
(b)将所述低分子量糖和所述弱碱与铁的氢氧化物混合,得到本发明第一方面所述的磷结合剂。(b) mixing the low molecular weight sugar and the weak base with a hydroxide of iron to obtain the phosphorus binder according to the first aspect of the invention.
在另一优选例中,所述铁的氢氧化物为已配好、或现配的。In another preferred embodiment, the iron hydroxide is either formulated or ready to be used.
在另一优选例中,所述弱碱为柠檬酸钠、柠檬酸钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、或它们的混合物。In another preferred embodiment, the weak base is sodium citrate, potassium citrate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a mixture thereof.
在另一优选例中,所述弱碱为柠檬酸、柠檬酸钠、和/或柠檬酸钠水合物。In another preferred embodiment, the weak base is citric acid, sodium citrate, and/or sodium citrate hydrate.
在另一优选例中,所述柠檬酸钠水合物包括二水合柠檬酸三钠。In another preferred embodiment, the sodium citrate hydrate comprises trisodium citrate dihydrate.
在另一优选例中,所述弱碱包括柠檬酸钠。In another preferred embodiment, the weak base comprises sodium citrate.
在另一优选例中,所述步骤(b)中,所述低分子量糖与所述弱碱的质量比为1:0.01-1,较佳地,1:0.1-0.5,更佳地,1:0.2-0.3。In another preferred embodiment, in the step (b), the mass ratio of the low molecular weight sugar to the weak base is 1:0.01-1, preferably 1:0.1-0.5, more preferably,1. : 0.2-0.3.
在另一优选例中,所述步骤(b)中,所述低分子量糖与所述铁的氢氧化物的质量比为1:0.2-4,较佳地,1:0.5-1,更佳地,1:0.6-0.7。In another preferred embodiment, in the step (b), the mass ratio of the low molecular weight sugar to the iron hydroxide is 1:0.2-4, preferably 1:0.5-1, more preferably Ground, 1:0.6-0.7.
在另一优选例中,在步骤(b)中,包括步骤(b1):将步骤(a)的低分子量糖、柠檬酸钠和碱在水中混合,加铁盐和碱,得到产物,分离纯化,得到本发明第一方面所述的磷结合剂。In another preferred embodiment, in the step (b), the step (b1) is included: mixing the low molecular weight sugar of the step (a), sodium citrate and a base in water, adding an iron salt and a base to obtain a product, and separating and purifying The phosphorus binder of the first aspect of the invention is obtained.
在另一优选例中,所述步骤(b1)具有一个或多个以下特征:In another preferred embodiment, said step (b1) has one or more of the following features:
(i)溶液温度为20-100℃,较佳地,60-95℃,更佳地,80-90℃;(i) the solution temperature is 20-100 ° C, preferably 60-95 ° C, more preferably 80-90 ° C;
(ii)反应时间为1-48h,较佳地,1-24h,更佳地,4-16h;
(ii) the reaction time is 1-48 h, preferably 1-24 h, more preferably 4-16 h;
(iii)冷却温度为0-40℃;(iii) the cooling temperature is 0-40 ° C;
(iv)pH调节至6-12,较佳地,7-10。(iv) pH adjustment to 6-12, preferably 7-10.
在另一优选例中,所述步骤(b1)中,用乙醇进行纯化。In another preferred embodiment, in the step (b1), purification is carried out with ethanol.
在另一优选例中,所述乙醇含有5-20%的水。In another preferred embodiment, the ethanol contains 5-20% water.
在另一优选例中,所述乙醇为无水乙醇或90-95%的乙醇。In another preferred embodiment, the ethanol is anhydrous ethanol or 90-95% ethanol.
在另一优选例中,所述乙醇与水(v/v)为1:0.05-1:10。In another preferred embodiment, the ethanol and water (v/v) are from 1:0.05 to 1:10.
在另一优选例中,所述步骤(b1)还包括搅拌和冷却步骤。In another preferred embodiment, the step (b1) further comprises a stirring and cooling step.
在另一优选例中,在步骤(b1)中,所述铁盐选自下组:二价铁盐、三价铁盐、或其组合。In another preferred embodiment, in the step (b1), the iron salt is selected from the group consisting of a divalent iron salt, a ferric salt, or a combination thereof.
在另一优选例中,在步骤(b1)中,所述铁盐为三价铁盐,选自下组:氯化铁、硝酸铁、硫酸铁、柠檬酸铁、或其组合。In another preferred embodiment, in the step (b1), the iron salt is a ferric salt selected from the group consisting of ferric chloride, iron nitrate, iron sulfate, iron citrate, or a combination thereof.
在另一优选例中,在步骤(b1)中,所述碱选自下组:自氢氧化钠、氢氧化钾、氨水、或其组合。In another preferred embodiment, in step (b1), the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, aqueous ammonia, or a combination thereof.
在另一优选例中,所述碱与低分子量糖的质量比为1:1-5,优选1:2-4。In another preferred embodiment, the mass ratio of the base to the low molecular weight sugar is from 1:1 to 5, preferably from 1:2-4.
在另一优选例中,所述方法还包括步骤(c),通过干燥分离产物,以得到干粉形式的所述磷结合剂。In another preferred embodiment, the method further comprises the step (c) of separating the product by drying to obtain the phosphorus binder in the form of a dry powder.
在另一优选例中,所述干燥包括产物晾干、加热烘干、喷雾干燥或流化喷雾干燥。In another preferred embodiment, the drying comprises product drying, heat drying, spray drying or fluidized spray drying.
在另一优选例中,所述方法还包括步骤(d),将步骤(c)得到的所述干粉形式的磷结合剂进行制剂。In another preferred embodiment, the method further comprises the step (d) of formulating the phosphorus binder in the dry powder form obtained in the step (c).
本发明第四方面提供了一种组合物,包括:本发明第一方面所述的磷结合剂;和A fourth aspect of the invention provides a composition comprising: the phosphorus binder of the first aspect of the invention;
药学上可接受的载体。A pharmaceutically acceptable carrier.
在另一优选例中,所述组合物包括药物组合物、保健组合物、食品组合物、或其组合。In another preferred embodiment, the composition comprises a pharmaceutical composition, a health care composition, a food composition, or a combination thereof.
在另一优选例中,所述的组合物为口服制剂。In another preferred embodiment, the composition is an oral preparation.
在另一优选例中,所述的组合物为选自下组的制剂:末剂、散剂、片剂、糖衣剂、胶囊剂、颗粒剂、悬浮剂、溶液剂、糖浆剂、滴剂、舌下含片。In another preferred embodiment, the composition is a preparation selected from the group consisting of a terminal preparation, a powder, a tablet, a sugar coating agent, a capsule, a granule, a suspension, a solution, a syrup, a drop, and a tongue. Under the tablet.
在另一优选例中,所述的组合物含有治疗有效量的铁盐、碳水化合物、以及选自下组的添加剂:矫味剂、防腐剂、分散剂、着色剂、香料、胶囊壳、助溶剂、崩解剂、润滑剂、助流剂,或其组合。
In another preferred embodiment, the composition contains a therapeutically effective amount of an iron salt, a carbohydrate, and an additive selected from the group consisting of flavoring agents, preservatives, dispersing agents, coloring agents, perfumes, capsule shells, and helpers. A solvent, a disintegrant, a lubricant, a glidant, or a combination thereof.
在另一优选例中,在所述组合物中,含有0.1-99wt%,较佳地10-90wt%所述的磷结合剂,以所述组合物的总重量计。In another preferred embodiment, the composition contains from 0.1 to 99% by weight, preferably from 10 to 90% by weight, of the phosphorus binder, based on the total weight of the composition.
在另一优选例中,所述的组合物为单元剂型(一片、一粒胶囊或一小瓶),每个单元剂型中所述组合物的质量为0.05-5g,较佳地为0.5-2g。In another preferred embodiment, the composition is a unit dosage form (one tablet, one capsule or one vial), and the mass of the composition in each unit dosage form is from 0.05 to 5 g, preferably from 0.5 to 2 g.
本发明第五方面提供了一种抑制血磷浓度升高的方法,对抑制对象施用有效量的本发明第一方面所述的磷结合剂,或本发明第四方面所述的组合物。A fifth aspect of the invention provides a method for inhibiting an increase in blood phosphorus concentration, wherein an effective amount of the phosphorus binder of the first aspect of the invention, or the composition of the fourth aspect of the invention, is administered to the subject.
在另一优选例中,所述对象包括人或非人哺乳动物。In another preferred embodiment, the subject comprises a human or a non-human mammal.
在另一优选例中,所述非人哺乳动物包括啮齿动物,如小鼠、大鼠。In another preferred embodiment, the non-human mammal comprises a rodent such as a mouse or a rat.
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
图1显示了本发明的磷结合剂中的铁的氢氧化物核心(铁核)为无定形态。Fig. 1 shows that the hydroxide core (iron core) of iron in the phosphorus binder of the present invention is in an amorphous form.
本发明人经过长期而深入的研究,意外地发现,以柠檬酸钠为催化剂,将铁盐、低分子量糖以一定比例混合在一起,具有显著的降低血磷浓度的效果。在此基础上,本发明人完成了本发明。After long-term and intensive research, the inventors have unexpectedly found that the use of sodium citrate as a catalyst to mix iron salts and low molecular weight sugars in a certain ratio has a remarkable effect of lowering blood phosphorus concentration. On the basis of this, the inventors completed the present invention.
铁的氢氧化物Iron hydroxide
本发明的铁的氢氧化物没有特别限制,一种优选的铁的氢氧化物为氢氧化铁、羟基氧化铁、铁的氧化物。The iron hydroxide of the present invention is not particularly limited, and a preferred iron hydroxide is iron hydroxide, iron oxyhydroxide, and iron oxide.
在本发明中,在磷结合剂中,铁的质量比没有特别限制,一种优选的质量比为10wt%-45wt%,较佳地,20wt%-40wt%;更佳地,25wt%-32wt%。In the present invention, in the phosphorus binder, the mass ratio of iron is not particularly limited, and a preferred mass ratio is 10% by weight to 45% by weight, preferably 20% by weight to 40% by weight; more preferably 25% by weight to 32% by weight %.
单糖单元Monosaccharide unit
在本发明中,所述每个低分子量糖平均包括1-20个(较佳地,1-10,更佳地,3-9,更佳地,4-7)单糖单元或所述每个低分子量糖平均包括3-20个(较佳地,3-10,更佳地,4-9,更佳地,4-7)单糖单元,通常低分子量糖的大小(即单糖单
元数)可以通过预处理(例如,使用酸和/或加热或酶,如α-淀粉酶)而降低,低分子量糖可以是以(1→4)糖苷键连接的单糖单元的直链;或可以通过形成(1→6)糖苷键而支化。In the present invention, each of the low molecular weight sugars comprises on average 1 to 20 (preferably, 1 to 10, more preferably, 3 to 9, more preferably 4 to 7) monosaccharide units or each of the above The low molecular weight sugars on average comprise from 3 to 20 (preferably, 3 to 10, more preferably, 4 to 9, more preferably 4 to 7) monosaccharide units, usually of small molecular weight (ie, monosaccharide singles)
The number of elements may be reduced by pretreatment (for example, using an acid and/or heat or an enzyme such as an alpha-amylase), and the low molecular weight sugar may be a linear chain of monosaccharide units linked by a (1→4) glycosidic bond; Or it may be branched by forming a (1→6) glycosidic bond.
低分子糖(低分子量糖)Low molecular weight sugar (low molecular weight sugar)
在本发明中,所述低分子量糖指单糖单元数为1-20个(较佳地,1-10,更佳地,3-9,更佳地,4-7)或3-20个(较佳地,3-10,更佳地,4-9,更佳地,4-7)的单糖、低聚糖和/或多聚糖,优选膳食纤维性低分子量糖。In the present invention, the low molecular weight sugar refers to the number of monosaccharide units of 1-20 (preferably, 1-10, more preferably, 3-9, more preferably, 4-7) or 3-20 (preferably, 3-10, more preferably 4-9, more preferably 4-7) monosaccharides, oligosaccharides and/or polysaccharides, preferably dietary fiber low molecular weight sugars.
本发明的低分子量糖没有特别的限制,一种典型的低分子量糖包括低聚糖。其中,所述低聚糖选自下组:低聚果糖、低聚半乳糖、低聚乳糖、低聚葡萄糖、低聚甘露糖、低聚木糖、海藻糖、乳蔗糖、低聚麦芽糖、异麦芽低聚糖、环糊精、壳质低聚糖、大豆低聚糖、低聚龙胆糖、低聚琼脂糖、水苏糖、低聚果胶、乳果糖、棉子糖、帕拉金低聚糖、或其组合;所述单糖选自下组:葡萄糖、木糖、阿拉伯糖、半乳糖、甘露糖、果糖、鼠李糖、葡萄糖醛酸、或其组合,优选木糖和阿拉伯糖。The low molecular weight sugar of the present invention is not particularly limited, and a typical low molecular weight sugar includes an oligosaccharide. Wherein the oligosaccharide is selected from the group consisting of oligofructose, galactooligosaccharide, oligosaccharide, oligoglucose, oligomannose, xylooligosaccharide, trehalose, lactose, oligomaltose, and different Malto-oligosaccharides, cyclodextrins, chitosan oligosaccharides, soy oligosaccharides, oligosaccharides, oligomeric agarose, stachyose, oligomeric pectin, lactulose, raffinose, parakin An 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 arabin sugar.
一种典型的低分子量糖还包括单糖、和/或多聚糖,其中,所述单糖选自下组:果糖、阿拉伯糖、葡萄糖醛酸、葡萄糖、半乳糖、或其组合。所述多聚糖选自下组:阿拉伯胶、桃胶、瓜尔胶、魔芋胶、卡拉胶、海藻酸钠、果胶、葡聚糖、或其组合。A typical low molecular weight sugar further comprises a monosaccharide, and/or a polysaccharide, wherein the monosaccharide is selected from the group consisting of fructose, arabinose, glucuronic acid, glucose, galactose, or a combination thereof. The polysaccharide is selected from the group consisting of gum arabic, peach gum, guar gum, konjac gum, carrageenan, sodium alginate, pectin, dextran, or a combination thereof.
本发明中的部分低分子量糖,属于水溶性膳食纤维,不易被人体吸收,能直达大肠。在大肠内,能被场内益生菌酵解,有利于益生菌的生长,同时能抑制沙门氏菌等有害菌的生长,减少肠道内致癌物质和有害代谢物的生成和积累,真正起到清除肠道垃圾的作用,并且不会对干扰体内的铁代谢。The low molecular weight sugar in the present invention belongs to a water-soluble dietary fiber, is not easily absorbed by the human body, and can directly reach the large intestine. In the large intestine, it can be fermented by probiotics in the field, which is conducive to the growth of probiotics. At the same time, it can inhibit the growth of harmful bacteria such as Salmonella, reduce the formation and accumulation of carcinogens and harmful metabolites in the intestines, and truly clear the intestines. The role of garbage, and will not interfere with iron metabolism in the body.
本发明的磷结合剂及其制备Phosphorus binding agent of the invention and preparation thereof
通常,为了获得可用作药物的具有良好的磷酸盐结合能力的铁的氢氧化物,需要获得稳定的基于铁的化合物。已知铁的氢氧化物,尤其是三价铁的氢氧化物很不稳定,随时间会发生老化,导致最初随机分布的分子重新组合,并形成大致规则的晶体点阵。老化也可导致基于铁的磷结合剂释放铁,从含铁药物中释放铁可能会引起对安全性的担忧,因为过量的铁对身体器官是有毒的。人体每天摄入的铁量应不超过20mg,由于肠道铁吸收的不适当增加,导致过多
的铁储存于肝脏、心脏和胰腺等实质性细胞中,导致组织器官退行性变和弥漫性纤维化、代谢和功能失常。In general, in order to obtain a hydroxide of iron having good phosphate binding ability which can be used as a medicine, it is required to obtain a stable iron-based compound. 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 generally regular crystal lattice. Aging can also cause iron-based phosphorus binders to release iron, and the release of iron from iron-containing drugs can cause safety concerns because excess iron is toxic to body organs. The amount of iron ingested by the human body per day should not exceed 20 mg, resulting in excessive increase due to improper absorption of intestinal iron.
The iron is stored in substantial cells such as the liver, heart and pancreas, leading to degeneration of tissues and organs, diffuse fibrosis, metabolism and dysfunction.
一类典型的磷结合剂是用低分子糖和柠檬酸钠(催化剂)来预防铁的氢氧化物的老化。One type of typical phosphorus binder is the use of low molecular weight sugars and sodium citrate (catalyst) to prevent the aging of iron hydroxides.
在本发明中,“本发明的磷结合剂”包括铁的氢氧化物和低分子量糖,制备过程中,弱碱如柠檬酸钠起到使低分子量糖和铁的稳定结合的催化作用。本发明的低分子糖没有特别的限制,一种典型的低分子糖包括低聚糖。本发明的低分子糖,属于水溶性膳食纤维,不易被人体吸收,能直达大肠。在大肠内,能被场内益生菌酵解,有利于益生菌的生长,同时能抑制沙门氏菌等有害菌的生长,减少肠道内致癌物质和有害代谢物的生成和积累,真正起到清除肠道垃圾的作用,并且不会对干扰体内的铁代谢。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 plays a catalytic role for stable binding of a low molecular weight sugar and iron during preparation. The low molecular weight sugar of the present invention is not particularly limited, and a typical low molecular sugar includes oligosaccharides. The low molecular weight sugar of the invention belongs to a water-soluble dietary fiber, is not easily absorbed by the human body, and can directly reach the large intestine. In the large intestine, it can be fermented by probiotics in the field, which is conducive to the growth of probiotics. At the same time, it can inhibit the growth of harmful bacteria such as Salmonella, reduce the formation and accumulation of carcinogens and harmful metabolites in the intestines, and truly clear the intestines. The role of garbage, and will not interfere with iron metabolism in the body.
本发明的铁的氢氧化物没有特别限制,一种优选的铁的氢氧化物为氢氧化铁、羟基氧化铁、铁的氧化物。The iron hydroxide of the present invention is not particularly limited, and a preferred iron hydroxide is iron hydroxide, iron oxyhydroxide, and iron oxide.
在本发明中,所述的磷结合剂易溶于水,在水溶液中为3-50nm(优选5-35nm)的纳米颗粒。In the present invention, the phosphorus binder is easily soluble in water, and is 3 to 50 nm (preferably 5 to 35 nm) of nanoparticles in an aqueous solution.
在本发明中,所述的磷结合剂中的铁的氢氧化物核心(铁核)为无定形态(图1)。In the present invention, the hydroxide core (iron core) of iron in the phosphorus binder is in an amorphous state (Fig. 1).
在本发明中,在磷结合剂中,铁的质量比没有特别限制,一种优选的质量比为2-45wt%,较佳地,10-35wt%;更佳地,25-33wt%,以磷结合剂的总重计。In the present invention, in the phosphorus binder, the mass ratio of iron is not particularly limited, and a preferred mass ratio is 2 to 45 wt%, preferably 10 to 35 wt%; more preferably 25 to 33 wt%, The total weight of the phosphorus binder.
本发明的磷结合剂具有很高的磷结合能力。在本发明中,所述铁的氢氧化物与低分子糖的重量比为1:0.25-4,较佳地,1:0.5-1,更佳地,1:0.6-0.7。且铁的质量比为25-30%时,本发明的磷结合剂具有显著优异的磷结合能力(磷吸收量为200-300mg/g)。The phosphorus binder of the present invention has a high phosphorus binding ability. In the present invention, 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. When the mass ratio of iron is 25 to 30%, the phosphorus binder of the present invention has remarkably excellent phosphorus binding ability (phosphorus absorption amount is 200 to 300 mg/g).
本发明的磷结合剂可以用常规方法制备,在本发明中,本发明的磷结合剂用如下方法制备:The phosphorus binder of the present invention can be produced by a conventional method, and in the present invention, the phosphorus binder of the present invention is prepared by the following method:
(a)提供一低分子糖和柠檬酸钠;(a) providing a low molecular weight sugar and sodium citrate;
(b)将所述低分子糖和柠檬酸钠与铁的氢氧化物混合,得到本发明第一方面所述的磷结合剂。(b) mixing the low molecular weight sugar and sodium citrate with iron hydroxide to obtain the phosphorus binder according to the first aspect of the invention.
在一优选的实施方式中,所述方法还包括步骤(c),通过干燥分离产物,以得到干粉形式的所述磷结合剂。In a preferred embodiment, the method further comprises the step (c) of separating the product by drying to obtain the phosphorus binder in the form of a dry powder.
在一优选的实施方式中,所述方法还包括步骤(d),将步骤(c)得到的
所述干粉形式的磷结合剂进行制剂。In a preferred embodiment, the method further comprises the step (d), the step (c)
The phosphorus binder in the form of a dry powder is formulated.
一种优选的磷结合剂的制备方法包括如下几个步骤:A preferred method of preparing a phosphorus binder includes the following steps:
Ⅰ溶解:将糖与弱碱溶于水中,溶液温度为30-100℃;I dissolve: the sugar and the weak base are dissolved in water, the solution temperature is 30-100 ° C;
Ⅱ络合:在30-100℃温度下向溶液中滴加铁盐的水溶液,同时滴加碱溶液控制反应液的pH,滴加一定量的铁盐溶液和碱溶液后,停止滴加,并继续搅拌0-48h(如1-48h),得到产物溶液;II complexation: adding an aqueous solution of iron salt to the solution at a temperature of 30-100 ° C, while adding an alkali solution to control the pH of the reaction solution, dropping a certain amount of the iron salt solution and the alkali solution, stopping the dropping, and Continue stirring for 0-48h (such as 1-48h) to obtain a product solution;
Ⅲ分离:冷却至室温后,离心或过滤分离取红棕色液体,加入1-5倍体积的乙醇,完全析出沉淀后离心或过滤分离,并用乙醇或乙醚清洗;III separation: After cooling to room temperature, the reddish brown liquid is separated by centrifugation or filtration, and 1-5 volumes of ethanol are added, and the precipitate is completely precipitated, centrifuged or separated by filtration, and washed with ethanol or diethyl ether;
Ⅳ收粉:干燥分离步骤III所得到的产物;IV powder collection: drying the product obtained in step III;
Ⅴ制剂:将步骤Ⅳ得到的粉末进行制剂。Form V: The powder obtained in step IV was formulated.
在本发明中,铁盐没有特别限制,一种优选的铁盐为氯化铁。In the present invention, the iron salt is not particularly limited, and a preferred iron salt is ferric chloride.
组合物及其应用Composition and its application
本发明还提供了一种组合物,优选地,为药物组合物。所述组合物包括有效量的磷结合剂。在一优选例中,所述的组合物为液态制剂、固态制剂、半固态制剂。在一优选例中,所述的液态制剂选自下组:溶液制品或悬浮液制品。The invention also provides a composition, preferably a pharmaceutical composition. The composition includes an effective amount of a phosphorus binder. In a preferred embodiment, the composition is a liquid formulation, a solid formulation, or a semi-solid formulation. In a preferred embodiment, the liquid formulation is selected from the group consisting of a solution product or a suspension product.
在一优选例中,所述的组合物的剂型选自下组:粉末剂、散剂、片剂、糖衣剂、胶囊剂、颗粒剂、悬浮剂、溶液剂、糖浆剂、滴剂、和舌下含片。In a preferred embodiment, the dosage form of the composition is selected from the group consisting of powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, and sublingual lozenge.
本发明药物组合物可以以药物片剂,针剂或胶囊的任一种形式给药,所述药物制剂包括赋形剂、药物允许的媒介和载体,这些物质可根据给药途径进行选择。本发明中药物制剂可进一步包含辅助的活性组份。The pharmaceutical composition of the present invention can be administered in any form of a pharmaceutical tablet, an injection or a capsule, which comprises an excipient, a pharmaceutically acceptable vehicle and a carrier, which can be selected depending on the route of administration. The pharmaceutical preparation of the present invention may further comprise an auxiliary active ingredient.
乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮(PVP)、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油等都可用作本发明中药物组合物的载体、赋形剂或稀释剂等。Lactose, glucose, sucrose, sorbitol, mannose, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone (PVP), cellulose, water, syrup, Methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used as a carrier, an excipient or a diluent of the pharmaceutical composition of the present invention.
此外,本发明的药物组合物可进一步包括润滑剂、润湿剂、乳化剂、悬浮液稳定剂、防腐剂、甜味剂和香料等。本发明的药物组合物可通过多种公知的方法以肠衣制剂生产,以便于药物组合物的活性成分能顺利通过胃而不被胃酸所破坏。Further, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, an emulsifier, a suspension stabilizer, a preservative, a sweetener, a perfume, and the like. The pharmaceutical composition of the present invention can be produced in a casing formulation by various known methods so that the active ingredient of the pharmaceutical composition can smoothly pass through the stomach without being destroyed by gastric acid.
说明书中“药物有效量”是指可对人和/或动物产生功能或活性的且可被人和/或动物所接受的量。比如,在本发明中,可制备含有1%-99%(特别的,可
含有30%—90%;更特别地,可含有50%—80%)的磷结合剂的制剂。By "pharmaceutically effective amount" is meant an amount that is functional or active to a human and/or animal and that is acceptable to humans and/or animals. For example, in the present invention, it can be prepared to contain 1% to 99% (particularly,
A formulation comprising from 30% to 90%; more specifically, from 50% to 80% of a phosphorus binder.
当用于制备药物组合物时,所用的磷结合剂的有效剂量可随施用的模式和待治疗的疾病的严重程度而变化。适用于内服的剂量形式,包含与固态或液态药学上可接受的载体密切混合的约含有1%-99%(特别的,可含有30%—90%;更特别地,可含有50%—80%)的磷结合剂。可调节此剂量方案以提供最佳治疗应答。例如,由治疗状况的迫切要求,可每天给予若干次分开的剂量,或将剂量按比例地减少。When used in the preparation of a pharmaceutical composition, the effective dose of the phosphorus binding agent used will vary with the mode of administration and the severity of the condition being treated. Dosage forms suitable for internal administration comprising from about 1% to about 99% in admixture with a solid or liquid pharmaceutically acceptable carrier (particularly, may contain from 30% to 90%; more particularly, may contain from 50% to 80%) %) of a phosphorus binder. This dosage regimen can be adjusted to provide an optimal therapeutic response. For example, several separate doses may be administered per day, or the dose may be proportionally reduced, as is critical to the condition of the treatment.
所述的磷结合剂可通过口服等途径给予。固态载体包括:淀粉、乳糖、磷酸二钙、微晶纤维素、蔗糖和白陶土,而液态载体包括:培养基、聚乙二醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油),只要适合磷结合剂特性和所需的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括,例如调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。The phosphorus binder can be administered by oral or the like. Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include: medium, polyethylene glycol, nonionic surfactants and edible oils (such as corn oil, peanut oil). And sesame oil) as long as it is suitable for the characteristics of the phosphorus binder and the specific mode of administration required. Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, such as flavoring agents, coloring agents, preservatives, and antioxidants such as vitamin E, vitamin C, BHT, and BHA.
从易于制备和给药的立场看,优选的药物组合物是固态组合物,尤其是片剂和固体填充或液体填充的胶囊。口服给药是优选的。From the standpoint of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, especially tablets and solid filled or liquid filled capsules. Oral administration is preferred.
将本发明组合物施用给所述个体,每天给药1次或多次。给药剂量单位表示其形式上能分开且适用于人类或其他所有哺乳动物个体的剂量。每一单位含有药物允许的载体和有效治疗量的本发明的磷结合剂。给药量随病人的血磷水平、所包括的补充活性组份和所使用的磷结合剂而变化。此外如可能,可分开给药,并且如需要可连续给药。因此,所述给药量不会对本发明造成限制。此外,本发明中的“组合物”不仅意味着药品而且表示可作为功能性食品和健康补充食品。在一个优选例中,所述组合物包括:食品、保健品、药品等。在本发明的一个优选例中,还提供了一种食品组合物,它含有有效量的磷结合剂,以及余量的食品上可接受的载体,所述的食物组合物的剂型选自固体、乳品、溶液制品、粉末制品、或悬浮液制品。The composition of the invention is administered to the individual for one or more administrations per day. Dosage unit of administration means a dose that is formally separable and suitable for use in humans or all other mammalian individuals. Each unit contains a pharmaceutically acceptable carrier and a therapeutically effective amount of a phosphorus binder of the invention. The amount administered will vary with the patient's blood phosphorus level, the additional active ingredient included, and the phosphorus binder used. Further, if possible, it can be administered separately and can be administered continuously if necessary. Therefore, the amount administered does not limit the invention. Further, the "composition" in the present invention means not only a medicine but also a functional food and a health supplement. In a preferred embodiment, the composition comprises: food, health care products, pharmaceuticals, and the like. In a preferred embodiment of the invention, there is also provided a food composition comprising an effective amount of a phosphorus binder, and a balance of a food acceptable carrier, the dosage form of the food composition being selected from the group consisting of solids, Dairy, solution, powder, or suspension products.
在一优选例中,所述组合物的配方如下:In a preferred embodiment, the composition of the composition is as follows:
0.1-90wt%的磷结合剂;以及食品上或药学上可接受的载体,和/或赋形剂。0.1-90 wt% of a phosphorus binder; and a food or pharmaceutically acceptable carrier, and/or an excipient.
在另一优选例中,所述组合物的配方如下:In another preferred embodiment, the composition of the composition is as follows:
10-80wt%的磷结合剂;以及食品上或药学上可接受的载体,和/或赋形剂。10-80% by weight of a phosphorus binder; and a food or pharmaceutically acceptable carrier, and/or an excipient.
本发明的含有磷结合剂的组合物具有显著优异的磷结合能力,因此可以用来治疗和/或预防哺乳动物的高磷血症。本发明的哺乳动物可以指人,也可以指温血动物,尤其是猫、狗等。
The phosphorus binder-containing composition of the present invention has remarkably excellent phosphorus binding ability, and thus can be used for treating and/or preventing hyperphosphatemia in a mammal. The mammal of the present invention may be referred to as a human, and may also be a warm-blooded animal, especially a cat, a dog or the like.
本发明的主要优点包括:The main advantages of the invention include:
(1)本发明开发了一种由铁和低分子量糖的磷结合剂,使用了柠檬酸钠等弱碱催化反应,本发明能够显著提高其结合铁的能力、单位铁的磷吸收量等等,极大程度的降低了患者的服用剂量。(1) The present invention has developed a phosphorus binder composed of iron and a low molecular weight sugar, using a weak base catalyzed reaction such as sodium citrate, and the present invention can significantly improve the ability to bind iron, the amount of phosphorus absorbed per unit of iron, and the like. , greatly reducing the dosage of the patient.
(2)本发明所述的低分子量糖属于水溶性膳食纤维,不易被人体吸收,能直达大肠。在大肠内,能被场内益生菌酵解,有利于益生菌的生长,同时能抑制沙门氏菌等有害菌的生长,减少肠道内致癌物质和有害代谢物的生成和积累,真正起到清除肠道垃圾的作用,并且不会对干扰体内的铁代谢,有利于慢性肾功能不全患者的饮食控制。(2) The low molecular weight sugar of the present invention is a water-soluble dietary fiber which is not easily absorbed by the human body and can be directly delivered to the large intestine. In the large intestine, it can be fermented by probiotics in the field, which is conducive to the growth of probiotics. At the same time, it can inhibit the growth of harmful bacteria such as Salmonella, reduce the formation and accumulation of carcinogens and harmful metabolites in the intestines, and truly clear the intestines. The role of garbage, and will not interfere with iron metabolism in the body, is conducive to the dietary control of patients with chronic renal insufficiency.
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
通用方法:General method:
磷酸吸收能力测试方法为:配置浓度为2μg/mL的磷酸溶液,用盐酸氢氧化钠调节pH为3.0,并取样定为标液Control A。取Control A 25mL加入制备好的磷结合剂100±5mg(记为B),低速搅拌下在37℃下反应24h。24小时后,将反应液离心分离(14000rpm),取上层清液,其浓度为C。使用紫外分光光度计分别测定A和C的浓度。磷酸盐结合能力按一下公式计算:The test method for the absorption capacity of phosphoric acid was as follows: a phosphoric acid solution having a concentration of 2 μg/mL was prepared, and the pH was adjusted to 3.0 with sodium hydroxide hydrochloride, and the sample was designated as Control A. Add 25 mL of Control A to the prepared phosphorus binder 100 ± 5 mg (denoted as B), and react at 37 ° C for 24 h with low speed stirring. After 24 hours, the reaction solution was centrifuged (14,000 rpm), and the supernatant was taken at a concentration of C. The concentrations of A and C were determined using an ultraviolet spectrophotometer, respectively. The phosphate binding capacity is calculated by the formula:
吸附活性(mg/g)定义为每克API所能吸附的磷酸根(PO4
3-)的质量Adsorption activity (mg/g) is defined as the mass of phosphate (PO 4 3- ) adsorbed per gram of API
铁含量用ICP电感耦合等离子体发射光谱仪测定。The iron content was measured by ICP inductively coupled plasma optical emission spectrometry.
分子量的测定用GFC凝胶过滤色谱测定。The molecular weight was measured by GFC gel filtration chromatography.
实施例1Example 1
实验方法:experimental method:
将20g低聚半乳糖溶解在200g水中,加入4g柠檬酸钠,升高温度为80℃,搅拌至充分溶解;在80℃温度下向溶液中滴加20%质量比的六水合氯化铁水溶液250g,同时滴加20%质量比的NaOH水溶液控制反应液的pH为7.5-8.5,
滴加完毕后在90℃下搅拌4h,得到红棕色溶液;冷却至室温后,加入3倍体积的95%乙醇,完全析出沉淀后离心分离,并用80%乙醇洗涤固体两次;所得产品加热干燥,共收得28.6g产品,产品呈深黑褐色,颗粒大小为24.5nm,易溶于水。20 g of galactooligosaccharide was dissolved in 200 g of water, 4 g of sodium citrate was added, the temperature was raised to 80 ° C, and stirred until fully dissolved; 20% by mass aqueous solution of ferric chloride hexahydrate was added dropwise to the solution at a temperature of 80 ° C. 250g, while adding 20% by mass of NaOH aqueous solution to control the pH of the reaction solution is 7.5-8.5,
After the completion of the dropwise addition, the mixture was stirred at 90 ° C for 4 h to obtain a reddish brown solution; after cooling to room temperature, 3 volumes of 95% ethanol was added, the precipitate was completely precipitated, and the mixture was centrifuged, and the solid was washed twice with 80% ethanol; A total of 28.6g of product was obtained, the product was dark brown, the particle size was 24.5nm, and it was easily soluble in water.
实验结果:Experimental results:
产物研磨粉碎后,测得铁含量为32.4%,磷吸收为271.9mg/g。After grinding and pulverizing the product, the iron content was found to be 32.4%, and the phosphorus absorption was 271.9 mg/g.
实施例2Example 2
实验方法:experimental method:
将300g低聚果糖溶解在2000g水中,加入40g柠檬酸钠和20g碳酸钠,升高温度为90℃,搅拌至充分溶解;在90℃温度下向溶液中滴加30%质量比的六水合氯化铁水溶液2500g,同时滴加20%质量比的NaOH水溶液控制反应液的pH为7.0-8.5,滴加完毕后在90℃下搅拌8h,得到红棕色悬浊液;冷却至室温后,加入4倍体积的95%乙醇,完全析出沉淀后离心分离,并用80%乙醇洗涤固体两次;所得产品加热干燥,共收得402.4g产品,产品呈黑褐色,颗粒大小为28.3nm,易溶于水。Dissolving 300g of oligofructose in 2000g of water, adding 40g of sodium citrate and 20g of sodium carbonate, raising the temperature to 90 ° C, stirring until fully dissolved; adding 30% by mass of chlorine hexahydrate to the solution at 90 ° C 2500g of aqueous solution of iron, while adding 20% by mass of NaOH aqueous solution to control the pH of the reaction solution is 7.0-8.5, after the completion of the addition, stirring at 90 ° C for 8h, to obtain a reddish brown suspension; after cooling to room temperature, add 4 A volume of 95% ethanol, completely precipitated and then centrifuged, and washed the solid twice with 80% ethanol; the product was heated and dried to obtain 402.4 g of product, the product was dark brown, the particle size was 28.3 nm, and it was easily soluble in water. .
实验结果:Experimental results:
产物研磨粉碎后,测得铁含量为32.4%,磷吸收为342.1mg/g。After grinding and pulverizing the product, the iron content was found to be 32.4%, and the phosphorus absorption was 342.1 mg/g.
实施例3Example 3
实验方法:experimental method:
将200g阿拉伯糖溶解在2000g水中,加入40g柠檬酸钠,升高温度为90℃,搅拌至充分溶解;在90℃温度下向溶液中滴加30%质量比的六水合氯化铁水溶液2500g,同时滴加20%质量比的NaOH水溶液控制反应液的pH为8.0-9.0,滴加完毕后在90℃下搅拌4h,得到黑褐色悬浊液;冷却至室温后,加入4倍体积的95%乙醇,完全析出沉淀后离心分离,并分别用70%乙醇和80%乙醇,洗涤固体两次;所得产品加热干燥,共收得372.4g产品,产品呈深黑褐色,颗粒大小为11.2nm,易溶于水。200 g of arabinose was dissolved in 2000 g of water, 40 g of sodium citrate was added, the temperature was raised to 90 ° C, and stirred until fully dissolved; and 2500 g of a 30% by mass aqueous solution of ferric chloride hexahydrate was added dropwise to the solution at a temperature of 90 ° C. At the same time, a 20% by mass aqueous solution of NaOH was added dropwise to control the pH of the reaction solution to be 8.0-9.0. After the completion of the dropwise addition, the mixture was stirred at 90 ° C for 4 hours to obtain a dark brown suspension; after cooling to room temperature, 4 times by volume of 95% was added. Ethanol was completely precipitated and centrifuged, and the solid was washed twice with 70% ethanol and 80% ethanol respectively. The obtained product was heated and dried to obtain 372.4 g of product. The product was dark brown and the particle size was 11.2 nm. Dissolved in water.
实验结果:Experimental results:
产物研磨粉碎后,测得铁含量为31.2%,磷吸收为195.6mg/g。
After the product was ground and pulverized, the iron content was found to be 31.2%, and the phosphorus absorption was 195.6 mg/g.
实施例4Example 4
实验方法:experimental method:
将300g阿拉伯糖溶解在1800g水中,加入65g柠檬酸钠,反应温度为30℃,搅拌至充分溶解;在30℃温度下向溶液中滴加20%质量比的六水合氯化铁水溶液3500g,同时滴加40%质量比的NaOH水溶液控制反应液的pH为10.0-11.0,滴加完毕后在30℃下搅拌2h,得到红棕色悬浊液;冷却至室温后,加入4倍体积的95%乙醇,完全析出沉淀后离心分离,并分别用70%乙醇和80%乙醇,洗涤固体两次;所得产品加热干燥,共收得583g产品,产品呈红褐色,颗粒大小为10.6nm,易溶于水。300 g of arabinose was dissolved in 1800 g of water, 65 g of sodium citrate was added, the reaction temperature was 30 ° C, and stirred until fully dissolved; 3500 g of a 20% by mass aqueous solution of ferric chloride hexahydrate was added dropwise to the solution at a temperature of 30 ° C, The aqueous solution of 40% by mass of NaOH was added dropwise to control the pH of the reaction solution to be 10.0-11.0. After the completion of the dropwise addition, the mixture was stirred at 30 ° C for 2 hours to obtain a reddish brown suspension; after cooling to room temperature, 4 times by volume of 95% ethanol was added. The precipitate was completely separated and centrifuged, and the solid was washed twice with 70% ethanol and 80% ethanol respectively; the obtained product was dried by heating, and a total of 583 g of product was obtained. The product was reddish brown, the particle size was 10.6 nm, and it was easily soluble in water. .
实验结果:Experimental results:
产物研磨粉碎后,测得铁含量为32.4%,磷吸收为284.3mg/g。After grinding and pulverizing the product, the iron content was found to be 32.4%, and the phosphorus absorption was 284.3 mg/g.
实施例5Example 5
将200g果糖溶解在1000g水中,加入30g柠檬酸钠,反应温度为50℃,搅拌至充分溶解;在50℃温度下向溶液中滴加20%质量比的六水合氯化铁水溶液3000g,同时滴加40%质量比的NaOH水溶液控制反应液的pH为10.0-11.0,滴加完毕后在50℃下搅拌2h,得到红棕色悬浊液;冷却至室温后,加入4倍体积的95%乙醇,完全析出沉淀后离心分离,并分别用70%乙醇和80%乙醇,洗涤固体两次;所得产品加热干燥,共收得363g产品,产品呈红褐色,颗粒大小为14.2nm,易溶于水。200g of fructose is dissolved in 1000g of water, 30g of sodium citrate is added, the reaction temperature is 50 ° C, and stirred until fully dissolved; 30g of a 20% by mass aqueous solution of ferric chloride hexahydrate is added dropwise to the solution at a temperature of 50 ° C, while dropping The pH of the reaction solution was adjusted to 10.0-11.0 by adding a 40% by mass aqueous solution of NaOH. After the addition was completed, the mixture was stirred at 50 ° C for 2 hours to obtain a reddish brown suspension; after cooling to room temperature, 4 volumes of 95% ethanol were added. After the precipitate was completely precipitated, the mixture was centrifuged, and the solid was washed twice with 70% ethanol and 80% ethanol respectively; the obtained product was dried by heating, and a total of 363 g of the product was obtained. The product was reddish brown with a particle size of 14.2 nm and was easily soluble in water.
实验结果:Experimental results:
产物研磨粉碎后,测得铁含量为27.2%,磷吸收为306.5mg/g。After grinding and pulverizing the product, the iron content was determined to be 27.2%, and the phosphorus absorption was 306.5 mg/g.
实施例6Example 6
将200g半乳糖溶解在1000g水中,加入50g柠檬酸钠,反应温度为80℃,搅拌至充分溶解;在80℃温度下向溶液中滴加20%质量比的六水合氯化铁水溶液3000g,同时滴加40%质量比的NaOH水溶液控制反应液的pH为10.0-11.0,滴加完毕后在80℃下搅拌1h,得到红棕色悬浊液;冷却至室温后,加入4倍体积的95%乙醇,完全析出沉淀后离心分离,并分别用70%乙醇和80%乙醇,洗涤固体两次;所得产品加热干燥,共收得352g产品,产品呈红褐色,颗粒大
小为32.7nm,易溶于水。200 g of galactose was dissolved in 1000 g of water, 50 g of sodium citrate was added, the reaction temperature was 80 ° C, and stirred until fully dissolved; and at a temperature of 80 ° C, 3000 g of a 20% by mass aqueous solution of ferric chloride hexahydrate was added dropwise to the solution while The pH of the reaction solution was adjusted to 10.0-11.0 by adding 40% by mass of NaOH aqueous solution, and the mixture was stirred at 80 ° C for 1 hour to obtain a reddish brown suspension; after cooling to room temperature, 4 times by volume of 95% ethanol was added. After completely precipitating the precipitate, the mixture was centrifuged, and the solid was washed twice with 70% ethanol and 80% ethanol respectively; the obtained product was dried by heating, and a total of 352 g of the product was obtained, and the product was reddish brown and the particles were large.
Small 32.7nm, soluble in water.
实验结果:Experimental results:
产物研磨粉碎后,测得铁含量为39.6%,磷吸收为164.8mg/g。After grinding and pulverizing the product, the iron content was found to be 39.6%, and the phosphorus absorption was 164.8 mg/g.
实施例7Example 7
实验方法:experimental method:
65只雄性SD大鼠运送到达后适应一周,给每只大鼠编号和称重,并开始给予大鼠特殊高磷加高腺嘌呤饲料喂养,每笼2只大鼠。一周一次测定体重和摄食量,两周时测定6只大鼠血磷,三周时测定全部大鼠血磷,直到造模成功(血磷水平符合高磷血症的定义≥12mg/dL)。从65只大鼠中选出50只大鼠,将血磷值不达标的大鼠剔除。根据体重和血磷水平,随机分成5组,每组10只,按照表1实验分组计划进行给药。Sixty-five male Sprague-Dawley rats were acclimated for one week after delivery, and each rat was numbered and weighed, and rats were given special high-phosphorus adenine feed, 2 rats per cage. The body weight and food intake were measured once a week. The blood phosphorus of 6 rats was measured at two weeks, and the blood phosphorus of all rats was measured at three weeks until the modeling was successful (the blood phosphorus level was consistent with the definition of hyperphosphatemia ≥ 12 mg/dL). Fifty rats were selected from 65 rats, and the rats whose blood phosphorus levels were not up to standard were excluded. According to body weight and blood phosphorus levels, 5 groups were randomly divided into groups of 10, and administered according to the experimental group plan of Table 1.
表1Table 1
组别Group | 药物类型Drug type | 动物数量(只)Number of animals (only) | 给药量(质量比例)Amount of administration (mass ratio) |
溶媒对照组Solvent control group | 玉米淀粉corn starch | 1010 | 2%饮食2% diet |
阳性药对照组Positive drug control group | 碳酸司维拉姆Sevelamal | 1010 | 2%饮食2% diet |
测试化合物1Test compound 1 | 半乳糖铁Galactose iron | 1010 | 2%饮食2% diet |
测试化合物2Test compound 2 | 果糖铁Fructose iron | 1010 | 2%饮食2% diet |
测试化合物3Test compound 3 | 阿拉伯糖铁Arabian sugar iron | 1010 | 2%饮食2% diet |
实验期间实验动物自由摄食,无须人为干预,连续给药2周。治疗期间,观察及检测下列指标:动物存活(实验期间)、24小时摄食量、体重(一周一次)、血磷、血钙、铁、肌酐、BUN(给药前1天,给药后第2周)、尿量(24小时)、尿铁、尿磷(给药前1天,给药后第2周)。During the experiment, the experimental animals were fed freely without human intervention and continued for 2 weeks. During treatment, the following indicators were observed and tested: animal survival (during the experiment), 24-hour food intake, body weight (once a week), blood phosphorus, blood calcium, iron, creatinine, BUN (1 day before administration, 2nd after administration) Week), urine volume (24 hours), urinary iron, urinary phosphorus (1 day before administration, 2 weeks after administration).
实验结果:Experimental results:
表2给药两周后的血磷值和血磷变化值Table 2 Blood phosphorus value and blood phosphorus change value after two weeks of administration
结果如表2所示。结果显示,治疗2周时,与基线相比,各组大鼠血清磷均有所降低;和对照组的血清磷变化值比较,阳性药、果糖铁和半乳糖铁三组的血清磷变化值有显著差异。其中,受试化合物中果糖铁的降血磷效果最优,和阳性化合物碳酸司维拉姆的效果相当,其次为阿拉伯糖铁。The results are shown in Table 2. The results showed that serum phosphorus decreased in each group compared with baseline at 2 weeks of treatment. Compared with the serum phosphorus changes in the control group, serum phosphorus changes in the positive, fructose and galactose groups There are significant differences. Among them, the antihypertensive effect of fructose iron in the test compound was the best, and the effect of the positive compound sevelamer was equivalent, followed by arabinose iron.
但是从服用药物中活性成分的量来看,果糖铁<阿拉伯糖铁<半乳糖铁<阳性药。因此,在本发明的磷结合剂中,少量剂量的活性成分就可以达到非常好的降血磷效果。因此,综合来看,本发明的磷结合剂的降血磷效果显著优于阳性药,具有非常显著的降血磷效果。However, from the amount of the active ingredient in the drug, fructose iron <arabinose iron <galactose iron < positive drug. Therefore, in the phosphorus binder of the present invention, a small amount of the active ingredient can achieve a very good hypophosphatemic effect. Therefore, in summary, the phosphorus-binding agent of the present invention has a significantly lower blood phosphorus-lowering effect than the positive drug, and has a very significant hypophosphatemic effect.
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.
Claims (10)
- 一种磷结合剂,其特征在于,包括:A phosphorus binder, characterized by comprising:铁的氢氧化物;和Iron hydroxide; and低分子量糖;Low molecular weight sugar;其中,所述低分子量糖的单糖单元数为1-20,并且以所述磷结合剂的总重计,铁的质量比为2-45wt%。Wherein the number of monosaccharide units of the low molecular weight sugar is from 1 to 20, and the mass ratio of iron is from 2 to 45% by weight based on the total weight of the phosphorus binder.
- 如权利要求1所述的磷结合剂,其特征在于,所述低分子量糖包括低聚糖。The phosphorus binder according to claim 1, wherein the low molecular weight sugar comprises an oligosaccharide.
- 如权利要求1所述的磷结合剂,其特征在于,所述铁的氢氧化物与所述低分子量糖的重量比为1:0.25-4,较佳地,1:0.5-1,更佳地,1:0.6-0.7。The phosphorus binder according to claim 1, wherein a weight ratio of said iron hydroxide to said low molecular weight sugar is 1:0.25-4, preferably 1:0.5-1, more preferably Ground, 1:0.6-0.7.
- 如权利要求1所述磷结合剂的用途,其特征在于,用于制备抑制血磷浓度升高的组合物。The use of a phosphorus binder according to claim 1, which is for use in the preparation of a composition for inhibiting an increase in blood phosphorus concentration.
- 如权利要求1所述磷结合剂的制法,其特征在于,包括步骤:A method of preparing a phosphorus binder according to claim 1, comprising the steps of:(a)提供一低分子量糖和弱碱;(a) providing a low molecular weight sugar and a weak base;(b)将所述低分子量糖和所述弱碱、铁的氢氧化物混合,得到权利要求1所述的磷结合剂。(b) mixing the low molecular weight sugar with the weak base or iron hydroxide to obtain the phosphorus binder according to claim 1.
- 如权利要求5所述的制法,其特征在于,所述步骤(b)中,所述低分子量糖与所述弱碱的质量比为1:0.01-1,较佳地,1:0.1-0.5,更佳地,1:0.2-0.3。The method according to claim 5, wherein in the step (b), the mass ratio of the low molecular weight sugar to the weak base is 1:0.01-1, preferably 1:0.1- 0.5, more preferably 1:0.2-0.3.
- 如权利要求5所述的制法,其特征在于,所述步骤(b)中,所述低分子量糖与所述铁的氢氧化物的质量比为1:0.2-4,较佳地,1:0.5-1,更佳地,1:0.6-0.7。The method according to claim 5, wherein in the step (b), the mass ratio of the low molecular weight sugar to the iron hydroxide is 1:0.2-4, preferably, 1 : 0.5-1, more preferably 1:0.6-0.7.
- 如权利要求5所述的制法,其特征在于,所述方法还包括步骤(c),通过干燥分离产物,以得到干粉形式的所述磷结合剂。A process according to claim 5, wherein the method further comprises the step (c) of separating the product by drying to obtain the phosphorus binder in the form of a dry powder.
- 一种组合物,其特征在于,包括:权利要求1所述的磷结合剂;和A composition comprising: the phosphorus binder of claim 1;药学上可接受的载体。A pharmaceutically acceptable carrier.
- 如权利要求9所述的组合物,其特征在于,在所述组合物中,含有0.1-99wt%,较佳地,10-90wt%所述的磷结合剂,以所述组合物的总重量计。 The composition of claim 9 wherein said composition comprises from 0.1% to 99% by weight, preferably from 10% to 90% by weight, of said phosphorus binder, based on the total weight of said composition meter.
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