WO2017198199A1

WO2017198199A1 - Phosphate binder comprising hydroxide of ferrum and low-molecular-weight sugars, preparation method therefor, and applications thereof

Info

Publication number: WO2017198199A1
Application number: PCT/CN2017/084944
Authority: WO
Inventors: 王伟; 许婧; 陆佳美; 包丽霞; 贺利军; 仇波; 肖飞
Original assignee: 欣凯医药化工中间体（上海）有限公司
Priority date: 2016-05-19
Filing date: 2017-05-18
Publication date: 2017-11-23
Also published as: CN107397760A; CN107397760B

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

Iron-based hydroxide-low molecular weight phosphorus binder, preparation method thereof and application thereof

Technical field

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.

Background technique

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.

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.

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.

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.

Summary of the invention

An object of the present invention is to provide a phosphorus binder which can greatly improve phosphorus adsorption ability and reduce side effects.

A first aspect of the invention provides a phosphorus binder comprising:

Iron hydroxide; and

Low molecular weight sugar;

Wherein the number of monosaccharide units of the low molecular weight sugar is 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.

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.

In another preferred embodiment, the low molecular weight sugar has a number of monosaccharide units of from 3 to 20.

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.

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.

In another preferred embodiment, the low molecular weight sugar comprises a monosaccharide, an oligosaccharide, and/or a polysaccharide.

In another preferred embodiment, the low molecular weight sugar comprises a monosaccharide and an oligosaccharide.

In another preferred embodiment, the low molecular weight sugar comprises an oligosaccharide.

In another preferred embodiment, the oligosaccharide is selected from the group consisting of 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.

In another preferred embodiment, the monosaccharide is selected from the group consisting of fructose, arabinose, glucuronic acid, glucose, galactose, or a combination thereof.

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.

In another preferred embodiment, the weight ratio of the iron hydroxide to the low molecular weight sugar is 1:0.25-4, preferably 1:0.5-1, more preferably 1:0.6-0.7.

In another preferred embodiment, the hydroxide of iron is selected from the group consisting of iron hydroxide, iron oxyhydroxide, oxides of iron, or combinations thereof.

In another preferred embodiment, the hydroxide of iron forms a stable structure with the low molecular weight sugar by hydrogen bonding or adsorption (coordination).

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%.

In another preferred embodiment, the residual amount of citrate in the phosphorus binder is <1%, preferably <0.5%, more preferably <0.1%.

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.

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.

In another preferred embodiment, the composition is also used to supplement iron.

In another preferred embodiment, the composition comprises a pharmaceutical composition, a health care composition, a food composition, or a combination thereof.

In another preferred embodiment, the composition comprises a safe and effective amount of (i) a hydroxide of iron; (ii) a low molecular weight sugar;

In another preferred embodiment, the composition is an oral preparation.

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.

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.

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) providing a low molecular weight sugar and a weak base;

(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.

In another preferred embodiment, the iron hydroxide is either formulated or ready to be used.

In another preferred embodiment, the weak base is sodium citrate, potassium citrate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or a mixture thereof.

In another preferred embodiment, the weak base is citric acid, sodium citrate, and/or sodium citrate hydrate.

In another preferred embodiment, the sodium citrate hydrate comprises trisodium citrate dihydrate.

In another preferred embodiment, the weak base comprises sodium citrate.

In another preferred embodiment, in the step (b), the mass ratio of the low molecular weight sugar to the weak base is 1:0.01-1, preferably 1:0.1-0.5, more preferably,1. : 0.2-0.3.

In another preferred embodiment, in the step (b), the mass ratio of the low molecular weight sugar to the iron hydroxide is 1:0.2-4, preferably 1:0.5-1, more preferably Ground, 1:0.6-0.7.

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.

In another preferred embodiment, said step (b1) has one or more of the following features:

(i) the solution temperature is 20-100 ° C, preferably 60-95 ° C, more preferably 80-90 ° C;

(ii) the reaction time is 1-48 h, preferably 1-24 h, more preferably 4-16 h;

(iii) the cooling temperature is 0-40 ° C;

(iv) pH adjustment to 6-12, preferably 7-10.

In another preferred embodiment, in the step (b1), purification is carried out with ethanol.

In another preferred embodiment, the ethanol contains 5-20% water.

In another preferred embodiment, the ethanol is anhydrous ethanol or 90-95% ethanol.

In another preferred embodiment, the ethanol and water (v/v) are from 1:0.05 to 1:10.

In another preferred embodiment, the step (b1) further comprises a stirring and cooling step.

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.

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.

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.

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.

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.

In another preferred embodiment, the drying comprises product drying, heat drying, spray drying or fluidized spray drying.

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).

A fourth aspect of the invention provides a composition comprising: the phosphorus binder of the first aspect of the invention;

A pharmaceutically acceptable carrier.

In another preferred embodiment, the composition is an oral preparation.

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.

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.

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.

In another preferred embodiment, the subject comprises a human or a non-human mammal.

In another preferred embodiment, the non-human mammal comprises a rodent such as a mouse or a rat.

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.

DRAWINGS

Fig. 1 shows that the hydroxide core (iron core) of iron in the phosphorus binder of the present invention is in an amorphous form.

detailed description

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.

Iron hydroxide

The iron hydroxide of the present invention is not particularly limited, and a preferred iron hydroxide is iron hydroxide, iron oxyhydroxide, and iron oxide.

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 %.

Monosaccharide unit

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.

Low molecular weight sugar (low molecular weight sugar)

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.

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.

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.

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.

Phosphorus binding agent of the invention and preparation thereof

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.

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.

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.

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.

In the present invention, the hydroxide core (iron core) of iron in the phosphorus binder is in an amorphous state (Fig. 1).

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.

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).

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) providing a low molecular weight sugar and sodium citrate;

(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.

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.

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.

A preferred method of preparing a phosphorus binder includes the following steps:

I dissolve: the sugar and the weak base are dissolved in water, the solution temperature is 30-100 ° C;

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 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 powder collection: drying the product obtained in step III;

Form V: The powder obtained in step IV was formulated.

In the present invention, the iron salt is not particularly limited, and a preferred iron salt is ferric chloride.

Composition and its application

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

In a preferred embodiment, the composition of the composition is as follows:

0.1-90 wt% of a phosphorus binder; and a food or pharmaceutically acceptable carrier, and/or an excipient.

In another preferred embodiment, the composition of the composition is as follows:

10-80% by weight 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 main advantages of the invention include:

(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) 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.

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.

General method:

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:

Adsorption activity (mg/g) is defined as the mass of phosphate (PO ₄ ^3- ) adsorbed per gram of API

The iron content was measured by ICP inductively coupled plasma optical emission spectrometry.

The molecular weight was measured by GFC gel filtration chromatography.

Example 1

experimental method:

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.

Experimental results:

After grinding and pulverizing the product, the iron content was found to be 32.4%, and the phosphorus absorption was 271.9 mg/g.

Example 2

experimental method:

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. .

Experimental results:

After grinding and pulverizing the product, the iron content was found to be 32.4%, and the phosphorus absorption was 342.1 mg/g.

Example 3

experimental method:

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.

Experimental results:

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.

Example 4

experimental method:

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. .

Experimental results:

After grinding and pulverizing the product, the iron content was found to be 32.4%, and the phosphorus absorption was 284.3 mg/g.

Example 5

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.

Experimental results:

After grinding and pulverizing the product, the iron content was determined to be 27.2%, and the phosphorus absorption was 306.5 mg/g.

Example 6

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.

Experimental results:

After grinding and pulverizing the product, the iron content was found to be 39.6%, and the phosphorus absorption was 164.8 mg/g.

Example 7

experimental method:

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.

Table 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

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).

Experimental results:

Table 2 Blood phosphorus value and blood phosphorus change value after two weeks of administration

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.

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.

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

A phosphorus binder, characterized by comprising:

Iron hydroxide; and

Low molecular weight sugar;

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.
The phosphorus binder according to claim 1, wherein the low molecular weight sugar comprises an oligosaccharide.
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.
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.
A method of preparing a phosphorus binder according to claim 1, comprising the steps of:

(a) providing a low molecular weight sugar and a weak base;

(b) mixing the low molecular weight sugar with the weak base or iron hydroxide to obtain the phosphorus binder according to claim 1.
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.
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.
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.
A composition comprising: the phosphorus binder of claim 1;

A pharmaceutically acceptable carrier.
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.