JPH0455737B2 - - Google Patents

Description

[Detailed description of the invention]

[Technical Field of the Invention] The present invention relates to an adsorbent comprising a MgO-TiO ₂ composite and an antihyperphosphatemic agent for the adsorbent. [Technical Background of the Invention] In patients with kidney or liver dysfunction, the ability to excrete metabolic waste products from the body is insufficient, and these substances accumulate in the body, resulting in various physiological disorders. ing. Therefore, in order to improve the pathological conditions of these functionally impaired individuals, metabolic waste products and the like are generally removed from the living body. For example, patients with renal failure are known to be typical of patients with renal dysfunction;
Treatment methods include blood purification using a dialysis membrane and blood perfusion using activated carbon. Incidentally, in patients with renal failure, hyperphosphatemia associated with a decline in the ability to excrete phosphorus into the urine is a problem, but the conventional treatments described above cannot improve the condition of hyperphosphatemia. There is. That is, the former blood purification method using a dialysis membrane cannot sufficiently control the phosphorus concentration in the blood, and is completely powerless against intestinal absorption of phosphorus, which is the most important factor in hyperphosphatemia. On the other hand, the latter treatment method using activated carbon has a problem due to the characteristics of activated carbon itself, that is, its adsorption power for inorganic substances such as phosphorus is extremely poor. For this reason, conventionally, as a symptomatic treatment for hyperphosphatemia, phosphorus binders based on aluminum compounds such as aluminum hydroxide and aluminum carbonate have been taken. However, aluminum compound-based phosphorus binders are not suitable for people who consume large amounts of phosphorus (1500
mg/day), and there is a risk of side effects such as constipation, nausea, and vomiting if taken in large doses.Moreover, there have been reports recently that it may cause Al osteopathy and Al encephalopathy. being done. [Purpose of the Invention] In view of the above-mentioned circumstances, the inventors of the present invention have conducted intensive studies with the aim of providing an adsorbent that is highly safe for living organisms and has extremely stable phosphorus adsorption properties over time. The inventors have discovered that a MgO-TiO ₂ composite having the following composition is extremely suitable for this purpose, and have completed the present invention. [Structure of the Invention] That is, based on the above knowledge, the present invention provides an _adsorbent (hereinafter referred to as
(referred to as the adsorbent of the present invention) and the use of the adsorbent as an antihyperphosphatemic agent. Composition ratio: MgO/TiO ₂ (molar ratio) = 99.99/
0.01 to 80/20 Specific surface area: 50 to 700 m ² /g (BET method) Crystal structure: Shows a crystal diffraction pattern of MgO in powder X-ray diffraction method. [Disclosure of the Invention] The present invention will be described in detail below. The adsorbent of the present invention is produced by mixing a magnesium compound and a titanium compound, and calcining the resulting precipitate by hydrolysis. That is, the adsorbent of the present invention is produced by a heterogeneous precipitation method in which salts such as magnesium chloride and titanium tetrachloride are mixed in a given ratio and then hydrolyzed with an alkali such as aqueous ammonia, or by using urea in place of the alkali. The homogeneous coprecipitation method used, the method of mixing and hydrolyzing metal alkoxides, the method of kneading metal hydroxides, etc., and the method of immersing the other metal oxide in an aqueous solution of one metal salt, It can be produced by firing a precipitate prepared by adding ammonia water thereto. The purpose of the calcination process is to combine MgO and TiO ₂ and improve their adsorbent properties, such as specific surface area,
The goal is to adjust the surface chemical structure, such as surface OH groups. Firing conditions vary depending on the preparation method, adjustment conditions, blending ratio, etc., and are not particularly limited, but usually
Temperatures of 200°C to 1000°C, preferably 300°C to 700°C, more preferably 350°C to 500°C are suitable. In addition, in the composite obtained by the above manufacturing method, as the amount of TiO ₂ , which is one of the constituent components, increases, the disorder of the crystal structure increases, and MgO-
TiO ₂ composite becomes MgO when the ratio of TiO ₂ exceeds 20%
The powder X-ray diffraction pattern unique to the crystal disappears, and at the same time, the phosphorus adsorption performance decreases significantly. Moreover, when the ratio of TiO ₂ is small, it becomes difficult to distinguish from magnesium oxide alone in terms of X-ray diffraction. However, in contrast to those composed of magnesium oxide alone whose phosphorus adsorption performance deteriorates over time due to the influence of carbon dioxide in the atmosphere, in the present invention, due to the presence of TiO ₂ , MgO− TiO ₂ composite exhibits the excellent property of maintaining stable adsorption performance for a long time even in the atmosphere. Therefore, in the adsorbent of the present invention, in the MgO-TiO ₂ composite produced by the above method, MgO/TiO ₂ (molar ratio) = 99.99/0.01 to 80/20, preferably 99.9/
0.1 to 90/10, a specific surface area of 50 to 700 m ² /g, preferably 100 to 500 m ² /g, and a crystal diffraction pattern of MgO, for example, 2θ = 43.07°, 62.55°, in powder X-ray diffraction. It is something to do. The adsorbent of the present invention has excellent adsorption properties for phosphorus and phosphorus compounds. Moreover, the adsorbent of the present invention has JCl
- When administered orally to SDD rats at 5000 mg/Kg,
No abnormalities are shown in terms of acute toxicity. Therefore, the adsorbent of the present invention can be used alone or in the form of a pharmaceutical composition as an antihyperphosphatemic agent. When used as the antihyperphosphatemia agent, the adsorbent of the present invention may be in the form of powder, granules, spheres, etc., or as a composition of these with a pharmaceutically acceptable carrier and/or adjuvant. Various formulation forms are possible. Specific formulation forms include tablets, sublingual tablets, pills, powders, granules, capsules, suppositories, troches, aqueous or oily solvents, suspensions,
They come in various forms such as emulsions, syrups, and gelling agents. Tablets, powders, capsules, etc. may include enteric-coated dosage forms. Pharmaceutically acceptable carriers are not particularly limited, but generally include water, gelatin, lactose, starch,
Pectin, magnesium stearate, stearic acid, talc, vegetable oil, gum arabic, polyalkylene glycol, petrolatum, sorbitan triolate, polyoxyethylene sorbitan monooleate, alkyl phenol, aliphatic alcohol,
Examples include polyvinylpyrrolidone. Further, when preparing the formulation, it is also possible to use conventional pharmaceutical auxiliaries such as sweeteners, flavorants, coloring agents, preservatives, salts for adjusting osmotic pressure, and buffering agents, if necessary. The composition can be taken orally or enterally. Although the content of the adsorbent of the present invention in the pharmaceutical composition may vary as appropriate, it can be contained in the range of 1% to 99% by weight, preferably 10% to 99% by weight. The dosage varies depending on the severity of the disease, etc.
Usually 0.1 to 2 g/time as MgO-TiO ₂ composite, 1
About 3 times a day is appropriate. Of course, this does not apply in cases of emergency. When applied to patients with renal failure, the period may be either the predialysis period or the dialysis period. The adsorbent of the present invention can be used as an adsorbent for blood perfusion, either alone or by coating with a biocompatible substance such as heparin, in addition to being used as an oral preparation as described above. Hereinafter, the present invention will be explained in detail with reference to Examples. Example 1 After dropping 0.57 g of titanium tetraisopropoxide [(CH ₃ ) ₂ CHO] ₄ Ti into stirred water, 1.2 g of nitric acid (61 wt%) was added. Then to this solution,
After adding a solution of 51.3 g _of magnesium nitrate Mg(NO ₃ ) 2.6H ₂ O dissolved in 50 ml of water, 30 g of 28% aqueous ammonia was gradually added for hydrolysis, and the resulting precipitate was centrifuged. After thoroughly washing the obtained precipitate with water, the temperature was raised to 400°C at a rate of 200°C/hr under a nitrogen stream, held at 400°C for 1 hour, and 7.0g of MgO/TiO ₂
A composite with a molar ratio of 99/1 was obtained. FIG. 1 shows a powder X-ray diffraction pattern of this MgO-TiO ₂ composite. Example 2 After dropping 5.7 g of titanium tetraisopropoxide [(CH ₃ ) ₂ CHO] ₄ Ti into stirred water, 12.4 g of nitric acid (61 wt%) was added. Then to this solution,
After adding a solution of 46.2 g of magnesium nitrate Mg(NO ₃ ) _{2.6H 2 O} dissolved in 50 ml of water, 29 g of 28% aqueous ammonia was gradually added for hydrolysis, and the resulting precipitate was centrifuged. After thoroughly washing the obtained precipitate with water, the temperature was raised to 400°C at 200°C/hr under a nitrogen stream.
7.3g of MgO/ _TiO2 (molar ratio
A composite of 90/10) was obtained. Comparative example 1 51.3g of magnesium nitrate Mg (NO ₃ ) ₂・6H ₂ O
was dissolved in 50 ml of water with stirring, and 29 g of 28% ammonia water was gradually added for hydrolysis, and the precipitate formed was centrifuged. After thoroughly washing the obtained precipitate with water, the temperature was raised to 400°C at 200°C/hr under a nitrogen stream.
The mixture was maintained at 400°C for 1 hour to obtain 6.4g of magnesium oxide. FIG. 2 shows the powder X-ray diffraction pattern of this product. Example 3 Table 1 shows the results of specific surface area (BET method) and powder X-ray diffraction measurements of the samples obtained in Examples 1 and 2 and Comparative Example 1.

[Table] Example 4 The left renal artery branch of an 11-week-old Jcl-SD rat was partially ligated, and 7 days later, the renal hilum of the right kidney was ligated to create a renal failure model rat. After 30 days of follow-up observation using 4 rats, blood was collected from the tail vein, and serum creatinine and inorganic phosphorus concentrations were determined.
1.7 ± 0.3 (mg/dl) and 7.1 ± 0.3 (mg/dl), the feed (CE-2: manufactured by CLEA Japan) was mixed with 0.1% of the sample obtained in Example 1 for 5 minutes.
It was allowed to be taken ad libitum for days. After 5 days of administration, blood was collected from the tail vein and the inorganic phosphorus concentration in the serum was measured. The results are shown in Table 2. Measuring equipment Creatinine: Beckman creatinine analyzer (manufactured by Beckman) Inorganic phosphorus: RaBA-Mark (manufactured by Kyoto Daiichi Kagaku)

[Table] Example 5 When the samples obtained in Examples 1 and 2 and Comparative Example 1 were left in the air, changes in the amount of phosphorus adsorbed over time were tracked. The results are shown in FIG. Comparative example 1
With MgO obtained alone, the phosphorus adsorption performance deteriorates over time, whereas with the MgO-TiO ₂ composites obtained in Examples 1 and 2, no change was observed in the adsorption amount and it could be kept stable. Ta. The amount of phosphorus adsorbed is thorium dihydrogen phosphate.
50 ml of a solution with a NaH ₂ PO ₄ concentration of 3.22 mmole/l was placed in a stoppered Erlenmeyer flask, 100 mg of each sample was added, and the mixture was shaken at room temperature for 2 hours, filtered, and the phosphorus concentration in the solution was measured using RaBA Ace (Kyoto Daiichi Scientific Co., Ltd.). The amount of phosphorus adsorption was determined by measuring the amount of phosphorus adsorbed by

[Brief explanation of drawings]

FIG. 1 and FIG. 2 respectively show the MgO-
FIG. 3 is a diagram showing X _- ray diffraction patterns of a TiO 2 composite and a comparative material, and FIG. 3 is a diagram showing changes over time in the amount of phosphorus adsorbed in the MgO-TiO ₂ composite of the present invention and a comparative material.

Claims (1)

[Claims] 1. A phosphorus adsorbent comprising a MgO-TiO ₂ composite. 2. The adsorbent according to claim 1, wherein the MgO- _TiO2 composite has a MgO/ _TiO2 ratio of 99.99/0.01 to 80/20 in molar ratio. 3 Specific surface area of MgO- _TiO2 composite is 50-700
The adsorbent according to claim 1, wherein the adsorbent has a particle size of m ² /g. 4. The adsorbent according to claim 1, which exhibits a crystal diffraction pattern of MgO in powder X-ray diffraction. 5. The adsorbent according to claim 1, which is an antihyperphosphatemic agent. 6 Claim 1 which is an adsorbent for blood perfusion
Adsorbent as described in section.