COMPLEX OF MAGNESIUM OXIDE AND TITANIUM DIOXIDE AS A PHOSPHATE ADSORBENT

Abstract: A phosphate adsorbent comprising an MgO-TiO₂ complex as an active ingredient is useful as an antihyperphosphoremial agent, an adsorbent for hemoperfusion and a therapeutical agent for renal diseases. The complex can be deposited on active carbon. In a preferred embodiment, the MgO:TiO₂ molar ratio in the complex is in the range of 99.99:0.01 to 80:20, the specific surface area of the adsorbent as measured by BET method is in the range of 50 to 700 m²/g and the adsorbent shows a crystal diffraction pattern of MgO in powder X-ray diffractometry.

Description: The present invention relates to a phosphate adsorbent comprising an MgO-TiO₂ complex. Patients suffering from functional disturbance in kidney or liver are increasing recently. These patients have a weak function to excrete waste metabolites out of a body system, so that such waste materials are accumulated in the system to cause various physiological troubles. Therefore, means and treatments for improving conditions of the patients suffering from such functional disturbance have been performed by removing such waste metabolites. Chronic renal failure is a typical case of functional disturbance of kidney. At present, methods such as hemocatharsis by a dialysis membrane and hemoperfusion by active carbons are applied for treatments of the renal failure. The patients with chronic renal failure have weak renal function to excrete phosphate into urine. However, said hemocatharsis using a dialysis membrane is incapable of sufficiently controlling the phosphate concentration in blood and quite ineffective for the adsorption of phosphate in an intestinal tract. On the other hand, the adsorption method using active carbons has the problem that adsorptivity of inorganic substance such as phosphate is very poor comparing with adsorptivity of organic substance, due to the nature of active carbons. Accordingly, the patients with chronic renal failure cannot avoid suffering from hyperphosphoremia as a complication. Conventionally, to prevent such complication, a phosphate binding agent of an aluminum compound, such as aluminum hydroxide or aluminum carbonate, has been administered to the patient. This type of phosphate binding agent, however, has little effect on a patient who takes a large amount of phosphorus (in excess of 1,500 mg/day) because of the low phosphate adsorptivity of said binding agent. Further, administration of this type of binding agent in a large amount could lead to the development of adverse side effects such as constipation, nausea, vomiting. Furthermore, it has been recently reported that aluminum accumulates in patients with chronic renal failure to cause osteomalacia or encephalopathy. On the other hand, a report has been made recently on the possible use of MgO alone as a phosphate adsorbent. Use of MgO alone, however, involves the serious problem that its storage and handling are very complicated and troublesome because MgO is susceptible to the presence of carbon dioxide in an atmosphere and when it is left there, its phosphate adsorptivity is reduced with time. Further there are several reports concerning phosphate adsorbents, such as US-A-4,474,853 and JP-A-59-76,536 (1984) and 60-132,644 (1985). However, all these reports disclose zirconium compounds only as the adsorbent. In addition, Chemical Abstracts, Volume 93,1980, page 32329, No. 32329a discloses a catalyst mixture of MgO-TiO₂; Chemical Abstracts, volume 94, 1981, page 342, No. 197402c discloses a porous TiO₂ prepared by kneading Mg(OH)₂, and Ti(OH)₄ and calcining the mixture, and Patent Abstracts of Japan, Volume 10, No. 214 (c-362)(2270), July 1986 (3), discloses a mixture of oxides selected from Group IIa and transition elements and deposited on or in activated carbons. In view of these circumstances, the present inventors have studied extensively to provide an adsorbent which is highly safe in vivo, has excellent phosphate adsorbing characteristics and is capable of maintaining such characteristics for a long time and as a result have found that MgO-TiO₂ complex, comprising a specific composition, has 7 to 8 times higher phosphate adsorptivity than the conventional aluminum hydroxide type adsorbents, is capable of maintaining high phosphate adsorptivity for a long time and is quite apposite to the object of this invention. Furthermore, the present inventors have found that an adsorbent having said MgO-TiO₂ complex deposited on an internal surface of active carbons shows a very excellent phosphate adsorptivity while maintaining inherent adsorbing characteristics of active carbons without being impaired. According to the invention there is provided an MgO/TiO₂ complex suitable for use as a phosphate adsorbent in which the MgO:TiO₂ molar ratio is from 99.99:0.01 to 80:20. In a preferred embodiment of the invention the complex has a specific surface area as measured by the BET method of 50 to 700m²/g and shows a crystal diffraction pattern of MgO when subjected to powder X-ray diffraction. The MgO-TiO₂ complex may be carried on active carbon . This may be achieved by depositing the complex on active carbon. The resulting adsorbent has the inherent adsorbing characteristics of active carbons as well as phosphate adsorptivity. In another embodiment, the MgO-TiO₂ complex is deposited on spherical active carbons, having very low dust formation. Preferably the complex is deposited on spherical active carbons having an average particle diameter of 0.1 to 1 mm, a specific surface area of from 500 to 2,000 m²/g as measured by the methanol adsorption method and a pore volume, for pores with a radius of 10 to 7500 nm of from 0.1 to 1.0 cm³/g. The invention further provides a process for the preparation of an MgO/TiO₂ complex as described above, which process comprises mixing a magnesium compound and a titanium compound in proportions with respect to Mg and Ti such that the resulting complex has an MgO:TiO₂ molar ratio of from 99.99:0.01 to 80:20, hydrolysing the mixture, and calcining the hydrolysed mixture. Preferably, the process comprises mixing and dissolving an alkoxide of magnesium and an alkoxide of titanium in an aqueous solution of an acid in proportions with respect to Mg and Ti such that the resulting complex has an MgO:TiO₂ molar ratio of from 99.99:0.01 to 80:20, immersing the active carbon in the solution, hydrolysing the alkoxides with an aqueous solution of an alkali and calcining the resulting material. The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a complex as described above or which has been produced by a process as described above. The pharmaceutical composition may be prepared by mixing the complex with a pharmaceutically acceptable carrier or diluent. A complex as described above may be used in the treatment of hyperphosphoremia, as an adsorbent for hemoperfusion or in the treatment of renal diseases. It is therefore possible to provide a phosphate adsorbent which is highly safe even in vivo, has an excellent phosphate adsorptivity and can maintain its excellent adsorptivity for a long time. When administered orally, this agent shows an excellent adsorptivity of waste metabolites represented by creatinine, causes no adverse side effects such as constipation and also has excellent phosphate adsorptivity. In the accompanying drawings: Figures 1 and 2 show the X-ray diffraction patterns of an MgO-TiO₂ complex according to the present invention and of a comparative adsorbent, respectively. Figure 3 shows the change with time of phosphate adsorptivity of the MgO-TiO₂ complex according to the present invention and of the comparative adsorbent. Figure 4 shows a comparison of phosphate adsorptivities of the adsorbents between the present invention and the comparative example. The phosphate adsorbent comprising an MgO-Tio₂ complex according to the present invention can be produced by mixing a magnesium compound and a titanium compound, hydrolysing the mixture and calcining the resulting precipitate. Various methods have been known to hydrolyze each of said metal compounds, but the preferable methods to hydrolyze metal compounds for the complex of the present invention comprise the following steps: mixing an aqueous solution of magnesium salt and an aqueous solution of titanium salt and hydrolysing the mixed solution with an aqueous solution of an alkali such as ammonia, or mixing alkoxides of said metals and hydrolyzing the mixture. The object of calcination or precipitates on hydrolysis is not only complexing MgO and TiO₂ but also adjusting the characteristics, such as number of OH groups on the surface, chemical structure of the surface, specific surface area, etc., of the complex as a phosphate adsorbent. The calcination temperature is variable depending on the precipitate preparing method, adjusting conditions, blending ratio and other factors, but usually is preferable to perform at a temperature in a range of 200 to 1,000°C, more preferable 300 to 700°C and specifically preferably 350 to 500°C. The calcination atmosphere is preferably free of water and carbon dioxide and an atmosphere of nitrogen is especially preferable for the calcination of the present invention. Regarding the composition of the phosphate adsorbent according to the present invention, an MgO/TiO₂ molar ratio is in the range of 99.99/0.01 to 80/20, preferably 99.9/0.1 to 90/10, more preferably 99/1 to 95/5. The specific surface area of the complex, as measured by BET method, is preferably in the range of 50 to 700 m²/g, more preferably 100 to 500 m²/g. In the MgO-TiO₂ complex, a small amount of TiO₂, which is one of the constituents of the complex, improves the phosphate adsorptivity, let alone a stability of the adsorptivity, as compared with single use of MgO, however, as the amount of TiO₂ in the complex increases, a disturbance in the crystal structure of MgO increases and when the molar ratio of TiO₂ exceeds 20%, the powder X-ray diffraction pattern specific to MgO crystal disappears and the phosphate adsorptivity of the complex is greatly reduced. Also, when the molar ratio of TiO₂ in the complex is extremely small or when MgO alone is used, the resulting product is susceptible to the presence of carbon dioxide in an atmosphere and the adsorptivity reduces with a standing time. The MgO-TiO₂ complex of the present invention, in which TiO₂ is present in a specified ratio, can maintain a stable phosphate adsorptivity for a long time even standing in an atmosphere containing carbon dioxide, as one of the excellent characteristics of the present adsorbent. An adsorbent obtained by depositing an MgO-TiO₂ complex of the present invention on active carbons is also an embodiment within the scope of the claimed invention. This adsorbent is provided with both the organic substance adsorptivity inherent to active carbons and the stable phosphate adsorptivity of said complex and is very useful as an antihyperphosphoremial agent, an adsorbent for hemoperfusion or an orally administable therapeutic agent for renal diseases. As active carbons for the present invention, there can be used granular carbon obtained by baking coconut charcoal or by binding powdery active carbons, but it is preferable to use spherical active carbons made of pitches or organic synthetic polymers as the starting material, because such spherical active carbons are substantially free from dust forming and is especially suitable as an adsorbent for hemoperfusion. Such spherical active carbons can be manufactured by known methods such as disclosed in GB-A-1,383,085 and US-A-4,221,695, 4,371,454 and 4,420,443. As the starting materials for said spherical active carbons, there can be used, as pitches, petroleum and coal pitches and, as organic synthetic polymers, thermosetting resins such as phenol resin, epoxy resin, etc., or thermoplastic resins such as styrene resin, vinylidene chloride resin and their copolymer resins. Among these spherical active carbons, especially preferred is the one having an average particle diameter of 0.1 to 1 mm, a specific surface area (measured by methanol adsorption method) of 500 to 2,000 m²/g and a pore volume, with a radius of 10 to 7500 nm, of 0.1 to 1.0 cm³/g, because this specified type of spherical active carbons shows an excellent adsorptivity of waste metabolites represented by creatinine and, when administered orally, causes no adverse side effects such as constipation which can be serious problems when ordinary active carbons are used. The phosphate adsorbent of the present invention comprising the MgO-TiO₂ complex deposited on active carbons can be produced, for instance, in the following way. Alkoxides of magnesium and titanium are mixed and dissolved in an aqueous solution of an acid, such as nitric acid, then active carbons are immersed in the solution, followed by hydrolysis with an aqueous solution of an alkali, such as ammonia or urea, to obtain an adsorbent precursor, and this precursor is calcined. The same calcining temperature as that of the complex can be applied and the calcination atmosphere free of water, carbon dioxide and oxygen is also preferable. Calcination in a nitrogen atmosphere is more preferable as in case of the complex preparation. In the phosphate adsorbent of the present invention obtained by depositing an MgO-TiO₂ complex on active carbons (hereinafter referred to as "Mg-Ti-AC adsorbent"), it is preferable that the MgO-TiO₂ complex be deposited in an amount of 1 to 10% by weight. When the deposit is less than 1% by weight, no satisfactory effect on phosphate adsorption is obtained. When the deposit exceeds 10% by weight, a proportional increase of phosphate adsorptivity can not be expected and accordingly the use of said complex in excess of 10% by weight is meaningless. The adsorbent of the present invention composed of an MgO-TiO₂ complex (hereinafter referred to as Mg-Ti adsorbent) is excellent in adsorption of phosphate. Further, in an acute toxicity test using Jcl-SD rats, the Mg-Ti adsorbent causes no abnormality in the test rats when administered orally even at a dose of 5,000 mg/kg. Thus, the Mg-Ti adsorbent, either in its single form or in the form of a pharmaceutical composition, can be used as an antihyperphosphoremial agent. In this use, said adsorbent can also be made into a composition mixed with a pharmaceutically acceptable carrier and/or adjuvants and be offered in various forms, such as powder, granules, spherules, etc. The available forms of pharmaceutical preparations of said adsorbent include tablet, sublingual tablet, pill, powder, granule, capsule, suppository, trouch, aqueous or oleaginous solution, suspension, emulsion, syrup, gell, etc. Tablet, powder, capsule, etc., can have enteric coating. Although the pharmaceutically acceptable carriers usable in the composition of the present invention are not limited to the specific types; carriers such as water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils, gum arabic, polyalkylene glycol, vaseline, sorbitan trioleate, polyoxyethylene sorbitan monooleate, alkylphenols, aliphatic alcohols, polyvinyl pyrrolidone and the like can be exemplified, in general. For the pharmaceutical preparations in the present invention, ordinary adjuvants such as sweetener, spice, coloring material, preservative, salt for adjusting osmotic pressure, buffering agent, etc. can be added according to necessity. Although the content of the MgO-TiO₂ complex in the pharmaceutical compositions may be varied according to symptoms and other factors, it is usually 1 to 99% by weight, preferably 10 to 99% by weight. The pharmaceutical preparations can be administered either orally or per rectum. The dosage amount is variable depending on symptoms, etc., but it is usually 0.1 to 2 g per administration as MgO-TiO₂ complex, and the preparation may be administered one to three times a day. Generally, this can not be applied in case of emergency. In case of application to a patient of renal failures, the administration may be made either during pre-hemodialysis therapy or during hemodialysis therapy. The Mg-Ti adsorbent, beside its use as an oral agent, can also be used as a phosphate adsorbent for hemoperfusion in a single form or in a coated form with a bio-compatible substance such as heparin. The Mg-Ti-AC adsorbent is not only capable of maintaining its stable adsorptivity of phosphorus compounds such as phosphoric acid ions but also has the adsorbing characteristics of active carbons, for example, an ability to remove the uremic organic metabolites, represented by creatinine. In other words, the Mg-Ti-AC adsorbent is not only useful for the treatment of hyperphosphoremia because of its adsorptivity of phosphorus compounds but can also be applied as an adsorbent for hemoperfusion as it has the ability to adsorb and remove the uremic metabolites such as creatinine. The Mg-Ti-AC adsorbent can be coated with polymeric substances such as gelatin, albumin, poly(2-hydroxyethyl methacrylate) and the like. Also, it can be used in admixture with other types of adsorbent or in combination with other therapeutic treatment such as hemodialysis. Further, it can be used as an oral agent singly or in a form of a pharmaceutical composition for the purpose of removing phosphorus compounds, creatinine, etc., in a digestive tracts. When the Mg-Ti-AC adsorbent is used in a form of tablet, capsule or the like, it can also be applied as an enteric agent. The Mg-Ti-AC adsorbent of this invention prepared by depositing, for instance, 8.9% by weight of MgO-TiO₂ complex on active carbons caused no abnormality on the test animals in an acute toxicity test in which said adsorbent was orally administered to Jcl-SD rats at a dose of 15,000 mg/kg. The content of the Mg-Ti-AC adsorbent in pharmaceutical compositions is subject to change according to symptoms of the disease, but it is preferably in the range of 50 to 99% by weight, more preferably 70 to 99% by weight. Although the dose is also variable depending on symptoms of the disease, usually it is 0.5 to 10 g per administration as active carbons deposited with the complex, and the agent is preferably given to the patient one to three times a day. This, however, shall not necessarily be applied in the event of emergency. Further, the time of administration can be either during a pre-hemodialysis therapy or a hemodialysis therapy The following Examples illustrate the invention: Example 1 : 0.57 g of titanium tetraisopropoxide, [(CH₃)₂CHO]₄Ti, was added dropwise into water under stirring and 1.2 g of nitric acid (61 wt%) was added. To this solution was added an aqueous solution of 51.3 g of magnesium nitrate, Mg(NO₃)₂·6H₂O, dissolved in 50 ml of water, followed by gradual addition of 30 g of 28% aqueous solution of ammonia to perform hydrolysis and the produced precipitate was separated by centrifugation. The obtained precipitate was washed well with water, heated up to 400°C at a rate of 200°C/hr under a nitrogen flow and maintained at 400°C for one hour to obtain 7.0 g of a MgO-TiO₂ complex (MgO/TiO₂ molar ratio = 99/1). A powder X-ray diffraction pattern of the MgO-TiO₂ complex obtained is shown in Figure 1. Example 2 : 5.7 g of titanium tetraisopropoxide, [(CH₃)₂CHO]₄Ti, was added dropwise into water under stirring and then 12.4 g of nitric acid (61 wt%) was added thereto. To the solution was added an aqueous solution of 46.2 g of magnesium nitrate, Mg(NO₃)₂·6H₂O, dissolved in 50 ml of water, followed by gradual addition of 29 g of 28% aqueous solution of ammonia to perform hydrolysis and the produced precipitate was separated by centrifugation. The precipitate was washed well with water, heated up to 400°C at a rate of 200°C/hr under a nitrogen flow and maintained at 400°C for one hour to obtain 7.3 g of an MgO-TiO₂ complex (MgO/TiO₂ molar ratio = 90/10). Comparative Example 1 : To an aqueous solution of 51.3 g of magnesium nitrate, Mg(NO₃)₂·6H₂O, dissolved in 50 ml of water was gradually added 29 g of 28% aqueous solution of ammonia to perform hydrolysis and the produced precipitate was separated with centrifugation. The precipitate was washed well with water, heated up to 400°C at a rate of 200°C/hr under a nitrogen flow and maintained at 400°C for one hour to obtain 6.4 g of magnesium oxide. A powder X-ray diffraction pattern of this product is shown in Figure 2. Example 3 : The specific surface area (measured by BET method) and powder X-ray diffraction of the specimens obtained in Examples 1 and 2 and Comparative Example 1 were determined. The results are shown in Table 1. Characteristics of the specimen Item Example 1 Example 2 Comparative Example 1 Specific Surface Area (m²/g) 220 350 120 Crystal Diffraction Pattern of MgO Present Present Present Example 4 : Model rats of renal failure are prepared by partially ligating a branch of left renal artery of Jcl-SD rats (11-week-old) first and 7 days after the first ligating, by ligating the hilum of right kidney. After 30 days of observation on 4 model rats, blood was drawn from the tail vein of each rat and from the time when creatinine and phosphate concentrations in the serum have reached 1.7 ± 0.3 mg/dl and 7.1 ± 0.3 mg/dl (as P concentration), respectively, the rats were allowed to take freely for 5 days a diet prepared by mixing 0.1% of the specimen of Example 1 with a standard diet (CE-2, manufactured by NIHON KUREA). After the feeding is over, blood was drawn from tail vein of each rat and phosphate concentration in the serum was measured. The results are shown in Table 2. Measuring Devices : Creatinine: measured by Beckman Creatinine Analyser (Manufactured by Beckman & Inc.). Phosphate: measured by RaBA-Mark II (Manufactured by KYOTO DAIICHI KAGAKU Co., Ltd). Antihyperphosphoremial Agent Dose of MgO-TiO₂ Complex of Example 1 (mg/day/rat) Phosphoate Concentration (as P) in Serum (mg/dl) Before Administration After Administration 13.9 ± 1.8 7.1 ± 0.3 5.8 ± 0.5 Example 5 : Using the specimens obtained in Examples 1 and 2 and Comparative Example 1, change of phosphate adsorptivity of the specimens with time when they were left in the air was studied. The results are shown in Figure 3. In the specimen of Comparative Example 1, which is MgO alone, the phosphate adsorptivity was reduced with time, whereas with the specimens of MgO-TiO₂ complexes obtained in Examples 1 and 2 any change of adsorptivity with time was not observed and could maintain stable adsorptivity. When the time left in the air is zero, the phosphate adsorptivity of said complexes is higher than the single MgO when MgO/TiO₂ molar ratio is 99/1, but slightly lower when the MgO/TiO₂ molar ratio was 90/10. This indicates that the phosphate adsorptivity of the complexes reaches the peak when the MgO/TiO₂ molar ratio is around 99/1. The phosphate adsorptivity was measured by putting 50 ml of a solution of sodium dihydrogenphosphate, NaH₂PO₄, with a concentration of 3.22 m mol/l into a triangle flask with a ground stopper, adding thereto 100 mg of specimen, shaking the flask at room temperature for 2 hours, filtering the solution and measuring the phosphate concentration in the filtrate by RaBA Ace. Example 6 : The phosphate adsorptivity of the MgO-TiO₂ complex obtained in Example 1 (MgO/TiO₂ molar ratio = 99/1) and that of aluminum hydroxide were compared. The measurement of phosphate adsorptivity was conducted by the same procedure as used in Example 5. The amount of each specimen added was changed and the adsorption isotherms were prepared. The results are shown in Figure 4. As seen from the figure, the MgO-TiO₂ complex shows 7 to 8 times higher phosphate adsorptivity than aluminum hydroxide. Preparation of Spherical Active Carbons : A pitch obtained by crude oil cracking and an organic solvent compatible with the pitch were mixed, and the mixture was melted and dispersed in water containing a suspending medium. The organic solvent was removed from the obtained spherical particles and the spherical particles of pitch were infusibilized, carbonized and activated at 900°C to obtain spherical active carbons having an average particle diameter of 0.4 mm, a specific surface area (measured by methanol adsorption method) of 1,200 m²/g, and a pore volume (measured by mercury porosimetry )at a radius of 10 to 7500 nm, of 0.3 cm³/g. Example 7 : 0.22 g of titanium tetraisopropoxide [(CH₃)₂CHO]₄Ti, was added into water under stirring, and the precipitate was filtered, washed well with water, dispersed in 2 ml of water, and made a solution by adding 0.52 g of nitric acid (61 wt%). To the solution was added an aqueous solution of 20 g of magnesium nitrate, Mg(NO₃)₂·6H₂O, dissolved in 9 ml of water to prepare a magnesium/titanium mixed solution. 10g of spherical active carbons produced as described above was added to the mixed solution and stirred at 50°C for 2 hours. The spherical active carbons were filtered out, dried at 80°C for 4 hours and charged into 50 ml of 20% aqueous solution of ammonia and was stirred for 6 hours. Then the spherical active carbons were filtered out again, washed well with water, heated up to 400°C at a rate of 200°C/hr in a nitrogen flow, maintained at 400°C for one hour, and cooled. 10.89 g of adsorbent were obtained, which consists of the spherical active carbons with 8.9 wt% of an MgO-TiO₂ complex (MgO/TiO₂ molar ratio = 99/1) deposited thereon. Example 8 : 8 ml of water was added to the magnesium/titanium mixed solution prepared in Example 7 and 10 g of spherical active carbons produced as described above were added to the solution and stirred at 50°C for 2 hours. The spherical active carbons were filtered out, dried at 80°C for 4 hours, then supplied into 50 ml of 20% aqueous solution of ammonia and stirred for 6 hours. From this solution, the spherical active carbons were filtered out, washed well with water, heated up to 400°C at a rate of 200°C/hr in a nitrogen flow, maintained at 400°C for one hour , then cooled. 10.66 g of adsorbent were obtained, which consists of the spherical active carbons with 6.6% of an MgO-TiO₂ complex (MgO/TiO₂ molar ratio = 99/1) deposited thereon. Example 9 : 23 ml of water was added to the magnesium/titanium mixed solution prepared in Example 7, followed by addition of 10 g of spherical active carbons produced by the above-described method and by 2-hour stirring at 50°C. The spherical active carbons were filtered out, dried at 80°C for 4 hours, supplied into 50 ml of 20% aqueous solution of ammonia and stirred for 6 hours. Then the spherical active carbons were filtered out, washed well with water, heated up to 400°C at a rate of 200°C/hr in a nitrogen flow, maintained at 400°C for one hour, then cooled. 10.47 g of adsorbent were obtained, which consists of the spherical active carbons with 4.7% of an MgO-TiO₂ complex (MgO/TiO₂ molar ratio = 99/1) deposited thereon. Example 10 : NaH₂PO₄·2H₂O was added to human serum to adjust its phosphate concentration to 10.1 mg/dl (as P concentration), and creatinine was further added thereto to have a creatinine concentration of 9.8 mg/dl. 10 ml of said serum were put into triangle flasks with ground stoppers, and then each 0.5 g of the adsorbents obtained in Examples 7 to 9 (comprising active carbons with an MgO-TiO₂ complex deposited thereon) and 0.5 g of spherical active carbons produced by the method described above were charged into the respective flask, followed by shaking at 37°C for 2 hours. The supernatant serum was collected and the phosphate concentration and creatinine concentration were measured by RaBA-Mark II and Beckman Creatinine Analyzer, respectively. The results are shown in Table 3. Example 11 : The adsorbent obtained in Example 7 having an MgO-TiO₂ complex deposited on active carbons was left in an air and the change of adsorptivity with time was measured by the same method as used in Example 10, provided that the initial phosphate and creatinine concentrations of the solution is 10.3 mg/dl (as P concentration) and 10.7 mg/dl, respectively. The results are shown in Table 4. Regarding the residual concentrations of phosphate and creatinine, no change with time was observed. Adsorbent Obtained in the Following Example Residual Concentration Phosphate as P, (mg/dl) Creatinine (mg/dl) Example 7 2.2 0.4 Example 8 3.0 0.5 Example 9 4.3 0.3 Control 9.7 0.3 Time Left in an Air (hour) 0 72 Substance Measured Phosphate as P Creatinine Phosphate as P Creatinine (mg/dl) 2.3 0.3 2.0 0.4

Claims: Claims for the following Contracting States : DE, FR, GB, IT, NL An MgO/TiO₂ complex suitable for use as a phosphate adsorbent in which the MgO:TiO₂ molar ratio is from 99.99:0.01 to 80:20. A complex according to claim 1, which has a BET specific surface area of from 50 to 700 m²/g and which shows a crystal diffraction pattern of MgO when subjected to powder X-ray diffraction. A complex according to claim 1 or 2, in which the MgO:TiO₂ molar ratio is from 99.9:0.1 to 90:10 and which has a BET specific surface area of from 100 to 500 m²/g. A process for the preparation of an MgO/TiO₂ complex as claimed in claim 1, which process comprises mixing a magnesium compound and a titanium compound in proportions with respect to Mg and Ti such that the resulting complex has an MgO:TiO₂ molar ratio of from 99.99:0.01 to 80:20, hydrolysing the mixture and calcining the hydrolysed mixture. A complex according to any one of claims 1 to 3 carried on active carbon. A complex according to claim 5, which is deposited on spherical active carbon particles which have an average particle diameter of from 0.1 to 1 mm, a specific surface area of from 500 to 2000 m²/g as measured by the methanol adsorption method and a pore volume, for pores with a radius of 10 to 7500 nm, of from 0.1 to 1.0 cm³/g. A process for the preparation of a complex according to claim 5 or 6, which process comprises mixing and dissolving an alkoxide of magnesium and an alkoxide of titanium in an aqueous solution of an acid in proportions with respect to Mg and Ti such that the resulting complex has an MgO:TiO₂ molar ratio of from 99.99:0.01 to 80:20, immersing the active carbon in the solution, hydrolysing the alkoxides with an aqueous solution of an alkali and calcining the resulting material. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and , as active ingredient, a complex as claimed in any one of claims 1 to 3, 5 and 6 or which has been produced by a process as claimed in claim 4 or 7. A complex as defined in any one of claims 1 to 3, 5 and 6 for use in the treatment of hyperphosphoremia, as an adsorbent for hemoperfusion or in the treatment of renal diseases. Use of a complex as defined in any one of claims 1 to 3, 5 and 6 in the preparation of a medicament for use in the treatment of hyperphosphoremia, as an adsorbent for hemoperfusion or in the treatment of renal diseases. Claims for the following Contracting State : ES A process for the preparation of an MgO/TiO₂ complex suitable for use as a phosphate adsorbent in which the MgO:TiO₂ molar ratio is from 99.99:0.01 to 80:20, which process comprises mixing a magnesium compound and a titanium compound in proportions with respect to Mg and Ti such that the resulting complex has an MgO:TiO₂ molar ratio of from 99.99:0.01 to 80:20, hydrolysing the mixture, and calcining the hydrolysed mixture. A process according to claim 1, which further comprises depositing the complex on active carbon. A process according to claim 2, wherein the active carbon is spherical active carbon particles which have an average particle diameter of from 0.1 to 1 mm, a specific surface area of from 500 to 2000 m²/g as measured by the methanol adsorption method and a pore volume, for pores with a radius of 10 to 7500 nm, of from 0.1 to 1.0 cm³/g. A process according to claim 2 or 3, which process comprises mixing and dissolving an alkoxide of magnesium and an alkoxide of titanium in an aqueous solution of an acid in proportions with respect to Mg and Ti such that the resulting complex has an MgO:TiO₂ molar ratio of from 99.99:0.01 to 80:20, immersing the active carbon in the solution, hydrolysing the alkoxides with an aqueous solution of an alkali and calcining the resulting material. A process according to any one of the preceding claims which further comprises mixing a complex as produced by a process as claimed in any one of the preceding claims with a pharmaceutically acceptable carrier or diluent.

Inventors: ENDO, HIROSHI, HINO, KUNIAKI, OKAZAKI, SUSUMU
Applicants: KUREHA KAGAKU KOGYO KABUSHIKI KAISHA
Application year: 1988
Main classification: B01J20
IPC codes: B01J20, A61M1