TWI639435B - Cationic binder and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention provides a pharmaceutical composition for treating a patient suffering from or susceptible to hyperphosphatemia, which comprises Mg-Fe-Cl HTln. In one embodiment, Mg-Fe-Cl HTln is as shown in formula (I). The phosphorus absorption capacity of the pharmaceutical composition is greater than . The present invention also provides a method of treating a patient suffering from or susceptible to hyperphosphatemia via the use of such a pharmaceutical composition. The invention also provides a method of making such a pharmaceutical composition.

Description

Cationic binder and pharmaceutical composition containing the same

The present invention generally relates to a cationic binder, and a pharmaceutical composition for treating a patient suffering from or susceptible to hyperphosphatemia, and methods of use thereof. In particular, the present invention is directed to a cationic binder comprising magnesium, iron and chloride, a pharmaceutical composition comprising the same, and methods of use thereof.

It is well known that patients with chronic kidney deficiency in most cases also suffer from self-regulatory disorders of calcium and phosphorus. Therefore, the most common is the need to mention kidney disease complicated with renal bone disease.

In renal osteopathy, calcium absorption in the intestine is reduced, followed by calcium reduction into the bone, leading to the so-called acalcinosis, which manifests as mineralisation deficiencies and osteoporosis. (osteoporosis). In addition, in renal osteopathy, it can be noted that the excretion of phosphorus is insufficient, and the level of phosphorus in the blood which causes hyperphosphataemia is increased. The interaction between the two phenomena is characterized by secondary hyperparathyroidism, which in turn leads to bone destruction.

Therefore, in kidney diseases such as chronic kidney disease, in order to prevent secondary hyperthyroidism and metastatic calcification, it is necessary to carefully control the intestines and blood. Phosphorus accumulation in liquid or serum.

Accordingly, the present invention provides a cationic binder that can be used to bind an anion such as a phosphate. These cationic binders can be used as a pharmaceutical composition for treating a patient suffering from hyperphosphatemia or as a pharmaceutical composition for prophylactic treatment of a patient suffering from hyperphosphatemia. Patients suitable for the present pharmaceutical composition include humans and animals.

According to one embodiment, a cationic binder is provided. It contains magnesium, iron (III) and chloride, and in the raw material for synthesizing the cationic binder, the atomic ratio of Mg ^{+ 2} and Fe ^{+ 3} is between 2:1 and 60:1, and this cation is combined. The anion uptaking capacity of the agent is greater than 100 .

According to one embodiment, a pharmaceutical composition for treating a patient suffering from or susceptible to hyperphosphatemia is provided. The pharmaceutical composition comprises a cationic binder and a pharmacologically acceptable carrier, wherein the cationic binder comprises magnesium, iron (III) and chloride, and in the raw material for synthesizing the cationic binder, Mg ⁺² The atomic ratio of Fe ⁺³ is between 2:1 and 60:1, and the anionic absorption of the cationic binder is greater than 100. .

According to another embodiment, a method of treating or prophylactically treating a patient suffering from or susceptible to hyperphosphatemia is provided. The method comprises administering to a patient a pharmaceutical composition wherein the cationic binder comprises magnesium, iron (III) and chloride, and the atomic ratio of Mg ^{+ 2} and Fe ^{+ 3} in the raw material used to synthesize the cationic binder Between 2:1 and 60:1, the anionic absorption of this cationic binder is greater than 100 .

Figure 1 is a schematic representation of the formation of a nano-platform (HTln) of a Mg-Fe-Cl hydrotalcite-like.

2A depicts an X-ray diffraction pattern of Mg-Fe-Cl Htln powder having different Mg ⁺² /Fe ⁺³ molar ratios to synthesize the compound. Fig. 2B shows an X-ray powder diffraction pattern of the synthesized Mg-Fe-Cl HTln powder.

Figure 3 depicts PO ₄ ^3- sorption after the addition of HTln powder.

Figure 4 depicts images of Renagel (Figure 4a) and Mg-Fe-Cl HTln (Figure 4b) before and after mixing with 7 milliliters (ml) of milk for 90 minutes.

Figure 5 shows the dietary phosphorus binding performance of Mg-Fe-Cl HTln in milk at pH 6.

Figure 6 shows an X-ray diffraction pattern of Mg-Fe-Cl HTln before and after the 90-minute phosphorus binding experiment in milk.

Figure 7A shows the FT-IR spectrum of a Mg-Fe-Cl Htln powder having a different Mg ^{+ 2} /Fe ^{+ 3} molar ratio for synthesizing a compound. Figure 7B shows the FT-IR spectrum of 1 gram of Mg-Fe-Cl HTln and the HTln spectrum after phosphate uptake in 25 ml of milk at pH 6.

Figure 8 shows the change in pH of 0.5 grams of Mg-Fe-Cl HTln and 0.5 grams of Renagel as a function of time in 25 ml of milk.

Figure 9 shows the morphology and viability of L919 cells cultured in Mg-Fe-Cl HTln medium.

Figures 10, 11, and 12 are bar graphs showing blood urea nitrogen, creatinine, and phosphorus levels of serum after administration of Mg-Fe-Cl HTln.

The preferred embodiments will be described in detail to better understand the present invention. The preferred embodiment of the invention will be illustrated in the drawings with numbered elements.

Patients with end-stage renal disease (ESRD) require oral phosphate binders. Conventional phosphate binders may leave the disadvantage of aluminum poisoning or cardiac calcification. Here, the nano-chip (HTln) of Mg-Fe-Cl hydrotalcite is the first to highlight its phosphorus absorption capacity and cellular cytotoxicity in milk, and is a potential oral phosphate binder. A new method was developed for the synthesis of Mg-Fe-Cl HTln powders with different ratios of Mg ⁺² :Fe ⁺³ from raw materials, Mg(OH) ₂ and FeCl ₃ ‧6H ₂ O, from Mg(OH) The atomic ratio of Mg ^{+ 2 to} Fe ^{+ 3} in ₂ and FeCl ₃ ‧6H ₂ O is between 2:1 and 60:1. The ratio of Mg ⁺² :Fe ⁺³ in the cationic binder is from 6.0:1 to 1.5:1, preferably from 4.0:1 and 2.0:1, most preferably 2.8:1. In one embodiment, Mg-Fe-Cl HTln is as represented by formula (I):

It was confirmed that adding 0.5 g of Mg-Fe-Cl HTln to milk can reduce its phosphorus content by 40% in 30 minutes, showing 150 Phosphate absorbance and reduce by 65% in 90 minutes, showing 325 Phosphate absorbency. In a low pH environment, Mg-Fe-Cl HTln can exhibit relatively high phosphorus absorption properties. Phosphorus restoration does not occur during the 90 minute reaction of HTln in milk. In vitro cytotoxicity assay of Mg-Fe-Cl HTln showed no potential cytotoxicity. The cells cultured in the medium containing the HTln extract were even more viable than the cells cultured in the unextracted medium (blank control). The Mg-Fe-Cl HTln extract results in hundreds of ppm of Mg ions and several ppm of Fe ions in the medium, which should have a positive effect on good cell viability. In addition, by dietary treatment, a dose of 10 mg/kg to 30 mg/kg can lower serum levels of blood urea nitrogen (BUM), creatinine and phosphorus, indicating superior effects on the treatment of kidney disease.

The following will be an experiment showing the effect of the cationic binding agent (Mg-Fe-Cl HTln) provided by the present invention on phosphate absorption and treatment of kidney disease.

Experiment 1 Synthesis and identification of synthetic Mg-Fe-Cl HTlnMg(OH) ₂ and FeCl ₃ ‧6H ₂ O powders for the synthesis of Mg-Fe-Cl HTln. In Table 1, A represents Mg(OH) ₂ and B represents FeCl ₃ ‧6H ₂ O. Three powder samples, each containing A and B, are designated 2A_0.1B, 2A_0.4B, and 2A_0.6B. Each powder sample was immersed in 500 ml of distilled water at 50 °C. The pH of the aqueous solution was adjusted to pH 1 by completely dissolving the chemical by adding HCl (aqueous solution). The pH of the ionic solution was then increased to 9.5 via the dropwise addition of NaOH (aq.) (2.5 M). When the pH is stable at 50 ° C at a pH of 9.5, a reddish brown suspension is present in the solution. The pH of the solution was maintained at pH 9.5 at 50 ° C for 2 hours. The above mixture was vigorously stirred with a magnetic force, and 1 L of Ar gas was forcedly introduced into the aqueous solution to foam during the entire synthesis. The solution with the reddish brown suspension was then extracted using a centrifuge, rinsed 5 times with distilled water, and then dried under vacuum. The crystal structure of the synthesized product was identified by X-ray powder diffraction using a Bruker D2 Phaser diffractometer. For this purpose, Ni filtered Cu Kα 1 (1.5406 Å) radiation was used. The synthesized product was also subjected to Fourier Transform Infrared (FT-IR) analysis on a Perkin-Elmer Spectrum RX-I spectrometer. For FT-IR analysis, 0.002 g of HTln powder was mixed with 0.2 g of oven dried (80 ° C, 1 hour) spectral grade KBr and pressed under a pressure of 8 tons under vacuum for 1 minute to form a circle having a diameter of 12.91 mm. plate. An FT-IR spectrum with a wave number of 400 to about 4000 cm ^-1 was obtained. Elemental chemical analysis of the synthesized product was carried out via X-ray photoelectron spectroscopy (XPS). The morphology of the synthesized product was observed using a JEOL JSM-7000F field emission scanning electron microscope.

Table 1

Please refer to FIG. 1 , FIG. 2A and FIG. 2B , wherein FIG. 1 shows a schematic diagram of a nano-chip (HTln) forming Mg-Fe-Cl hydrotalcite, and FIG. 2A shows a different Mg ⁺² /Fe ⁺³ mo. The ear ratio is an X-ray diffraction pattern of the Mg-Fe-Cl Htln powder from which the compound is synthesized, and FIG. 2B shows an X-ray powder diffraction pattern of the synthesized Mg-Fe-Cl HTln powder. In Figure 1, the inset in the SEM image shows the nanochip structure of HTln. The preparation conditions for the synthesis of Mg-Fe-Cl HTln have been shown in Table 1. Figure 2A shows an X-ray diffraction pattern of Mg-Fe-Cl Htln powders having different Mg ^{+ 2} /Fe ^{+ 3} molar ratios to synthesize this compound. Mg(OH) ₂ and FeCl ₃ ‧6H ₂ O are raw materials for synthesis. In Fig. 2B, Mg ^{+ 2} /Fe ^{+ 3} molar ratio represents the atomic ratio of Mg ^{+ 2} and Fe ^{+ 3} from the raw material for synthesis. The X-ray diffraction pattern of Mg ^{+ 2} /Fe ⁺³ molar ratios of 2, 4, 8, and 60 is plotted from bottom to top in Fig. 2B. Characteristic peaks at approximately 2θ = 11° and 22° correspond to typical substrate spacings (d ₀₀₃ ) and (d ₀₀₆ ) of the LDH phase, respectively. As shown in Figure 2B, the reflection peaks at 10.90° and 21.65° were identified as base reflections (003) and (006) from hydrotalcite. Here, the substrate spacing of Mg-Fe-Cl HTln (003), 8.11 A, is similar to that of Mg-Fe-Cl HTln obtained by a general method. The (003) substrate spacing of HTln (8.11 Å) exceeds (7.97 Å) of Mg-Fe-CO ₃ HTln. As shown in Fig. 2B, each X-ray intensity peak of Mg-Fe-Cl HTln is shifted from the corresponding X-ray peak of Mg-Fe-CO ₃ HTln to a low angle, indicating that the carbonate ion is not the main interlayer anion. Although it is difficult to prevent contamination of carbonate ions in the preparation of HTln, the synthetic methods developed herein have succeeded in minimizing carbonate contamination. Based on the X-ray reflection pattern in Fig. 2B, HTln made of 2A_0.6B showed greater crystallinity than HTln made of 2A_0.1B and 2A_0.4B. Table 2 shows the contents of Mg ²⁺ , Fe ³⁺ , Cl ^- and Na ⁺ (in atom%) obtained from XPS for samples 2A_0.1B, 2A_0.4B and 2A_0.6B. The chemical composition of each sample was calculated from the corresponding XPS spectra of Mg 2p, Fe 2p3, Cl 2p and Na 1s. In Table 2, A_0.1B contains 0.8% Cl ^- , 2A_0.4B contains 1.2% Cl ^- , and 2A_0.6B contains 2.3% Cl ^- . Importantly, not detected in the various samples of sodium, supporting Cl ^- is not associated with it is inserted into the remaining NaCl HT1n interlayer discovery. The general formula of HTln is [M _1-x ²⁺ M _x ³⁺ (OH) ₂ ] _x ⁺ (A _x/n ^n- )‧nH ₂ O ¹ , where x is equal to M ²⁺ /(M ²⁺ +M ³⁺ ). Table 2 lists the x values of 2A_0.1B, 2A_0.4B, and 2A_0.6B. The x value of 2A_0.6B is 0.26. In the present invention, the ratio of 2A_0.6B is 2.8:1, which is close to the optimum ratio. Therefore, based on the synthesis method explored herein, Mg-Fe-Cl HTln synthesized using 2A_0.6B was used in the following phosphate binding experiments.

Experiment 2 Absorption and desorption of anions by Mg-Fe-Cl HTln in aqueous KH ₂ PO ₄ solution

The ability of the synthesized Mg-Fe-Cl HTln powder to absorb PO ₄ ^3- from an aqueous KH ₂ PO ₄ solution was evaluated using an aqueous solution of KH ₂ PO ₄ (100 ml) containing about 1000 ppm of PO ₄ ^3- . In each course of the experiment, 0.2 g of Mg-Fe-Cl HTln powder was immersed in 100 ml of an aqueous KH ₂ PO ₄ solution. Each solution in the experiment was purged with argon to reduce gaseous carbon dioxide in the atmosphere to form carbonate anions. Ion chromatography (IC; ICS-900, DIONEX) was used to simultaneously measure the concentrations of Cl ^- and residual PO ₄ ^3- in the aqueous KH ₂ PO ₄ solution. In the anion sorption and desorption experiments, dilute nitric acid (2 vol%) was used to maintain the pH of the aqueous solution at pH 3.0 ± 0.2 or pH 6.0 ± 0.2. The concentration error of PO ₄ ^3- produced by maintaining the pH of the solution by adding an aqueous solution of nitric acid is less than 5%.

Please refer to FIG. 3, which shows PO ₄ ^3- sorption after addition of HTln powder, wherein (a) shows 0.2 g of Mg in 100 ml of KH ₂ PO ₄ aqueous solution (original 55 ppm of PO ₄ ^3- ) -Fe-Cl HTln PO ₄ ^3- sorption. (b, c) shows the adsorption of PO ₄ ^3- and the desorption of Cl- when 0.2 g of Mg-Fe-Cl HTln is immersed in 100 ml of an aqueous KH ₂ PO ₄ solution (original 1000 ppm of PO ₄ ^3- ), Among them, (b) sorption and desorption experiments were carried out at pH 3, and (c) sorption and desorption experiments were carried out at pH 6. The phosphate absorption capacity of Mg-Fe-Cl HTln was calculated via the formula (I).

As shown in Fig. 3(a), when 0.2 g of HTln powder was added to 100 ml of an aqueous KH ₂ PO ₄ solution (which originally contained 55 ppm of PO ₄ ^3- ) at room temperature, HTln was almost absorbed in 20 minutes. All PO ₄ ^{3- in} solution. To determine the PO ₄ ³ -absorbency of Mg-Fe-Cl HTln, 0.2 g of powder of HTln was added to a 100 ml KH ₂ PO ₄ aqueous solution of PO ₄ ^3- initial content of 1000 ppm (Fig. 3). Figure 3 (b) shows that when 0.2 g of Mg-Fe-Cl HTln was added to 100 ml of KH ₂ PO ₄ aqueous solution maintained at pH 3, the original PO ₄ ^3- concentration was 1000 ppm, and the solution remained after 10 minutes. PO ₄ ^3- is only ~430ppm (57% absorption), and almost no PO ₄ ^3- is absorbed from 10 minutes to 300 minutes.

Dechlorination of the chloride anion from Mg-Fe-Cl HTln during the same experiment provided evidence of anion intercalation and de-intercalation. FIG. 3 (c) shows that, in aqueous pH6 ₄ PO 100 mL of KH ₂ PO ₄ ^3- have 1000ppm in, 0.2 grams of Mg-Fe-Cl HTln absorbed PO ₄ ^3-, phosphoric acid over 100 minutes The salt content dropped to about 540 ppm, and almost no PO ₄ ^3- was absorbed from 100 minutes to 300 minutes. Here, the phosphate absorption capacity of Mg-Fe-Cl HTln in the KH ₂ PO ₄ aqueous solution at pH 6 is about 46%, which is lower than the result of HT1n at pH 3.

As shown in Fig. 3(b), the Mg-Fe-Cl HTln powder exhibits an excellent ability to absorb phosphate from an acidic solution in a KH ₂ PO ₄ aqueous solution of pH 3, and the concentration of the phosphate is lowered from about 1000 ppm to about 450 ppm. . Importantly, HTln stably maintained the phosphate content of the aqueous KH ₂ PO ₄ solution at about 450 ppm throughout the experiment for 5 hours during the absorption of the phosphate in a KH ₂ PO ₄ aqueous solution having a pH of pH 3, indicating HTln. The structure did not decompose under acidic conditions, so no phosphate recovery occurred. The increase in chloride concentration during this period indicates direct evidence of anion exchange. Table 3 summarizes the phosphorus uptake of Mg-Fe-Cl HTln at pH 3 and pH 1. In the present invention, the phosphorus absorption force of Mg-Fe-Cl HTln is at least 100 Even greater than 200 .

Experiment 3 Characteristics of Mg-Fe-Cl HTln powder and sevelamer hydrochloride (Renagel) in milk and subsequent phosphorus absorption experiments

The phosphate binding performance of the Mg-Fe-Cl HTln powder in milk was compared to the binding performance of a commercial phosphate binder, sevelamer hydrochloride (Renagel). To 25 ml of milk, 0.5 g of Mg-Fe-Cl HTln or 1 g of Mg-Fe-Cl HTln or 1 g of sevelamer hydrochloride powder was added. The initial pH of the milk is about 6.7. Two experimental methods were used to study the effect of pH on the ability of HTln to absorb phosphorus. First, the pH of the milk was adjusted to pH 6.0 ± 0.2 via the addition of an aqueous HNO ₃ solution (50% by volume), and this pH was maintained throughout the phosphorus uptake experiment. Second, the pH of the milk did not remain constant during the phosphorus uptake experiment. The residual phosphorus concentration in milk (mg/kg, mass ppm) was measured by inductively coupled plasma atomic emission spectrometry (ICP-AES) using US EPA Method 3050B. The above quantitative analysis was performed by the chemical laboratory - Taipei SGS TAIWAN Co., Ltd. The Mg-Fe-Cl HTln before phosphorus absorption was compared with the Mg-Fe-Cl after phosphorus absorption using X-ray powder diffraction. Fourier transform infrared (FT-IR) analysis was performed to obtain spectra of both Mg-Fe-Cl HTln and sevelamer hydrochloride (Renagel) before and after phosphorus absorption in milk. To measure the volume change of each of the binders of Mg-Fe-Cl HTln and sevelamer hydrochloride (Renagel) after mixing with milk for 90 minutes, a 25 ml volumetric graduated cylinder with a 0.5 ml fractional mark was used. 0.5 g of mass of Mg-Fe-Cl HTln or 0.5 g of sevelamer hydrochloride (Renagel) was mixed with 7 ml of milk in the graduated cylinder. The initial volume is read immediately after mixing. The volume was read again after 90 minutes. A volume change (ΔV%) is thus obtained.

Please refer to Figure 4, which shows images of Renagel (Fig. 4(a)) and Mg-Fe-Cl HTln (Fig. 4(b)) after mixing with 7 ml of milk for 90 minutes. In at least three in vitro swelling tests, 0.5 grams of Renagel powder was expanded by about 1150% when placed in milk. In the same experiment, it was found that 0.5 The gram of Mg-Fe-Cl HTln powder only swelled by about 33% by volume when placed in milk. As indicated, the volume of 0.5 grams of Renagel slurry is greater than the volume of 0.5 grams of Mg-Fe-Cl HTln slurry. Figure 5 shows the dietary phosphorus binding performance of Mg-Fe-Cl HTln in milk at pH 6, which falls within a pH range of 5 to 6.7 in the gastrointestinal tract (this is the highest pH recorded within 5 minutes of eating). ). During the digestion process, the stomach forms a chyme and transfers it to the duodenum. The small intestine is essential for phosphate absorption. Therefore, the use of a phosphate binder to remove most of the phosphate during digestion in the stomach is important for patients with ESRD. Since most of the meal is digested in the stomach, usually the stomach empties the food in about 90 minutes, so the following experiment is performed for 90 minutes. As shown in Figure 5, 0.5 g of mass of Mg-Fe-Cl HTln (added to 25 ml of milk at pH 6) effectively reduced the phosphorus content by about 40% in 30 minutes and after 90 minutes It is reduced to about 65%. In addition, the phosphorus binding force of 1 gram of Mg-Fe-Cl HTln (in 25 ml of milk at pH 6) was similar to that of 0.5 g of Mg-Fe-Cl HTln. In contrast, Renagel's phosphorus binding performance in the pH7 environment is much lower than that of Renagel's phosphorus binding in pH 3. Mg-Fe-Cl HTln has similar results, as shown in Figure 3 (b, c), ie HTln exhibits a relatively low phosphorus binding performance in a pH 6 solution. Thus, as depicted by the data in Figure 5, 0.5 grams and 1 gram of sample exhibited similar performance for the absorption of phosphorus, which may be due to the negative effects of pH 6 in the test milk.

Figure 6 shows an X-ray diffraction pattern of Mg-Fe-Cl HTln before and after the phosphorus binding experiment in milk for 90 minutes. One gram of mass of Mg-Fe-Cl HTln has the ability to absorb phosphorus in milk, reducing the phosphorus content in milk from 1030 ppm to 359 ppm in 90 minutes (Figure 5). As shown in Fig. 6, the X-ray diffraction pattern of Mg-Fe-Cl HTln after the 90-minute experiment is similar to the X-ray diffraction pattern of the original Mg-Fe-Cl HTln, indicating that the absorption of phosphorus from milk did not change HTln. Layer structure. FT-IR was used to identify chemical bonds in Mg-Fe-Cl HTln after experiment in milk of different states. Figure 7A shows the FT-IR spectrum of Mg-Fe-Cl HTln powders having different Mg ^{+ 2} /Fe ^{+ 3} molar ratios for the synthesis of compounds. Mg(OH) ₂ and FeCl ₃ ‧6H ₂ O are raw materials for synthesis. In Fig. 7B, Mg ^{+ 2} /Fe ^{+ 3} molar ratio indicates the atomic ratio for synthesizing Mg ^{+ 2} and Fe ^{+ 3} from the raw material. The Mg ^{+ 2} /Fe ⁺³ molar ratios from bottom to top FT-IR spectra were 2, 4, 8 and 60, plotted in Figure 7B. The belt centered at 426 cm ^-1 is attributed to OMO vibration. The strong absorption band at 3470 cm ^-1 is attributed to the H bond stretching vibration of the OH group (ν _OH ) in the brucite-like layer. The band of 1650 cm ^-1 is due to the bending vibration (δ _H2O ) of the H ₂ O molecules in the interlayer. The band at 1355 cm ^-1 corresponds to the mode ν of the interlayer carbonate species. Figure 7B shows the FT-IR spectrum of Mg-Fe-Cl HTln (expressed as 0 minutes) and 25 grams of milk after pH 6 phosphate absorption (expressed as 30 minutes, 60 minutes and 90 minutes), 1 gram of HTln spectrum. The FT-IR spectrum of the dry milk powder is also shown for comparison. The band centered at 570 cm ^-1 is attributed to the MOM vibration, which is similar to the MOH bend at about 446 cm ^-1 , involving the translational motion of oxygen cations in the quasi-manganite layer. The strong absorption band at 3470 cm ^-1 is attributed to the H bond stretching vibration of the OH group (ν _OH ) in the brucite-like layer. The band at 1638 cm ^-1 is attributed to the bending vibration (δ _H2O ) of the H ₂ O molecules in the interlayer. The weak band at 1360 cm ^-1 corresponds to the mode ν3 of the interbed carbonate species, which is a contaminant from the surrounding atmosphere. More importantly, the absorption band at 1095 cm ^-1 was attributed to the asymmetric vibration of PO ₄ and was clearly identified in the spectrum of the HTln sample after the phosphate uptake experiment, indicating that the phosphorus was successfully inserted into the HTln. In the interlayer, accompanied by the release of Cl ^- (as shown previously in Figure 3). Mg-Fe-Cl HTln also adsorbs fat, as shown by the bands 2923, 2850 and 1746, which are characteristic of fat and are related to the vibration of CH and C=O bonds. These bands were observed in the spectrum of dry milk and showed that the fat was from milk. Figure 8 depicts the pH course of 25 ml of milk during the absorption of 0.5 grams of Renagel and 0.5 grams of Mg-Fe-Cl HTln phosphorus (the pH of the milk did not remain constant). The pH curve of Renagel's milk rose significantly from 6.7 to 8.8 in 3 minutes and then flattened until the end of the experiment. However, the pH profile of the milk of Mg-Fe-Cl HTln gradually increased over time, reaching a pH of 8.2 at 90 minutes. This result is attributed to the pH buffering effect of HTln. The increase in alkalinity of Renagel solution is more intense than that of Mg-Fe-Cl HTln. Renagel has been reported to have gastrointestinal side effects (nausea, vomiting, abdominal pain, bloating, diarrhea, and constipation) in 38% of patients, probably because of its rapid increase in pH and its large-scale expansion when taken with fluids ( Figure 4). Under the pH condition shown in Figure 8, according to the analysis of ICP-AES, 0.5 g of Mg-Fe-Cl HTln can absorb about 11% of phosphorus from milk in 30 minutes, and absorb about 22% at 90 minutes. Phosphorus. Although Renagel removed 30% of the phosphorus from the milk in 30 minutes, the recovery of phosphorus was observed in the milk after 30 minutes, and finally about 26% of the phosphorus was found at 90 minutes.

Experiment 4 Evaluation of in vitro cytotoxicity of Mg-Fe-Cl HTln

The cytotoxicity of the Mg-Fe-Cl HTln powder was studied using L929 cells from the mouse fibroblast cell line according to the specifications of ISO 10993-5. The Mg-Fe-Cl HTln powder was immersed in an incubator with Dulbecco's modified Eagle's medium (DMEM) (0.02 and 0.2 g/ml) at 37 ° C and 5% CO ₂ for different times (10 min and 12 hours). The concentration of Mg and Fe ions (in ppm) in the extract was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The lower limit of detection of Mg ions was 0.001 ppm, and the Fe ion was 0.044 ppm. The extract was then used to treat cell monolayers for 24 hours and then the morphological changes of the cells were examined to assign a toxicity score. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and measured using a microplate luminometer (wavelength 570 nm) Optical Density (OD): A higher OD value indicates higher cell viability. Base medium without extract (DMEM) was used as a blank control, DMEM treated with 10% dimethyl sulfoxide was used as a positive control (PC), and biomedical grade zirconia tablets were used as a negative control (NC). If the cell viability is less than 70% of the blank group (medium only), the extract is considered to be potentially cytotoxic.

Figure 9 shows the morphology and viability of L919 cells after 24 hours of culture in DMEM containing different doses of 0.02 and 0.2 g/ml of Mg-Fe-Cl HTln powder extract. Fig. 9 (a, b) shows the extracts obtained by separately immersing the Mg-Fe-Cl HTln powder in the medium for 10 minutes and 12 hours. As shown in Fig. 9 (a, b), regardless of the concentration of the extract, there is no morphological difference between the L929 cells cultured in the medium containing the extract and the cells cultured in the unextracted medium (blank), even More slightly energetic. These results indicate that the Mg-Fe-Cl HTln powder extract in this study Not potentially cytotoxic. In clinical applications, the phosphate form of the tablet (0.8-1.6 g) is administered three times a day in food. Assuming that the tablets are taken in 50 ml of water, the concentration of the phosphate binder is from 0.016 to 0.032 g/ml, which is close to the dose of 0.02 g/ml of Mg-Fe-Cl HTln powder extract used herein. A dose of the higher 0.2 g/ml Mg-Fe-Cl HTln powder extract was also used to simulate the excess dose. In this investigation, it was assumed that the phosphate binder stayed in the human body for less than 6 hours (interval between meals). After soaking for 12 hours, a powder extract of Mg-Fe-Cl HTln was obtained, which was obtained during the interval between dinner and the next day of breakfast, and the Mg-Fe-Cl HTln powder extract obtained after soaking for 10 minutes, Corresponds to the rapid absorption of phosphate binder during meals. As shown in Fig. 9, even if the dose or continuous exposure time of the Mg-Fe-Cl HTln powder exceeded the clinical application expectations, no evidence of powder cytotoxicity showing Mg-Fe-Cl HTln was obtained. It is worth noting that the viability of the experimental group exceeded the blank control group. Decreasing the concentration of the Mg-Fe-Cl HTln powder extract from 0.2 g/ml to 0.02 g/ml increases cell viability. The body needs about 250-500 mg of magnesium per day to maintain physiological processes and cellular health functions, with an average of 70 kg of human body containing about 20 g of magnesium. Magnesium ions have been shown to have a significant effect on the performance of osteoblasts both in vivo and in vitro. Iron ions are also essential for metabolic processes, including oxygen transport. Studies have shown that pure iron extract has negligible cytotoxic effects on human endothelial cells. As shown in Fig. 9(b), the fact that Mg-Fe-Cl HTln powder enhances cell viability (compared to the blank group) is partly attributed to the positive effect of metal ions (mainly magnesium ions) on cellular responses. Increasing the dose of Mg-Fe-Cl HTln powder extract from 0.2 g/ml to 0.02 g/ml further increased cell viability. According to ICP-MS analysis, the concentrations of magnesium and iron ions in the Mg-Fe-Cl HTln powder extract were about 1800 ppm and 8 ppm, respectively (dose 0.2 g/ml, infiltration time 12 h). A powder extract of Mg-Fe-Cl HTln at a dose of 0.02 g/ml and a dipping time of 12 h produced a magnesium ion concentration of about 200 ppm with undetectable iron ions. This result indicates that approximately <1800 ppm of magnesium ions have a positive effect on cell viability, while lower concentrations (about 200 ppm) of magnesium ions have even more positive effects.

Experiment 5 Effect of Dietary Treatment with Mg-Fe-Cl HTln on Serum Urea Nitrogen, Creatinine, Phosphorus, Calcium, Chlorine, Sodium and Potassium Levels

The in vivo effect of Mg-Fe-Cl HTln was tested by administering a rat of 10 mg/kg, 20 mg/kg, 30 mg/kg of Mg-Fe-Cl HTln for 4 weeks. Please refer to Fig. 10, Fig. 11 and Fig. 12, which show the administration of 0 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg of Mg-Fe-Cl HTln for one week, two weeks, three weeks and A histogram of blood urea nitrogen, creatinine and phosphorus levels in the serum after four weeks. As shown in Figure 10, compared with the control group, treatment with 10 mg / kg, 20 mg / kg, 30 mg / kg dose of Mg-Fe-Cl HTln can significantly (P <0.05) reduce serum blood urea nitrogen concentration . A similar situation can also be seen in Figures 11 and 12. Treatment with Mc-Fe-Cl HTln reduced serum creatinine levels and phosphorus levels. It is shown that the treatment of Mg-Fe-Cl HTln can effectively reduce blood urea nitrogen levels by aspirating serum phosphorus, indicating its pharmacological function in the treatment or prophylactic treatment of patients with hyperphosphatemia. In another experiment, it was shown that treatment with Mg-Fe-Cl did not affect serum calcium, serum chlorine, serum sodium, and serum potassium concentrations (data not shown).

In summary, the present invention provides a cationic binding agent containing Mg-Fe-Cl HCln which can be used as a pharmaceutical composition for treating a patient suffering from or susceptible to hyperphosphatemia. In one embodiment, Mg-Fe-Cl HTln is as shown in formula (I). The phosphorus absorption capacity of the pharmaceutical composition is greater than 100 . The present invention also provides a method of using such a pharmaceutical composition to treat a patient suffering from or susceptible to hyperphosphatemia. The above are only the preferred embodiments of the present invention, and all changes and modifications made to the scope of the present invention should be within the scope of the present invention.

Claims (14)

A cationic binder comprising the formula (I): [Mg _(1-x) Fe _x (OH) _x/n ] ^{x +} [Cl] ^- _x(1-2/k) [CO ₃ ] ^-2 _x/k ‧mH ₂ O,x=0.23~0.38 n=1.16~1.34 k=2.37~3.28 Formula (I). The cationic binder of claim 1, wherein the raw material for synthesizing the cationic binder is Mg(OH) ₂ and FeCl ₃ ‧6H ₂ O. The cationic binder of claim 1, wherein the ratio of Mg ⁺² :Fe ⁺³ in the cationic binder is between 6:1 and 1.5:1. The cationic binding agent of claim 1, wherein the anionic absorption of the cationic binding agent means a phosphate absorption force. The cationic binding agent of claim 1, wherein the cationic binding agent comprises carbonate. The cationic binder of claim 1, wherein the atomic ratio of Mg ^{+ 2} and Fe ^{+ 3} in the raw material for synthesizing the cationic binder is between 2:1 and 60:1, and the cationic binder is An anion taking capacity greater than 100 . A pharmaceutical composition for treating a subject suffering from or susceptible to hyperphosphatemia, comprising a cationic binding agent and a pharmacologically acceptable carrier, wherein the cationic binding agent comprises formula (I): [Mg _{( 1-x)} Fe _x (OH) _x/n ] ^x+ [Cl] ^- _x(1-2/k) [CO ₃ ] ^-2 _x/k ‧mH ₂ O,x=0.23~0.38 n=1.16~1.34 k=2.37~3.28 Formula (I). The pharmaceutical composition according to claim 7, wherein the raw material for synthesizing the cationic binder is Mg(OH) ₂ and FeCl ₃ ‧6H ₂ O. The pharmaceutical composition of claim 7, wherein the ratio of Mg ⁺² :Fe ⁺³ in the cationic binder is between 4:1 and 2:1. The pharmaceutical composition of claim 7, wherein the cationic binder has a hydrotalcite-like nanochip (HTln) structure. The pharmaceutical composition of claim 7, wherein the anionic absorption of the cationic binder means a phosphate absorption force. The pharmaceutical composition of claim 7, wherein the cationic binder comprises carbonate. The pharmaceutical composition according to claim 7, wherein the atomic ratio of Mg ^{+ 2} and Fe ^{+ 3} in the raw material for synthesizing the cationic binder is between 2:1 and 60:1, and the cationic binder is An anionic absorption force greater than 100 . The pharmaceutical composition of claim 7, wherein the subject comprises a human and an animal.