Lanthanum carbonate medicinal composition, application thereof and medicine for treating hyperphosphatemia

Abstract

The invention provides a lanthanum carbonate medicinal composition, application thereof and a medicine for treating hyperphosphatemia, and belongs to the technical field of medicines. The lanthanum carbonate pharmaceutical composition provided by the invention comprises lanthanum carbonate and ethylenediamine tetraacetic acid cross-linked beta-cyclodextrin, wherein the mass ratio of the lanthanum carbonate to the ethylenediamine tetraacetic acid cross-linked beta-cyclodextrin is 1: (0.2-5.0). The lanthanum carbonate pharmaceutical composition provided by the invention can reduce and even block absorption of lanthanum ions into blood while the phosphorus reduction effect of lanthanum carbonate is not influenced. Results of test cases show that compared with commercially available lanthanum carbonate granules, the lanthanum carbonate granules prepared from the lanthanum carbonate medicinal composition provided by the invention can prevent lanthanum ions from being absorbed into blood, so that the curative effect of the lanthanum carbonate granules is improved. Therefore, the problems of accumulation of lanthanum in vivo and bone poisoning caused by the fact that trace lanthanum ions are still absorbed into blood while lanthanum carbonate plays a role in reducing phosphorus in gastrointestinal tracts are solved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a lanthanum carbonate pharmaceutical composition and an application thereof and a drug for treating hyperphosphatemia. Background Art

[0002] Hyperphosphatemia refers to a pathological condition in which the phosphate concentration in the patient's blood is higher than normal. Long-term high phosphate concentration in the blood will affect calcium and phosphorus deposition, which will in turn cause secondary hyperthyroidism, renal osteodystrophy, etc., and may also cause serious cardiovascular complications. Hyperphosphatemia is a common and serious disease in patients with chronic kidney disease (CKD). Currently, phosphate binders are the only approved treatment for hyperphosphatemia. Traditional phosphate binders include calcium carbonate, calcium acetate, and aluminum hydroxide, but they can cause adverse reactions such as increased blood calcium and aluminum absorption poisoning. The new generation of calcium-aluminum-free phosphate binders include lanthanum carbonate and sevelamer hydrochloride / carbonate.

[0003] Lanthanum carbonate (trade name Fosrenol) is a calcium-free, aluminum-free, non-resin phosphate binder developed by Shire. Compared with traditional phosphate binders, lanthanum carbonate is more effective and safer. It can not only reduce the phosphate level in the patient's serum, but also does not cause increased blood calcium and other serious side effects, and has good tolerance.

[0004] The mechanism of action of lanthanum carbonate in treating hyperphosphatemia is as follows: lanthanum carbonate enters the digestive tract through oral administration, and generates trivalent lanthanum ions under the action of gastric acid, which have a strong affinity with phosphorus in food. After the trivalent lanthanum ions combine with phosphorus, they form insoluble lanthanum phosphate precipitates that are not easily absorbed by the digestive tract and are excreted from the body with feces, thereby reducing the patient's phosphorus intake from food and playing a phosphorus-lowering role. However, after oral administration of lanthanum carbonate, there is a problem that trace amounts of lanthanum are absorbed into the blood and deposited in tissues. Summary of the invention

[0005] The object of the present invention is to provide a lanthanum carbonate pharmaceutical composition and its application and a drug for treating hyperphosphatemia. The lanthanum carbonate pharmaceutical composition provided by the present invention can effectively reduce or even block the problem of lanthanum ions being absorbed into the blood and then deposited in tissues after oral administration of lanthanum carbonate, and does not affect the phosphorus-lowering effect of lanthanum carbonate.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The invention provides a lanthanum carbonate pharmaceutical composition, comprising lanthanum carbonate and ethylenediaminetetraacetic acid cross-linked beta-cyclodextrin, wherein the mass ratio of the lanthanum carbonate to the ethylenediaminetetraacetic acid cross-linked beta-cyclodextrin is 1:0.2-5.0.

[0008] The present invention provides the use of the lanthanum carbonate pharmaceutical composition described in the above technical solution in the preparation of a drug for treating hyperphosphatemia.

[0009] Preferably, the hyperphosphatemia includes hyperphosphatemia caused by chronic renal failure with hemodialysis or without hemodialysis or continuous ambulatory peritoneal dialysis.

[0010] The present invention provides a drug for treating hyperphosphatemia, comprising the lanthanum carbonate pharmaceutical composition described in the above technical solution and pharmaceutically acceptable excipients.

[0011] Preferably, the content of lanthanum in the drug for treating hyperphosphatemia is 100-1000 mg.

[0012] Preferably, the drug for treating hyperphosphatemia is an oral preparation.

[0013] Preferably, the dosage form of the drug for treating hyperphosphatemia includes tablets, granules, powders or dry syrups.

[0014] Preferably, the tablet comprises a chewable tablet or an orally disintegrating tablet.

[0015] Preferably, the pharmaceutically acceptable excipients include one or more of a diluent, a disintegrant, a glidant and a lubricant.

[0016] Preferably, the diluent includes one or more of starch hydrolyzed oligosaccharides, mannitol, sorbitol, sucrose, lactose and low-substituted hydroxypropyl cellulose; the disintegrant includes one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, starch, starch derivatives, cellulose and cellulose derivatives; the glidant includes silicon dioxide and / or micro-powdered silica gel; and the lubricant includes magnesium stearate.

[0017] The present invention provides a lanthanum carbonate pharmaceutical composition, comprising lanthanum carbonate and ethylenediaminetetraacetic acid cross-linked β-cyclodextrin, wherein the mass ratio of the lanthanum carbonate to ethylenediaminetetraacetic acid cross-linked β-cyclodextrin (EDTA-β-CD) is 1:0.2-5.0. The lanthanum carbonate pharmaceutical composition provided by the present invention can reduce or even block the absorption of lanthanum ions into the blood without affecting the phosphorus-reducing effect of lanthanum carbonate. Specifically, after oral administration of lanthanum carbonate, lanthanum ions are dissociated under the action of gastric acid, and the lanthanum ions are adsorbed by EDTA-β-CD to form a lanthanum ion-EDTA-β-CD inclusion complex; at the same time, since lanthanum ions can form insoluble lanthanum phosphate precipitates with phosphorus in food, phosphorus can competitively capture the adsorbed lanthanum from the lanthanum ion-EDTA-β-CD inclusion complex to continue to generate lanthanum phosphate precipitates, thereby greatly reducing the chance of free lanthanum ions being absorbed by the gastrointestinal tract; and the lanthanum carbonate pharmaceutical composition provided by the present invention can not only reduce or even block the problem of lanthanum ion absorption into the blood, but also completely does not affect the phosphorus-reducing effect of lanthanum carbonate. The results of the test examples show that the lanthanum carbonate granules prepared using the lanthanum carbonate pharmaceutical composition provided by the present invention can prevent lanthanum ions from being absorbed into the blood compared with commercially available lanthanum carbonate granules, thereby solving the problem that while lanthanum carbonate exerts a phosphorus-reducing effect in the gastrointestinal tract, a trace amount of lanthanum ions are still absorbed into the blood, causing lanthanum accumulation in the body and bone poisoning. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 1 is the dissolution curve of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in 0.1 mol / L hydrochloric acid;

[0019] Figure 2 1 is the dissolution curve of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in pH 3.0 acetate buffer;

[0020] Figure 3 1 is the dissolution curve of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in pH 5.0 acetate buffer;

[0021] Figure 4 is the Langmuir fitting curve of the lanthanum carbonate chewable tablet in different media in Example 2;

[0022] Figure 5 The Langmuir fitting curves of the lanthanum carbonate chewable tablets in different media in Comparative Example 2;

[0023] Figure 6 This is a graph showing the test results of lanthanum concentration in plasma at different times. DETAILED DESCRIPTION

[0024] The invention provides a lanthanum carbonate pharmaceutical composition, comprising lanthanum carbonate and ethylenediaminetetraacetic acid cross-linked beta-cyclodextrin, wherein the mass ratio of the lanthanum carbonate to the ethylenediaminetetraacetic acid cross-linked beta-cyclodextrin is 1:0.2-5.0.

[0025] Lanthanum carbonate is currently the most selective new drug for the treatment of hyperphosphatemia in kidney disease. After oral administration of lanthanum carbonate, trivalent lanthanum ions combine with phosphorus to form insoluble lanthanum phosphate precipitates that are not easily absorbed by the digestive tract and excreted from the body with feces, but trace amounts of lanthanum are still absorbed into the blood and deposited in tissues. The public review report of the US FDA shows that the absolute bioavailability of Fosrenol lanthanum in animals after oral administration is 0.00127±0.0008%. Studies have shown that the bones, liver and gastrointestinal tract of animals are the main sites of lanthanum deposition. After oral administration of lanthanum carbonate to humans, the deposition of lanthanum in bone tissue reaches a steady state in about 17 years. After 15 years of treatment, the lanthanum concentration in the bones is 13900-46000μg / kg. After rats with normal renal function were given lanthanum, their tissue sections showed that lanthanum was bone toxic and bone damage occurred. Because the data on lanthanum concentration in bones after long-term exposure are very limited, drug regulatory agencies are concerned about the actual deposition, accumulation and toxicity of lanthanum in bones. The instructions for the chewable, granular and orally disintegrating lanthanum carbonate tablets originally developed and marketed by Bayer in Japan show that the steady-state plasma lanthanum concentration of 9 healthy Japanese adult men who took lanthanum carbonate (1000 mg in terms of lanthanum) three times a day for 10 consecutive days reached the highest value at 6 hours after administration. max and AUC 0-8 The average plasma lanthanum concentrations at weeks 8, 52 and 156 were 0.406 ng / mL, 0.463 ng / mL and 0.558 ng / mL, respectively. It can be seen that a small amount of lanthanum is absorbed into the blood and causes tissue accumulation after oral administration of lanthanum carbonate, which is always a potential safety factor for the lanthanum carbonate preparations on the market. Therefore, it is necessary to develop a lanthanum carbonate composition that can reduce or even block the problem of lanthanum ion absorption into the blood without affecting its phosphorus-lowering effect.

[0026] The inventors have found that adding EDTA-β-CD to the lanthanum carbonate prescription can solve the above-mentioned problem of lanthanum ion absorption into the blood. EDTA-β-CD is a cross-linked polymer of β-cyclodextrin (β-CD) modified by ethylenediaminetetraacetic acid (EDTA), which is specifically obtained by esterification condensation reaction between EDTA and β-CD. β-CD is a seven-unit cyclic oligosaccharide produced by starch enzymatic hydrolysis, and the high-density hydroxyl groups around the cavity can be used as coordination sites to form a complex with trivalent lanthanum ions. The EDTA in EDTA-β-CD not only plays a role in cross-linking, but also plays a role in providing active sites, and adsorbs trivalent lanthanum ions through mechanisms such as electrostatic interaction, chelation and complexation. Specifically, the mechanism of action of the lanthanum carbonate pharmaceutical composition provided by the present invention is: after oral administration of lanthanum carbonate, it dissociates into lanthanum ions under the action of gastric acid, and the lanthanum ions are adsorbed by EDTA-β-CD to form a lanthanum ion-EDTA-β-CD inclusion complex; at the same time, because lanthanum ions can form insoluble lanthanum phosphate precipitates with phosphorus in food, phosphorus can competitively seize the adsorbed lanthanum from the lanthanum ion-EDTA-β-CD inclusion complex to continue to generate lanthanum phosphate precipitates, thereby greatly reducing the chance of free lanthanum ions being absorbed by the gastrointestinal tract. The inventors were pleasantly surprised to find that the lanthanum carbonate pharmaceutical composition provided by the present invention can not only reduce or even block the problem of lanthanum ion absorption into the blood, but also does not affect the phosphorus-reducing effect of lanthanum carbonate at all. The lanthanum carbonate pharmaceutical composition provided by the present invention is described in detail below.

[0027] As an embodiment of the present invention, the molecular formula of the lanthanum carbonate is La2(CO3)3·xH2O, wherein x is 4-5.

[0028] In the present invention, the mass ratio of lanthanum carbonate and EDTA-β-CD in the lanthanum carbonate pharmaceutical composition is 1:0.2-5.0, specifically 1:0.2, 1:0.5, 1:0.8, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, 1:4.5 or 1:5.0.

[0029] In the present invention, the EDTA-β-CD is specifically obtained by esterification condensation reaction of EDTA and β-CD; as an embodiment of the present invention, the preparation method of the EDTA-β-CD comprises the following steps:

[0030] β-CD, EDTA, sodium monohydrogen phosphate and water are mixed to carry out a first-stage reaction, and then polyethylene glycol is added to the obtained liquid to carry out a second-stage reaction to obtain the EDTA-β-CD.

[0031] As an embodiment of the present invention, the usage ratio of the β-CD, EDTA, sodium monohydrogen phosphate and water can be 35mmol:204mmol:100mmol:200mL; the sodium monohydrogen phosphate is specifically Na2HPO4·7H2O; the temperature of the first stage reaction can be 100°C and the time can be 1.5h.

[0032] As an embodiment of the present invention, the polyethylene glycol can be specifically polyethylene glycol 200, and the molar ratio of polyethylene glycol 200 to β-CD can be 25:35; the polyethylene glycol can be added dropwise; the temperature of the second stage reaction can be 155° C. and the reaction time can be 12 hours.

[0033] As an embodiment of the present invention, the second stage reaction may further include: grinding the condensation polymer obtained after the second stage reaction and soaking it in water, then filtering and washing the filter cake with hydrochloric acid (0.1M), water, sodium hydroxide aqueous solution (0.1M), water and methanol in sequence, and drying the washed filter cake to obtain the EDTA-β-CD.

[0034] The present invention provides the use of the lanthanum carbonate pharmaceutical composition described in the above technical solution in the preparation of a drug for treating hyperphosphatemia. As an embodiment of the present invention, the hyperphosphatemia may include hyperphosphatemia caused by chronic renal failure with hemodialysis or non-hemodialysis or continuous ambulatory peritoneal dialysis.

[0035] As an embodiment of the present invention, the drug for treating hyperphosphatemia includes the lanthanum carbonate pharmaceutical composition described in the above technical solution and pharmaceutically acceptable excipients. Specifically, the drug for treating hyperphosphatemia includes lanthanum carbonate, EDTA-β-CD and pharmaceutically acceptable excipients; the content of lanthanum in the drug for treating hyperphosphatemia can be 100 to 1000 mg, specifically 100 mg, 250 mg, 500 mg, 750 mg or 1000 mg.

[0036] As one embodiment of the present invention, the drug for treating hyperphosphatemia can be an oral preparation, specifically a solid oral preparation; as one embodiment of the present invention, the dosage form of the drug for treating hyperphosphatemia can include tablets, granules, powders or dry syrups, wherein the tablets can include chewable tablets or orally disintegrating tablets. The lanthanum carbonate pharmaceutical composition of the present invention is particularly suitable for preparing oral preparations that avoid the intake of liquids such as water, such as chewable tablets, orally disintegrating tablets, powders, granules or dry syrups.

[0037] As an embodiment of the present invention, the pharmaceutically acceptable excipients may include one or more of a diluent, a disintegrant, a glidant and a lubricant; wherein the diluent may include one or more of starch hydrolyzed oligosaccharides, mannitol, sorbitol, sucrose, lactose and low-substituted hydroxypropyl cellulose; the disintegrant may include one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, starch, starch derivatives (for example, may include carboxymethyl starch or pregelatinized starch), cellulose and cellulose derivatives (for example, may include methyl cellulose or hydroxypropyl methyl cellulose or hydroxyethyl cellulose); the glidant includes silicon dioxide and / or micropowdered silica gel; the lubricant includes magnesium stearate.

[0038] As an embodiment of the present invention, the corresponding pharmaceutically acceptable excipients and preparation methods can be selected according to the dosage form of the drug for treating hyperphosphatemia, which will be described in detail below.

[0039] In an embodiment of the present invention, when the dosage form of the drug for treating hyperphosphatemia is granules, powders or dry syrups, the pharmaceutically acceptable excipients may include one or more of diluents, glidants and lubricants, specifically diluents, glidants and lubricants; the diluent may include one or more of starch hydrolyzed oligosaccharides, mannitol, sorbitol and sucrose, specifically starch hydrolyzed oligosaccharides; the glidant may include silicon dioxide and / or micro-powder silica gel, specifically micro-powder silica gel; the lubricant may be magnesium stearate. In an embodiment of the present invention, the preparation method of the powder or dry syrup may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid cross-linked β-cyclodextrin and pharmaceutically acceptable excipients to obtain a mixed material; packaging the mixed material to obtain the powder or dry syrup. In an embodiment of the present invention, the preparation method of the granules may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid cross-linked β-cyclodextrin and pharmaceutically acceptable excipients to obtain a mixture; dry granulating the mixture to obtain dry granules; and packaging the dry granules to obtain the granules.

[0040] In an embodiment of the present invention, when the dosage form of the drug for treating hyperphosphatemia is a chewable tablet, the pharmaceutically acceptable excipients may include one or more of a diluent, a glidant and a lubricant, specifically a diluent, a glidant and a lubricant; the diluent may include one or more of starch hydrolyzed oligosaccharides, lactose, low-substituted hydroxypropyl cellulose, mannitol and sorbitol, specifically starch hydrolyzed oligosaccharides; the glidant may include silicon dioxide and / or micro-powder silica gel, specifically micro-powder silica gel; the lubricant may be magnesium stearate. In an embodiment of the present invention, the preparation method of the chewable tablet may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid cross-linked β-cyclodextrin and pharmaceutically acceptable excipients to obtain a mixed material; dry granulating the mixed material and then tableting it to obtain the chewable tablet.

[0041] In an embodiment of the present invention, when the dosage form of the drug for treating hyperphosphatemia is an orally disintegrating tablet, the pharmaceutically acceptable excipients may include one or more of a diluent, a disintegrant, a glidant and a lubricant, specifically a diluent, a disintegrant, a glidant and a lubricant; the diluent may include one or more of starch hydrolyzed oligosaccharides, lactose, low-substituted hydroxypropyl cellulose, mannitol and sorbitol, specifically low-substituted hydroxypropyl cellulose; the disintegrant may include one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, starch, starch derivatives, cellulose and cellulose derivatives, specifically cross-linked polyvinylpyrrolidone; the glidant may include silicon dioxide and / or micro-powder silica gel, specifically micro-powder silica gel; the lubricant may be magnesium stearate. In an embodiment of the present invention, the preparation method of the orally disintegrating tablet may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid cross-linked β-cyclodextrin and pharmaceutically acceptable excipients to obtain a mixed material; granulating the mixed material using a dry granulation process, and then compressing to obtain the orally disintegrating tablet.

[0042] In the embodiments of the present invention, granules (i.e., lanthanum carbonate granules containing EDTA-β-CD), chewable tablets (i.e., lanthanum carbonate chewable tablets containing EDTA-β-CD) and orally disintegrating tablets (i.e., lanthanum carbonate orally disintegrating tablets containing EDTA-β-CD) are used as examples to verify the effect of the present invention. The formulas and preparation methods of the three preparations are described in detail below.

[0043] In an embodiment of the present invention, the lanthanum carbonate particles containing EDTA-β-CD include lanthanum carbonate, EDTA-β-CD, starch hydrolyzed oligosaccharides, micropowder silica gel and magnesium stearate; the mass ratio of the lanthanum carbonate to EDTA-β-CD can be 1:0.2-5.0, further can be 1:0.5-1.5, specifically can be 1:1.0; the mass ratio of the lanthanum carbonate to starch hydrolyzed oligosaccharides, micropowder silica gel and magnesium stearate can be 1:0.2-2.0:0.02-0.08:0.01-0.05, further can be 1:1.0-1.5:0.04-0.06:0.02-0.03, specifically can be 190.1:232.8:9.6:3.9. In an embodiment of the present invention, the method for preparing the lanthanum carbonate particles containing EDTA-β-CD may include the following steps: mixing lanthanum carbonate with EDTA-β-CD, mixing the resulting mixture with starch hydrolyzed oligosaccharides, micropowder silica gel and magnesium stearate, performing dry granulation, and directly packaging the resulting dry particles to obtain the lanthanum carbonate particles containing EDTA-β-CD.

[0044] In an embodiment of the present invention, the lanthanum carbonate chewable tablet containing EDTA-β-CD includes lanthanum carbonate, EDTA-β-CD, starch hydrolyzed oligosaccharides, micropowder silica gel and magnesium stearate; the mass ratio of the lanthanum carbonate to EDTA-β-CD can be 1:0.2-5.0, further can be 1:0.4-0.6, specifically can be 1:0.5; the mass ratio of the lanthanum carbonate to starch hydrolyzed oligosaccharides, micropowder silica gel and magnesium stearate can be 1:0.2-2.0:0.02-0.08:0.01-0.05, further can be 1:1.0-1.5:0.03-0.05:0.02-0.03, specifically can be 190.7:213.3:8.5:4.3. In an embodiment of the present invention, the preparation method of the lanthanum carbonate chewable tablets containing EDTA-β-CD may include the following steps: mixing lanthanum carbonate with EDTA-β-CD, mixing the resulting mixture with starch hydrolyzed oligosaccharides, micropowder silica gel and magnesium stearate, and sequentially performing dry granulation and tableting to obtain the lanthanum carbonate chewable tablets containing EDTA-β-CD.

[0045] In an embodiment of the present invention, the raw materials for preparing the lanthanum carbonate orally disintegrating tablet containing EDTA-β-CD include lanthanum carbonate, EDTA-β-CD, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, micro-powder silica gel and magnesium stearate; the mass ratio of the lanthanum carbonate to EDTA-β-CD can be 1:0.2-5.0, further can be 1:1.5-2.5, specifically can be 1:2.0; the mass ratio of the lanthanum carbonate to low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, micro-powder silica gel and magnesium stearate can be 1:0.5-1.0:1.0-1.5:0.02-0.08:0.01-0.05, further can be 1:0.6-0.7:1.1-1.2:0.03-0.05:0.02-0.03, specifically can be 190.3:122.1:210.5:8.2:4.6. In an embodiment of the present invention, the preparation method of the lanthanum carbonate orally disintegrating tablet containing EDTA-β-CD may include the following steps: mixing lanthanum carbonate with EDTA-β-CD, mixing the resulting mixture with low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, micropowder silica gel and magnesium stearate, and performing powder direct compression to obtain the lanthanum carbonate orally disintegrating tablet containing EDTA-β-CD.

[0046] The present invention provides a drug for treating hyperphosphatemia, comprising the lanthanum carbonate pharmaceutical composition described in the above technical solution and a pharmaceutically acceptable excipient. As an embodiment of the present invention, the drug for treating hyperphosphatemia has the same dosage form, pharmaceutically acceptable excipients and preparation method as the drug for treating hyperphosphatemia described in the above technical solution, and will not be described in detail here.

[0047] The drug for treating hyperphosphatemia provided by the present invention can prevent lanthanum ions from being absorbed into the blood, thereby solving the problem that while commercially available lanthanum carbonate drugs exert phosphorus-reducing effects in the gastrointestinal tract, trace amounts of lanthanum ions are still absorbed into the blood, causing lanthanum accumulation in the body and bone poisoning. The drug has a simple preparation process and is suitable for large-scale industrial production.

[0048] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0049] The molecular formula of lanthanum carbonate used in the following examples is La2(CO3)3·xH2O, wherein x is 4 to 5; the preparation method of EDTA-β-CD used is as follows:

[0050] β-cyclodextrin (β-CD, 40 g, 35 mmol), ethylenediaminetetraacetic acid (EDTA, 60 g, 204 mmol), Na2HPO4·7H2O (26.8 g, 100 mmol) and deionized water (200 mL) were added to a round-bottom flask and stirred in an oil bath at 100°C for 1.5 h; then polyethylene glycol 200 (5 g, 25 mmol) was added dropwise, and the resulting mixture was heated in an oven at 155°C for 12 h, then cooled to room temperature, the resulting condensation polymer was ground and immersed in 5000 mL of deionized water, then filtered and the filter cake was washed with a large amount of 0.1 M hydrochloric acid, deionized water, 0.1 M sodium hydroxide aqueous solution, deionized water and methanol in sequence, and the washed filter cake was vacuum dried at 60°C to obtain the EDTA-β-CD.

[0051] Example 1

[0052] 190.4 g of EDTA-β-CD and 190.1 g of lanthanum carbonate were mixed, and the resulting mixture was mixed with 232.8 g of starch hydrolyzed oligosaccharide, 9.6 g of micropowdered silica gel and 3.9 g of magnesium stearate, and dry granulated. The resulting dry granules were directly packaged to obtain lanthanum carbonate granules containing EDTA-β-CD.

[0053] Comparative Example 1

[0054] The procedure was carried out in accordance with Example 1, except that EDTA-β-CD was omitted.

[0055] Example 2

[0056] 95.4 g of EDTA-β-CD and 190.7 g of lanthanum carbonate were mixed, and the resulting mixture was mixed with 213.3 g of starch hydrolyzed oligosaccharide, 8.5 g of micropowdered silica gel and 4.3 g of magnesium stearate, and dry granulation and tableting were performed in sequence to obtain lanthanum carbonate chewable tablets containing EDTA-β-CD.

[0057] Comparative Example 2

[0058] The procedure was carried out in accordance with Example 2, except that EDTA-β-CD was omitted.

[0059] Example 3

[0060] 380.2 g of EDTA-β-CD and 190.3 g of lanthanum carbonate were mixed, and the resulting mixture was mixed with 122.1 g of low-substituted hydroxypropyl cellulose, 210.5 g of cross-linked polyvinylpyrrolidone, 8.2 g of micropowdered silica gel and 4.6 g of magnesium stearate, and the powder was directly compressed to obtain an orally disintegrating tablet of lanthanum carbonate containing EDTA-β-CD.

[0061] Comparative Example 3

[0062] The procedure was carried out in accordance with Example 3, except that EDTA-β-CD was omitted.

[0063] Comparison of dissolution curves in test example 1

[0064] The lanthanum carbonate particles prepared in Example 1 and Comparative Example 1 were subjected to dissolution tests in medium solutions (0.1 mol / L hydrochloric acid, pH 3.0 acetate buffer, and pH 5.0 acetate buffer), respectively, and the dissolution curves were compared.

[0065] The dissolution test conditions are as follows: the volume of the medium solution is 900 mL, the stirring speed during the dissolution process is 50 rpm, and sampling and testing are carried out at the corresponding time points according to the requirements in Table 1; the detection method is as follows: 5 mL of each test solution is accurately measured and placed in a conical flask, 45 mL of titration buffer solution (specifically acetate buffer, concentration of 0.2 mol / L, pH = 6.2) and 5 drops of xylenol orange indicator solution are added, and disodium ethylenediaminetetraacetic acid titrant (0.01 mol / L) is used to titrate until the solution changes from lavender to lemon yellow, and the volume of disodium ethylenediaminetetraacetic acid titrant consumed (recorded as V) is recorded, and each 1 mL of disodium ethylenediaminetetraacetic acid titrant (0.01 mol / L) is equivalent to 1.39 mg of lanthanum (La).

[0066] Table 1 Medium solution types and sampling time points

[0067] Medium solution name Sampling time point 0.1mol / L hydrochloric acid 5min, 10min, 15min, 20min, 30min, 40min, 60min, 90min, 120min pH 3.0 acetate buffer 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 24h pH 5.0 acetate buffer 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 24h

[0068] Table 2 shows the dissolution curve test results when the medium solution is 0.1 mol / L hydrochloric acid. Figure 1 The dissolution curves of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in 0.1 mol / L hydrochloric acid are shown; the results show that the similarity factor F2 value of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in 0.1 mol / L hydrochloric acid is 69 (>50), indicating that the dissolution behaviors of the two are consistent, that is, the EDTA-β-CD in the lanthanum carbonate pharmaceutical composition of the present invention does not affect the dissolution behavior of lanthanum carbonate.

[0069] Table 2 Dissolution curve test results (0.1 mol / L hydrochloric acid, pH = 1.2)

[0070]

[0071]

[0072] Table 3 shows the dissolution curve test results when the medium solution is pH 3.0 acetate buffer. Figure 2The dissolution curves of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in pH 3.0 acetate buffer solution are shown; the results show that the similarity factor F2 value of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in pH 3.0 acetate buffer solution is 72 (>50), indicating that the dissolution behaviors of the two are consistent, that is, the EDTA-β-CD in the lanthanum carbonate pharmaceutical composition of the present invention does not affect the dissolution behavior of lanthanum carbonate.

[0073] Table 3 Dissolution curve test results (pH 3.0 acetate buffer)

[0074]

[0075]

[0076] Table 4 shows the dissolution curve test results when the medium solution is pH 5.0 acetate buffer. Figure 3 The dissolution curves of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in pH 5.0 acetate buffer solution show that the similarity factor F2 value of the lanthanum carbonate particles in Example 1 and the lanthanum carbonate particles in Comparative Example 1 in pH 5.0 acetate buffer solution is 71 (>50), indicating that the dissolution behaviors of the two are consistent, that is, the EDTA-β-CD in the lanthanum carbonate pharmaceutical composition of the present invention does not affect the dissolution behavior of lanthanum carbonate.

[0077] Table 4 Dissolution curve test results (pH 5.0 acetate buffer)

[0078]

[0079]

[0080] Test Example 2 Comparison of Lanthanum-Phosphorus Binding Test

[0081] The lanthanum carbonate chewable tablets prepared in Example 2 and Comparative Example 2 were subjected to a lanthanum-phosphorus binding test in 0.1 mol / L hydrochloric acid (pH=1.2), pH 3.0 acetate buffer and pH 5.0 acetate buffer, respectively.

[0082] The design principle of the lanthanum-phosphorus binding test is as follows: under different pH conditions, after lanthanum carbonate combines with different concentrations of phosphorus and finally reaches equilibrium, the remaining phosphorus in the solution is measured to obtain the amount of phosphorus bound to lanthanum at the lanthanum-phosphorus binding equilibrium, and then the Langmuir curve equation is fitted, ceq / (x / m)=1 / (k1k2)+(1 / k2)ceq, where ceq is the concentration of free phosphate in the test solution at equilibrium, x is the amount of phosphorus bound to the drug at equilibrium, and m is the labeled amount of lanthanum carbonate chewable tablets (in terms of lanthanum). The slope of the curve a=1 / k2, The intercept b=1 / (k1k2), k1 (the affinity constant of lanthanum-phosphorus, indicating the affinity of lanthanum and phosphorus during the binding process) and k2 (the capacity factor of lanthanum-phosphorus binding, indicating the maximum amount of phosphorus that can be bound per unit mass of drug) under different pH conditions can be calculated. Under different pH conditions, the 90% confidence interval of the ratio of k2 of the lanthanum carbonate chewable tablet prepared in Example 2 to k2 of the lanthanum carbonate chewable tablet prepared in Comparative Example 2 is within the range of 80.00-120.00%, that is, the lanthanum carbonate chewable tablet prepared in Example 2 is determined to be bioequivalent to the lanthanum carbonate chewable tablet prepared in Comparative Example 2.

[0083] The lanthanum-phosphorus binding test steps are as follows: the lanthanum-phosphorus binding equilibrium of the lanthanum carbonate chewable tablets prepared in Example 2 and the lanthanum carbonate chewable tablets prepared in Comparative Example 2 are investigated in medium (1) (0.1 mol / L hydrochloric acid, pH=1.2), medium (2) (pH3.0 acetate buffer) and medium (3) (pH 5.0 acetate buffer), respectively, and the amount of free phosphorus therein is determined by the molybdenum-antimony resistance method. The detailed test steps are as follows:

[0084] Step 1:

[0085] Take the test sample, place it in a 500mL conical flask, add 200mL of 0.1mol / L hydrochloric acid, place the conical flask in a constant temperature incubation oscillator, set the temperature to 37.0℃, and the speed to 75r / min. After the solution system reaches 37.0℃, add 30mL of the medium and adjust to the target pH value. Put the conical flask with adjusted pH value back into the constant temperature incubation oscillator, monitor the pH value to stabilize the solution at the target value.

[0086] Step 2:

[0087] Place the conical flask of the medium solution in step 1 in a 37.0℃ water bath. While stirring, use a 25mL burette to dropwise add 20mL each of potassium dihydrogen phosphate solutions ①~⑧, 12 portions for each concentration; the concentrations of phosphorus in each series of conical flasks are: 8.00mmol / L (concentration ①), 10.16mmol / L (concentration ②), 14.48mmol / L (concentration ③), 21.76mmol / L (concentration ④), 28.96mmol / L (concentration ⑤), 43.44mmol / L (concentration ⑥), 58.00mmol / L (concentration ⑦), 86.88mmol / L (concentration ⑧).

[0088] Step 3:

[0089] Place the medium solution conical flask in step 2 in a constant temperature incubation oscillator, wait until the reaction system in the conical flask reaches 37.0°C, turn on the vibration, and treat it at 75r / min for 10h, then take an appropriate amount of the solution, filter it, and take the filtrate as the test solution.

[0090] Step 4:

[0091] Accurately measure 25 mL of water, phosphate standard curve solution, quality control solution, and diluted test solution sampled in the lanthanum-phosphorus binding equilibrium test, respectively, and place them in 50 mL conical flasks, accurately add 1 mL of 10 wt% ascorbic acid solution, mix well, and after 30 seconds, accurately add 2 mL of molybdate solution, mix well, and let it stand for 15 minutes. According to the UV-visible spectrophotometry, the absorbance is measured at a wavelength of 700 nm with water as a reference to calculate the residual phosphate content, and then the intercept and slope are obtained according to the plotted curve to calculate k1 and k2.

[0092] Step 5:

[0093] Accurately measure 25 mL of water, phosphate standard curve solution, quality control solution, and diluted test solution sampled in the lanthanum-phosphorus binding equilibrium test, respectively, and place them in 50 mL conical flasks. Accurately add 1 mL of 10 wt% ascorbic acid solution and mix well. After 30 seconds, accurately add 2 mL of molybdate solution, mix well, and let it stand for 15 minutes. Immediately determine the absorbance at a wavelength of 700 nm using UV-visible spectrophotometry with water as a reference to calculate the phosphate content.

[0094] The preparation method of the molybdate solution used in the above steps 4 and 5 is as follows: take ammonium molybdate ((NH4)6MO7O 24·4H2O) 13.0g, add 100mL of water to dissolve it, and mix it well; take 0.35g of potassium antimony tartrate (K(SbO)C4H4O6·1 / 2H2O), add 100mL of water to dissolve it, and mix it well; under stirring, slowly add 100mL of ammonium molybdate solution into 300mL of 50wt% sulfuric acid, then add 100mL of potassium antimony tartrate solution, mix it well, store it in a brown bottle, and store it at 4°C.

[0095] The test results are shown in Tables 5 to 10.

[0096] Table 5 Average results of 12 preparation units of lanthanum carbonate chewable tablets of Example 2 in hydrochloric acid at pH 1.2

[0097]

[0098] Table 6 Average results of 12 preparation units of lanthanum carbonate chewable tablets of Comparative Example 2 in pH 1.2 hydrochloric acid

[0099]

[0100] Table 7 Average results of 12 preparation units of lanthanum carbonate chewable tablets of Example 2 in pH 3.0 acetate buffer

[0101]

[0102]

[0103] Table 8 Average results of 12 preparation units of lanthanum carbonate chewable tablets of Comparative Example 2 in pH 3.0 acetate buffer

[0104]

[0105] Table 9 Average results of 12 preparation units of lanthanum carbonate chewable tablets of Example 2 in pH 5.0 acetate buffer

[0106]

[0107] Table 10 Average results of 12 preparation units of lanthanum carbonate chewable tablets of Comparative Example 2 in pH 5.0 acetate buffer

[0108]

[0109] Figure 4 is the Langmuir fitting curve of the lanthanum carbonate chewable tablets in different media in Example 2, Figure 51 is the Langmuir fitting curve of the lanthanum carbonate chewable tablet in different media in comparative example 2. Table 11 is a summary table of the lanthanum-phosphorus binding equilibrium test of the lanthanum carbonate chewable tablet of Example 2 and the lanthanum carbonate chewable tablet in comparative example 2.

[0110] Table 11 Summary of lanthanum-phosphorus binding equilibrium tests for lanthanum carbonate chewable tablets in Example 2 and Comparative Example 2

[0111]

[0112] The results of in vitro lanthanum-phosphorus binding behavior showed that there was no significant difference in the lanthanum-phosphorus binding capacity factor k2 value between the lanthanum carbonate chewable tablets in Example 2 and the lanthanum carbonate chewable tablets in Comparative Example 2 in three different pH media of pH = 1.2, pH = 3.0, and pH = 5.0, indicating that the maximum amount of phosphorus that can be bound per unit mass of lanthanum carbonate is basically the same; the k1% of the lanthanum carbonate chewable tablets in Example 2 relative to the lanthanum carbonate chewable tablets in Comparative Example 2 is in the range of 91.7-109.4%, the k2% is in the range of 98.8-101.1%, and the 90% confidence interval of k2% is in the range of 98.33-104.14%, indicating that the lanthanum-phosphorus binding affinity constants and the maximum lanthanum-phosphorus binding amounts of the two in the three media are basically the same, indicating that the lanthanum-phosphorus binding behaviors of the two are consistent in the lanthanum-phosphorus binding test.

[0113] The above test results show that the addition of EDTA-β-CD to the lanthanum carbonate pharmaceutical composition of the present invention will not affect its lanthanum-phosphorus binding behavior, that is, it will not affect the efficacy of lanthanum carbonate.

[0114] Test Example 3 Comparison of lanthanum absorption into blood after oral administration

[0115] Nine beagle dogs were orally administered one packet each of the lanthanum carbonate particles prepared in Example 1 (500 mg in terms of lanthanum) and lanthanum carbonate particles marketed in Japan (Fosrenol; 500 mg in terms of lanthanum) three times a day for three consecutive days immediately after a high-phosphorus meal. Blood was collected at 0h, 1h, 2h, 3h, 4h, 4.5h, 5h, 5.5h, 6h, 8h, 10h, 12h, 24h, and 48h, and the lanthanum concentration in plasma was determined by ICP-MS. It can be seen from the IF file of the lanthanum carbonate particles marketed in Japan that the prescription excipients are starch hydrolyzed oligosaccharides, magnesium stearate, and micro-powder silica gel.

[0116] Figure 6 Table 12 shows the pharmacokinetic parameters of lanthanum in plasma. The results show that after continuous oral administration of the lanthanum carbonate composition of the present invention, the concentration of lanthanum in plasma is below the detection limit, indicating that lanthanum is hardly absorbed into the blood after oral administration, while after continuous oral administration of the commercially available lanthanum carbonate particles (i.e., Fosrenol), the concentration of lanthanum in plasma is C max 0.43±0.26ng / mL, Tmax It was 4.0±0.82h, and the AUC was 7.32±2.82ng·h / mL.

[0117] Table 12 Pharmacokinetic parameters of lanthanum in plasma (Mean±SD, n=9)

[0118] sample <![CDATA[C max (ng / mL)]]> <![CDATA[T max (h)]]> AUC (ng·h / mL) Lanthanum carbonate particles of Example 1 0 / 0 Commercially available lanthanum carbonate particles (Fosrenol) 0.43±0.26 4.0±0.82 7.32±2.82

[0119] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A lanthanum carbonate pharmaceutical composition, characterized in that The invention comprises lanthanum carbonate and ethylenediaminetetraacetic acid cross-linked beta-cyclodextrin, wherein the mass ratio of the lanthanum carbonate and the ethylenediaminetetraacetic acid cross-linked beta-cyclodextrin is 1:0.2-5.

0.

2. Use of the lanthanum carbonate pharmaceutical composition according to claim 1 in the preparation of a medicament for treating hyperphosphatemia.

3. The use according to claim 2, characterized in that: The hyperphosphatemia includes hyperphosphatemia caused by chronic renal failure with or without hemodialysis or continuous ambulatory peritoneal dialysis.

4. A drug for treating hyperphosphatemia, characterized in that: The invention comprises the lanthanum carbonate pharmaceutical composition according to claim 1 and pharmaceutically acceptable excipients.

5. The drug for treating hyperphosphatemia according to claim 4, characterized in that: The content of lanthanum in the drug for treating hyperphosphatemia is 100-1000 mg.

6. The drug for treating hyperphosphatemia according to claim 4, characterized in that: The drug for treating hyperphosphatemia is an oral preparation.

7. The drug for treating hyperphosphatemia according to claim 6, characterized in that: The dosage form of the drug for treating hyperphosphatemia includes tablets, granules, powders or dry syrups.

8. The drug for treating hyperphosphatemia according to claim 7, characterized in that: The tablets include chewable tablets or orally disintegrating tablets.

9. The drug for treating hyperphosphatemia according to any one of claims 4 to 8, characterized in that: The pharmaceutically acceptable excipients include one or more of a diluent, a disintegrant, a glidant and a lubricant.

10. The drug for treating hyperphosphatemia according to claim 9, characterized in that: The diluent includes one or more of starch hydrolyzed oligosaccharides, mannitol, sorbitol, sucrose, lactose and low-substituted hydroxypropyl cellulose; the disintegrant includes one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, starch, starch derivatives, cellulose and cellulose derivatives; the glidant includes silicon dioxide and / or micro-powdered silica gel; and the lubricant includes magnesium stearate.

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