Lanthanum carbonate pharmaceutical composition and its application and medicine for treating hyperphosphatemia

Abstract

This invention provides a lanthanum carbonate pharmaceutical composition and its application in the treatment of hyperphosphatemia, belonging to the field of pharmaceutical technology. The lanthanum carbonate pharmaceutical composition provided by this invention comprises lanthanum carbonate and ethylenediaminetetraacetic acid (EDTA)-crosslinked β-cyclodextrin, wherein the mass ratio of lanthanum carbonate to EDTA-crosslinked β-cyclodextrin is 1:0.2–5.0. The lanthanum carbonate pharmaceutical composition provided by this invention can reduce or even block the absorption of lanthanum ions into the bloodstream without affecting the phosphorus-lowering effect of lanthanum carbonate. Test results show that lanthanum carbonate granules prepared using the lanthanum carbonate pharmaceutical composition provided by this invention, compared with commercially available lanthanum carbonate granules, can prevent the absorption of lanthanum ions into the bloodstream, thus solving the problem that while lanthanum carbonate exerts its phosphorus-lowering effect in the gastrointestinal tract, trace amounts of lanthanum ions are still absorbed into the bloodstream, causing lanthanum accumulation in the body and bone poisoning.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to lanthanum carbonate pharmaceutical compositions and their applications as drugs for treating hyperphosphatemia. Background Technology

[0002] Hyperphosphatemia is a pathological condition in which the concentration of phosphate in the blood is higher than normal. Long-term elevated blood phosphate levels can affect calcium and phosphorus deposition, leading to secondary hyperthyroidism, renal osteodystrophy, and potentially serious cardiovascular complications. Hyperphosphatemia is a common and serious condition 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 these can cause adverse reactions such as elevated blood calcium levels and aluminum absorption poisoning. Newer generation calcium- and 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, not only reducing serum phosphate levels in patients but also without causing elevated blood calcium or other serious side effects, and is well-tolerated.

[0004] The mechanism of action of lanthanum carbonate in treating hyperphosphatemia is as follows: Lanthanum carbonate enters the digestive tract orally and, under the action of gastric acid, generates trivalent lanthanum ions. These ions have a strong affinity for phosphorus in food, forming an insoluble lanthanum phosphate precipitate that is not easily absorbed by the digestive tract and is excreted in the feces. This reduces the patient's intake of phosphorus from food, thus lowering phosphorus levels. However, after oral administration of lanthanum carbonate, there is a possibility of trace amounts of lanthanum being absorbed into the bloodstream and deposited in tissues. Summary of the Invention

[0005] The purpose of this invention is to provide a lanthanum carbonate pharmaceutical composition and its application in the treatment of hyperphosphatemia. The lanthanum carbonate pharmaceutical composition provided by this invention can effectively reduce or even block the absorption of lanthanum ions into the blood and their deposition in tissues after oral administration of lanthanum carbonate, without affecting 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 present invention provides a lanthanum carbonate pharmaceutical composition comprising lanthanum carbonate and ethylenediaminetetraacetic acid crosslinked β-cyclodextrin, wherein the mass ratio of lanthanum carbonate to ethylenediaminetetraacetic acid crosslinked β-cyclodextrin is 1:0.2 to 5.0.

[0008] This invention provides the application of the lanthanum carbonate pharmaceutical composition described above in the preparation of a drug for treating hyperphosphatemia.

[0009] Preferably, the hyperphosphatemia includes hyperphosphatemia caused by chronic renal failure requiring hemodialysis, non-hemodialysis, or continuous ambulatory peritoneal dialysis.

[0010] This invention provides a medicament for treating hyperphosphatemia, comprising the lanthanum carbonate pharmaceutical composition described above and pharmaceutically acceptable excipients.

[0011] Preferably, the lanthanum content 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 tablets include chewable tablets or orally disintegrating tablets.

[0015] Preferably, the pharmaceutically acceptable excipients include one or more of diluents, disintegrants, glidants, and lubricants.

[0016] Preferably, the diluent comprises one or more of starch hydrolysate oligosaccharides, mannitol, sorbitol, sucrose, lactose, and low-substituted hydroxypropyl cellulose; the disintegrant comprises one or more of crospovidone, polyvinylpyrrolidone, crospovidone carboxymethyl cellulose sodium, starch, starch derivatives, cellulose, and cellulose derivatives; the flow aid comprises silica and / or micronized silica gel; and the lubricant comprises magnesium stearate.

[0017] This invention provides a lanthanum carbonate pharmaceutical composition comprising lanthanum carbonate and ethylenediaminetetraacetic acid (EDTA-β-CD) cross-linked β-cyclodextrin, wherein the mass ratio of lanthanum carbonate to EDTA-β-CD is 1:0.2–5.0. The lanthanum carbonate pharmaceutical composition provided by this invention can reduce or even block the absorption of lanthanum ions into the bloodstream without affecting the phosphorus-lowering effect of lanthanum carbonate. Specifically, after oral administration of lanthanum carbonate, it dissociates into lanthanum ions under the action of gastric acid. The lanthanum ions are adsorbed by EDTA-β-CD, forming a lanthanum ion-EDTA-β-CD inclusion complex. Simultaneously, because lanthanum ions can form insoluble lanthanum phosphate precipitates with phosphorus in food, phosphorus can competitively remove the adsorbed lanthanum from the lanthanum ion-EDTA-β-CD inclusion complex to continue generating lanthanum phosphate precipitates, thereby greatly reducing the chance of free lanthanum ions being absorbed by the gastrointestinal tract. Moreover, the lanthanum carbonate pharmaceutical composition provided by this invention not only reduces or even blocks the absorption of lanthanum ions into the bloodstream but also does not affect the phosphorus-lowering effect of lanthanum carbonate at all. The test results show that the lanthanum carbonate granules prepared using the lanthanum carbonate pharmaceutical composition provided by the present invention can prevent the absorption of lanthanum ions into the blood compared with commercially available lanthanum carbonate granules. This solves the problem that while lanthanum carbonate exerts its phosphorus-lowering effect in the gastrointestinal tract, trace amounts of lanthanum ions are still absorbed into the blood, causing lanthanum accumulation in the body and bone poisoning. Attached Figure Description

[0018] Figure 1 The dissolution curves of lanthanum carbonate particles in Example 1 and Comparative Example 1 in 0.1 mol / L hydrochloric acid are shown.

[0019] Figure 2 The dissolution curves of lanthanum carbonate particles in Example 1 and Comparative Example 1 in acetate buffer at pH 3.0 are shown.

[0020] Figure 3 The dissolution curves of lanthanum carbonate particles in Example 1 and Comparative Example 1 in acetate buffer at pH 5.0 are shown.

[0021] Figure 4 The Langmuir fitting curves of the lanthanum carbonate chewable tablets in different media in Example 2 are shown.

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

[0023] Figure 6 The graph shows the results of lanthanum concentration tests in plasma at different times. Detailed Implementation

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

[0025] Lanthanum carbonate is currently the most selective new drug for treating hyperphosphatemia in kidney disease. After oral administration of lanthanum carbonate, trivalent lanthanum ions combine with phosphorus to form an insoluble lanthanum phosphate precipitate that is not easily absorbed by the digestive tract and is excreted in the feces. However, trace amounts of lanthanum are still absorbed into the blood and deposited in tissues. Publicly available review reports from the US FDA show that the absolute bioavailability of lanthanum in animals after oral administration of Fosrenol is 0.00127 ± 0.0008%. Studies have shown that the main sites of lanthanum deposition in animals are bones, liver, and gastrointestinal tract. In humans, after oral administration of lanthanum carbonate, lanthanum deposition in bone tissue reaches a steady state within approximately 17 years. After 15 years of treatment, the concentration of lanthanum in bone is 13,900–46,000 μg / kg. In rats with normal renal function, tissue sections after administration of lanthanum showed bone toxicity and bone damage. Due to the very limited data on lanthanum concentration in bones after long-term exposure, regulatory agencies have concerns about the actual deposition, accumulation, and toxicity of lanthanum in bones. The product information for Bayer's lanthanum carbonate chewable tablets, granules, and orally disintegrating tablets, originally marketed in Japan, shows that in 9 healthy Japanese adult men who took lanthanum carbonate (1000 mg as lanthanum) three times daily for 10 consecutive days, the steady-state plasma lanthanum concentration reached its peak at 6 hours post-administration. max and AUC 0-8 The mean plasma lanthanum concentrations at weeks 8, 52, and 156 were 0.406 ng / mL, 0.463 ng / mL, and 0.558 ng / mL, respectively. This indicates that the small amount of lanthanum absorbed into the bloodstream after oral administration and its accumulation in tissues remains a potential safety factor for marketed lanthanum carbonate preparations. Therefore, it is necessary to develop a lanthanum carbonate composition that can reduce or even block the absorption of lanthanum ions into the bloodstream without affecting its phosphorus-lowering effect.

[0026] The inventors have discovered that adding EDTA-β-CD to the lanthanum carbonate formulation effectively solves the problem of lanthanum ion absorption into the bloodstream. EDTA-β-CD is a cross-linked polymer of ethylenediaminetetraacetic acid (EDTA) modified β-cyclodextrin (β-CD), specifically obtained through an esterification condensation reaction between EDTA and β-CD. β-CD is a seven-unit cyclic oligosaccharide produced by amylase hydrolysis; its high-density hydroxyl groups around the cavity can serve as coordination sites, forming complexes with trivalent lanthanum ions. EDTA in EDTA-β-CD not only acts as a cross-linking agent but also provides active sites, adsorbing trivalent lanthanum ions through electrostatic interactions, chelation, and complexation mechanisms. Specifically, the mechanism of action of the lanthanum carbonate pharmaceutical composition provided by this invention is as follows: After oral administration of lanthanum carbonate, it dissociates into lanthanum ions under the action of gastric acid. The lanthanum ions are adsorbed by EDTA-β-CD, forming a lanthanum ion-EDTA-β-CD inclusion complex. Simultaneously, because lanthanum ions can form insoluble lanthanum phosphate precipitate with phosphorus in food, phosphorus can competitively remove the adsorbed lanthanum from the lanthanum ion-EDTA-β-CD inclusion complex to continue generating lanthanum phosphate precipitate, 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 this invention can not only reduce or even block the absorption of lanthanum ions into the blood, but also does not affect the phosphorus-lowering effect of lanthanum carbonate at all. The lanthanum carbonate pharmaceutical composition provided by this invention will be 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 to 5.

[0028] In this invention, the mass ratio of lanthanum carbonate to EDTA-β-CD in the lanthanum carbonate pharmaceutical composition is 1:0.2 to 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 this invention, the EDTA-β-CD is specifically obtained by the esterification condensation reaction of EDTA and β-CD; as an embodiment of this invention, the preparation method of the EDTA-β-CD includes the following steps:

[0030] β-CD, EDTA, sodium monohydrogen phosphate, and water were mixed for the first stage reaction. Then, polyethylene glycol was added to the resulting solution for the second stage reaction to obtain the EDTA-β-CD.

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

[0032] As an embodiment of the present invention, the polyethylene glycol can specifically be 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 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, immersing it in water, filtering it, and washing the filter cake sequentially with hydrochloric acid (0.1M), water, sodium hydroxide aqueous solution (0.1M), water, and methanol, and drying the washed filter cake to obtain the EDTA-β-CD.

[0034] This invention provides the use of the lanthanum carbonate pharmaceutical composition described above in the preparation of a medicament for treating hyperphosphatemia. As one embodiment of this invention, the hyperphosphatemia may include hyperphosphatemia caused by chronic renal failure requiring hemodialysis, 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 lanthanum content in the drug for treating hyperphosphatemia can be 100-1000 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 another 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 diluents, disintegrants, flow aids, and lubricants; wherein the diluents may include one or more of starch hydrolysate oligosaccharides, mannitol, sorbitol, sucrose, lactose, and low-substituted hydroxypropyl cellulose; the disintegrants may include one or more of crospovidone, polyvinylpyrrolidone, crospovidone carboxymethyl cellulose sodium, starch, starch derivatives (e.g., may include carboxymethyl starch or pregelatinized starch), cellulose, and cellulose derivatives (e.g., may include methylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose); the flow aids include silica and / or micronized silica; and the lubricants include magnesium stearate.

[0038] As one embodiment of the present invention, appropriate pharmaceutically acceptable excipients and preparation methods can be selected according to the dosage form of the drug for treating hyperphosphatemia. Detailed description follows.

[0039] In embodiments 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, flow aids, and lubricants, specifically diluents, flow aids, and lubricants; the diluent may include one or more of starch hydrolysate oligosaccharides, mannitol, sorbitol, and sucrose, specifically starch hydrolysate oligosaccharides; the flow aid may include silica and / or micronized silica gel, specifically micronized silica gel; the lubricant may be magnesium stearate. In embodiments of the present invention, the preparation method of the powder or dry syrup may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid crosslinked β-cyclodextrin, and pharmaceutically acceptable excipients to obtain a mixture; and dispensing the mixture to obtain the powder or dry syrup. In this embodiment of the invention, the preparation method of the granules may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid crosslinked 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 this embodiment of the 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 flow aid, and a lubricant, specifically a diluent, a flow aid, and a lubricant; the diluent may include one or more of a starch hydrolyzed oligosaccharide, lactose, low-substituted hydroxypropyl cellulose, mannitol, and sorbitol, specifically a starch hydrolyzed oligosaccharide; the flow aid may include silica and / or micronized silica gel, specifically micronized silica gel; the lubricant may be magnesium stearate. In this embodiment of the invention, the preparation method of the chewable tablet may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid crosslinked β-cyclodextrin, and a pharmaceutically acceptable excipient to obtain a mixture; dry granulating the mixture and then compressing it into tablets to obtain the chewable tablet.

[0041] In this embodiment of the 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 diluents, disintegrants, flow aids, and lubricants, specifically diluents, disintegrants, flow aids, and lubricants; the diluent may include one or more of starch hydrolysate oligosaccharides, lactose, low-substituted hydroxypropyl cellulose, mannitol, and sorbitol, specifically low-substituted hydroxypropyl cellulose; the disintegrant may include one or more of crospovidone, polyvinylpyrrolidone, crospovidone sodium carboxymethyl cellulose, starch, starch derivatives, cellulose, and cellulose derivatives, specifically crospovidone; the flow aid may include silica and / or micronized silica, specifically micronized silica; and the lubricant may be magnesium stearate. In an embodiment of the present invention, the method for preparing the orally disintegrating tablet may include the following steps: mixing lanthanum carbonate, ethylenediaminetetraacetic acid crosslinked β-cyclodextrin, and pharmaceutically acceptable excipients to obtain a mixture; granulating the mixture using a dry granulation process, and then pressing it to obtain the orally disintegrating tablet.

[0042] In this embodiment of the 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 effectiveness of the present invention. The formulations and preparation methods of the three formulations are described in detail below.

[0043] In this embodiment of the invention, the lanthanum carbonate particles containing EDTA-β-CD include lanthanum carbonate, EDTA-β-CD, starch hydrolysate oligosaccharide, micronized silica gel, and magnesium stearate; the mass ratio of lanthanum carbonate to EDTA-β-CD can be 1:0.2-5.0, more preferably 1:0.5-1.5, and specifically 1:1.0; the mass ratio of lanthanum carbonate to starch hydrolysate oligosaccharide, micronized silica gel, and magnesium stearate can be 1:0.2-2.0:0.02-0.08:0.01-0.05, more preferably 1:1.0-1.5:0.04-0.06:0.02-0.03, and specifically 190.1:232.8:9.6:3.9. In an embodiment of the present invention, the preparation method of 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 hydrolysate oligosaccharide, micronized silica gel and magnesium stearate, performing dry granulation, and directly dispensing the resulting dry particles to obtain the lanthanum carbonate particles containing EDTA-β-CD.

[0044] In this embodiment of the invention, the lanthanum carbonate chewable tablet containing EDTA-β-CD comprises lanthanum carbonate, EDTA-β-CD, starch hydrolysate oligosaccharide, micronized silica gel, and magnesium stearate; the mass ratio of lanthanum carbonate to EDTA-β-CD can be 1:0.2-5.0, more preferably 1:0.4-0.6, and specifically 1:0.5; the mass ratio of lanthanum carbonate to starch hydrolysate oligosaccharide, micronized silica gel, and magnesium stearate can be 1:0.2-2.0:0.02-0.08:0.01-0.05, more preferably 1:1.0-1.5:0.03-0.05:0.02-0.03, and specifically 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 hydrolysate oligosaccharide, micronized silica gel and magnesium stearate, and performing dry granulation and tableting in sequence to obtain the lanthanum carbonate chewable tablets containing EDTA-β-CD.

[0045] In this embodiment of the invention, the raw materials for preparing the lanthanum carbonate orally disintegrating tablets containing EDTA-β-CD include lanthanum carbonate, EDTA-β-CD, low-substituted hydroxypropyl cellulose, crospovidone, micronized silica gel, and magnesium stearate; the mass ratio of lanthanum carbonate to EDTA-β-CD can be 1:0.2-5.0, more preferably 1:1.5-2.5, and specifically 1:2.0; the mass ratio of lanthanum carbonate to low-substituted hydroxypropyl cellulose, crospovidone, micronized silica gel, and magnesium stearate can be 1:0.5-1.0:1.0-1.5:0.02-0.08:0.01-0.05, more preferably 1:0.6-0.7:1.1-1.2:0.03-0.05:0.02-0.03, and specifically 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, crospovidone, micronized silica gel and magnesium stearate, and directly pressing the powder to obtain the lanthanum carbonate orally disintegrating tablet containing EDTA-β-CD.

[0046] This invention provides a medicament for treating hyperphosphatemia, comprising the lanthanum carbonate pharmaceutical composition described in the above-described technical solution and pharmaceutically acceptable excipients. As an embodiment of this invention, the dosage form, pharmaceutically acceptable excipients, and preparation method of the medicament for treating hyperphosphatemia described in the above-described technical solution are consistent with those of the medicament for treating hyperphosphatemia, and will not be repeated here.

[0047] The drug for treating hyperphosphatemia provided by this invention can prevent the absorption of lanthanum ions into the blood, thereby solving the problem that commercially available lanthanum carbonate drugs, while exerting their phosphorus-lowering effect in the gastrointestinal tract, still result in the absorption of trace amounts of lanthanum ions into the blood, causing lanthanum accumulation in the body and bone poisoning. Moreover, its preparation process is simple and suitable for large-scale industrial production.

[0048] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0049] The lanthanum carbonate used in the following examples has the molecular formula La2(CO3)3·xH2O, where x is 4 to 5; the preparation method of EDTA-β-CD 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. 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 soaked in 5000 mL of deionized water. The mixture was then filtered and the filter cake was washed successively with large amounts of 0.1 M hydrochloric acid, deionized water, 0.1 M sodium hydroxide aqueous solution, deionized water, and methanol. The washed filter cake was then dried under vacuum at 60 °C to obtain the EDTA-β-CD.

[0051] Example 1

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

[0053] Comparative Example 1

[0054] The procedure is the same as in Example 1, except that EDTA-β-CD is omitted.

[0055] Example 2

[0056] 95.4 g of EDTA-β-CD was mixed with 190.7 g of lanthanum carbonate. The resulting mixture was then mixed with 213.3 g of starch hydrolysate oligosaccharide, 8.5 g of micronized silica gel, and 4.3 g of magnesium stearate. The mixture was then subjected to dry granulation and tableting to obtain lanthanum carbonate chewable tablets containing EDTA-β-CD.

[0057] Comparative Example 2

[0058] The procedure is the same as in Example 2, except that EDTA-β-CD is omitted.

[0059] Example 3

[0060] 380.2g of EDTA-β-CD was mixed with 190.3g of lanthanum carbonate. The resulting mixture was then mixed with 122.1g of low-substituted hydroxypropyl cellulose, 210.5g of crospovidone, 8.2g of micronized silica gel, and 4.6g of magnesium stearate. The mixture was then directly compressed into powder to obtain lanthanum carbonate orally disintegrating tablets containing EDTA-β-CD.

[0061] Comparative Example 3

[0062] The procedure is the same as in Example 3, except that EDTA-β-CD is 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), 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 as required in Table 1; the detection method is as follows: accurately measure 5 mL of each test solution and place it in an Erlenmeyer flask, add 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, and titrate with disodium ethylenediaminetetraacetate titrant (0.01 mol / L) until the solution changes from light purple to lemon yellow, and record the volume of disodium ethylenediaminetetraacetate titrant consumed (denoted as V). Each 1 mL of disodium ethylenediaminetetraacetate titrant (0.01 mol / L) is equivalent to 1.39 mg of lanthanum (La).

[0066] Table 1. Types of Media Solution and Sampling Time Points

[0067] Medium solution name Sampling time point 0.1 mol / 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 detection results when the medium solution is 0.1 mol / L hydrochloric acid. Figure 1 The dissolution curves of lanthanum carbonate particles in Example 1 and Comparative Example 1 in 0.1 mol / L hydrochloric acid are shown. The results show that the similarity factor F2 value of lanthanum carbonate particles in Example 1 and Comparative Example 1 in 0.1 mol / L hydrochloric acid is 69 (>50), indicating that their dissolution behavior is consistent. That is, 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 detection results when the medium solution is pH 3.0 acetate buffer. Figure 2The dissolution curves of lanthanum carbonate particles in Example 1 and Comparative Example 1 in pH 3.0 acetate buffer are shown. The results show that the similarity factor F2 value of lanthanum carbonate particles in Example 1 and Comparative Example 1 in pH 3.0 acetate buffer is 72 (>50), indicating that their dissolution behavior is consistent. That is, 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 detection results (pH 3.0 acetate buffer)

[0074]

[0075]

[0076] Table 4 shows the dissolution curve detection results when the medium solution is pH 5.0 acetate buffer. Figure 3 The dissolution curves of lanthanum carbonate particles in Example 1 and Comparative Example 1 in pH 5.0 acetate buffer are shown. The results show that the similarity factor F2 value of lanthanum carbonate particles in Example 1 and Comparative Example 1 in pH 5.0 acetate buffer is 71 (>50), indicating that their dissolution behavior is consistent. That is, 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 detection results (pH 5.0 acetate buffer)

[0078]

[0079]

[0080] Comparison of test example 2: Lanthanum-phosphorus bonding test

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

[0082] The design principle of the lanthanum-phosphorus binding assay is as follows: Under different pH conditions, lanthanum carbonate binds to phosphorus of different concentrations until equilibrium is reached. By measuring the remaining phosphorus in the solution, the amount of phosphorus bound to lanthanum at equilibrium can be determined. This allows for the fitting of the Langmuir curve equation: 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, m is the labeled amount of lanthanum carbonate chewable tablets (calculated as lanthanum), and the slope of the curve is a=1 / k2. The intercept b = 1 / (k1k2) can be used to calculate k1 (the affinity constant of lanthanum-phosphorus, representing the affinity of lanthanum for phosphorus during the binding process) and k2 (the capacity factor for lanthanum-phosphorus binding, representing the maximum amount of phosphorus that can be bound per unit mass of drug) under different pH conditions. Under different pH conditions, the 90% confidence interval of the ratio of k2 of the lanthanum carbonate chewable tablets prepared in Example 2 to that prepared in Comparative Example 2 is within the range of 80.00% to 120.00%, which means that the lanthanum carbonate chewable tablets prepared in Example 2 are bioequivalent to those prepared in Comparative Example 2.

[0083] The lanthanum-phosphorus binding test procedure is 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 were investigated in media (1) (0.1 mol / L hydrochloric acid, pH=1.2), media (2) (pH3.0 acetate buffer), and media (3) (pH5.0 acetate buffer), respectively. The amount of free phosphorus was determined by the molybdenum antimony method. The detailed test procedure is as follows:

[0084] Step 1:

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

[0086] Step Two:

[0087] Take the medium solution from step one and place it in a 37.0℃ water bath. While stirring, add 20 mL of potassium dihydrogen phosphate solution ① to ⑧ dropwise using a 25 mL burette, with 12 portions for each concentration. The phosphorus concentrations in each series of flasks are as follows: 8.00 mmol / L (concentration ①), 10.16 mmol / L (concentration ②), 14.48 mmol / L (concentration ③), 21.76 mmol / L (concentration ④), 28.96 mmol / L (concentration ⑤), 43.44 mmol / L (concentration ⑥), 58.00 mmol / L (concentration ⑦), and 86.88 mmol / L (concentration ⑧).

[0088] Step 3:

[0089] Place the conical flask containing the medium solution from step two into a constant temperature incubator and shaker. Once the reaction system in the conical flask reaches 37.0°C, turn on the shaker and treat it at 75 r / min for 10 h. Then, take an appropriate amount of the solution, filter it, and collect the filtrate to obtain the test solution.

[0090] Step 4:

[0091] Accurately measure 25 mL each of water, phosphate standard curve solution, quality control solution, and diluted test sample solution from the lanthanum-phosphorus binding equilibrium test, and place them in 50 mL Erlenmeyer 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 stand for 15 minutes. Measure the absorbance at a wavelength of 700 nm using UV-Vis spectrophotometry with water as a reference to calculate the remaining phosphate content. Then, obtain the intercept and slope from the plotted curve, and calculate k1 and k2.

[0092] Step 5:

[0093] Accurately measure 25 mL each of water, phosphate standard curve solution, quality control solution, and diluted test sample solution from the lanthanum-phosphorus binding equilibrium test, and place them in 50 mL Erlenmeyer 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 stand for 15 minutes. Immediately measure the absorbance at a wavelength of 700 nm using ultraviolet-visible spectrophotometry with water as a reference to calculate the phosphate content.

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

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

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

[0097]

[0098] Table 6. Average results of 12 formulation units in the lanthanum-phosphorus binding equilibrium test of lanthanum carbonate chewable tablets in Comparative Example 2 at pH 1.2 hydrochloric acid.

[0099]

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

[0101]

[0102]

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

[0104]

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

[0106]

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

[0108]

[0109] Figure 4 The figures show the Langmuir fitting curves of the lanthanum carbonate chewable tablets in different media in Example 2. Figure 5The Langmuir fitting curves of the lanthanum carbonate chewable tablets in Comparative Example 2 in different media are shown in Table 11. Table 11 is a summary table of the lanthanum-phosphorus binding equilibrium tests of the lanthanum carbonate chewable tablets in Example 2 and the lanthanum carbonate chewable tablets in Comparative Example 2.

[0110] Table 11 Summary of Lanthanum-Phosphorus Binding Equilibrium Tests of Lanthanum Carbonate Chewable Tablets in Example 2 and Comparative Example 2

[0111]

[0112] The in vitro lanthanum-phosphorus binding behavior results showed that: the lanthanum carbonate chewable tablets in Example 2 and Comparative Example 2 showed no significant difference in the lanthanum-phosphorus binding capacity factor k2 values ​​in three different pH media (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 compared to the lanthanum carbonate chewable tablets in Comparative Example 2 was in the range of 91.7-109.4%, the k2% was in the range of 98.8-101.1%, and the 90% confidence interval of k2% was in the range of 98.33-104.14%, indicating that the lanthanum-phosphorus binding affinity constant and the maximum lanthanum-phosphorus binding amount of the two were basically the same in the three media, indicating that the lanthanum-phosphorus binding behavior of the two was consistent in the lanthanum-phosphorus binding experiment.

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

[0114] Comparison of lanthanum absorption into the bloodstream after oral administration in Test Example 3

[0115] Nine beagle dogs were administered one packet each of lanthanum carbonate granules (500 mg lanthanum) prepared in Example 1 and Fosrenol (500 mg lanthanum) commercially available in Japan, orally immediately after a high-phosphorus diet for three consecutive days. Blood samples were collected at 0h, 1h, 2h, 3h, 4h, 4.5h, 5h, 5.5h, 6h, 8h, 10h, 12h, 24h, and 48h, and the lanthanum concentration in the plasma was determined by ICP-MS. The IF document of the commercially available lanthanum carbonate granules in Japan indicates that its excipients are starch hydrolysate oligosaccharide, magnesium stearate, and micronized silica gel.

[0116] Figure 6 The graph shows the results of plasma lanthanum concentration tests at different time points, and 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 plasma lanthanum concentration is below the detection limit, indicating that almost no lanthanum is absorbed into the bloodstream after oral administration. In contrast, after continuous oral administration of commercially available lanthanum carbonate granules (i.e., Fosrenol), the plasma lanthanum concentration C... max The value was 0.43 ± 0.26 ng / mL, Tmax The valence was 4.0 ± 0.82 h, and the AUC was 7.32 ± 2.82 ng·h / mL.

[0117] Table 12. Plasma pharmacokinetic parameters of lanthanum (Mean ± SD, n = 9)

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

[0119] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition of lanthanum carbonate, characterized in that, The composition is lanthanum carbonate and ethylenediaminetetraacetic acid crosslinked β-cyclodextrin, wherein the mass ratio of lanthanum carbonate to ethylenediaminetetraacetic acid crosslinked β-cyclodextrin is 1:0.2 to 5.

0.

2. The use of the lanthanum carbonate pharmaceutical composition of claim 1 in the preparation of a medicament for treating hyperphosphatemia.

3. The application according to claim 2, characterized in that, The hyperphosphatemia includes hyperphosphatemia caused by chronic renal failure, whether on hemodialysis, non-hemodialysis, or continuous ambulatory peritoneal dialysis.

4. A drug for treating hyperphosphatemia, characterized in that, It includes the lanthanum carbonate pharmaceutical composition of claim 1 and pharmaceutically acceptable excipients.

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

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

7. The medicament for treating hyperphosphatemia according to claim 6, characterized in that, The dosage forms of the drugs for treating hyperphosphatemia include tablets, granules, powders, or dry syrups.

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

9. The medicament for treating hyperphosphatemia according to any one of claims 4 to 8, characterized in that, Pharmaceutically acceptable excipients include one or more of the following: diluents, disintegrants, glidants, and lubricants.

10. The medicament for treating hyperphosphatemia according to claim 9, characterized in that, The diluent includes one or more of starch hydrolysate oligosaccharides, mannitol, sorbitol, sucrose, lactose, and low-substituted hydroxypropyl cellulose; the disintegrant includes one or more of crospovidone, polyvinylpyrrolidone, crospovidone carboxymethyl cellulose sodium, starch, starch derivatives, cellulose, and cellulose derivatives; the flow aid includes silica and / or micronized silica; and the lubricant includes magnesium stearate.

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