A sevelamer carbonate pharmaceutical composition and a method of preparing the same

Abstract

The application discloses a pharmaceutical composition of sevelamer carbonate and a preparation method thereof. The pharmaceutical composition contains sevelamer carbonate, a stabilizer, an excipient and a wetting agent, and the stabilizer is sucralose. The sevelamer carbonate tablet provided by the application has more stable disintegration time and better compressibility, and can better play the role of a pharmaceutical active ingredient.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of anti-hyperphosphatemia, and particularly relates to a sevelamer carbonate pharmaceutical composition and a preparation method thereof. BACKGROUND

[0002] Hyperphosphatemia is common in patients with end-stage renal disease, and can cause hyperparathyroidism. Recent studies have found that hyperphosphatemia can also induce soft tissue and vascular calcification, which is an important factor for the increased mortality and cardiovascular disease of patients with end-stage renal disease. At present, the treatment of hyperphosphatemia mainly includes dietary phosphorus restriction, dialysis treatment, application of phosphorus binding agents and parathyroid resection if necessary. However, too strict restriction of phosphorus intake in the diet will cause malnutrition, which is particularly evident for dialysis patients; sufficient dialysis treatment can remove excess phosphorus in the body, but the current widely implemented hemodialysis method of 3 times a week and 4 hours each time is often insufficient to remove excess phosphorus in the body; about 90% of patients with end-stage renal disease need to take phosphorus binding agents to treat hyperphosphatemia.

[0003] Sevelamer carbonate is developed by Genzyme Corporation of the United States, and is a non-absorptive ion exchange resin for binding phosphate, with the trade name of Renvela TM , which is a cross-linked polyallylamine carbonate, and the chemical name is 1-chloro-2,3-epoxypropane propylene amine polymer carbonate, and the molecular structure is similar to the structure of a reticular resin. The structural formula is as follows:

[0004]

[0005] a, b: number of primary amine groups (a+b=9)

[0006] c: number of cross-linking groups (c=1)

[0007] m is a large number indicating an extended polymer network.

[0008] Studies have found that, compared with sevelamer hydrochloride, sevelamer carbonate can to some extent avoid acidosis in patients with renal failure due to the smaller amount of chloride ions contained therein. And due to the higher hydrophilicity of sevelamer carbonate, it can hydrate to form a gel in the gastrointestinal tract, and the volume expands several times. At physiological pH, the multiple amines carried thereby can be protonated in the small intestine to be positively charged, and bind to phosphate and bile acids in the small intestine through ion exchange and hydrogen bonding, thereby reducing the phosphate level in the blood of the human body. Meanwhile, compared with calcium-containing and aluminum-containing phosphorus binding agents, sevelamer carbonate does not cause hypercalcemia or aluminum poisoning. However, the compressibility of sevelamer carbonate raw material is poor, and the hardness of the compressed tablets is usually low, which cannot meet the requirements of the subsequent coating process, or the disintegration time of the coated tablets cannot meet the general requirements of tablets.

[0009] CN102908325A found that when adding a certain weight ratio of pharmaceutical excipients crosslinked polyvinylpyrrolidone and silicon dioxide, the obtained plain tablets can meet the technical requirements of the subsequent coating process, and the prepared sevelamer carbonate tablets have a small disintegration time. However, experimental research found that the disintegration time of the composition increases with the extension of storage time.

[0010] CN101043878B found that adding monovalent anions to sevelamer carbonate tablets can significantly increase the storage period, and can prevent the increase of disintegration time when stored under standard storage conditions. However, the composition obtained by this method has poor tablet formability. SUMMARY

[0011] The purpose of the present application is to overcome the above-mentioned problems in the prior art, and to provide a sevelamer carbonate pharmaceutical composition which has good stability and good compressibility.

[0012] Another object of the present application is to provide a preparation method of the sevelamer carbonate pharmaceutical composition.

[0013] The last object of the present application is to provide a preparation of the sevelamer carbonate pharmaceutical composition.

[0014] To achieve the above-mentioned objects, the technical solutions provided by the present application are as follows:

[0015] A sevelamer carbonate pharmaceutical composition, comprising sevelamer carbonate, a stabilizer, an excipient and a wetting agent, wherein the stabilizer is sucralose.

[0016] The weight ratio of sevelamer carbonate and the stabilizer is 1:(0.002-0.02), preferably 1:(0.002-0.012), further preferably 1:(0.002-0.008), and more preferably 1:0.002, 1:0.004 or 1:0.008.

[0017] The weight ratio of sevelamer carbonate and the excipient is 1:(0.02-1), preferably 1:(0.1-0.4), further preferably 1:(0.2-0.4), and more preferably 1:0.2, 1:0.3 or 1:0.4.

[0018] The excipient is microcrystalline cellulose, lactose or mannitol, preferably microcrystalline cellulose, lactose or mannitol, and further preferably microcrystalline cellulose.

[0019] The wetting agent is water, and the weight ratio of sevelamer carbonate and the wetting agent is 1:(0.05-0.2), preferably 1:(0.1-0.15), further preferably 1:(0.1-0.125), and more preferably 1:0.1 or 1:0.125.

[0020] The lubricant is stearic acid, PEG4000, PEG6000 or magnesium stearate, preferably stearic acid.

[0021] The weight ratio of sevelamer carbonate and lubricant is 1:(0.001-0.01), preferably 1:(0.001-0.004), further preferably 1:(0.002-0.003), more preferably 1:0.002, 1:0.0025 or 1:0.003.

[0022] Preferably, the pharmaceutical composition of sevelamer carbonate contains sevelamer carbonate, sucralose, microcrystalline cellulose, stearic acid and water, wherein the weight ratio of sevelamer carbonate, sucralose, microcrystalline cellulose, stearic acid and water is 1:(0.002-0.02):(0.02-1):(0.001-0.01):(0.05-0.2), preferably 1:(0.002-0.012):(0.1-0.4):(0.001-0.004):(0.1-0.15), further preferably 1:(0.002-0.008):(0.2-0.4):(0.002-0.003):(0.1-0.125), more preferably 1:0.004:0.2:0.0025:0.1.

[0023] The preparation method of the pharmaceutical composition of sevelamer carbonate comprises the following steps: mixing sevelamer carbonate with excipients and stabilizers uniformly, adding wetting agent, stirring granulation, obtaining soft material, passing the soft material through a screen to obtain granules.

[0024] Preferably, the screen aperture is 550-830 μm.

[0025] Further, the granules are mixed with lubricant, and tableting is performed to obtain tablets.

[0026] The preparation of the pharmaceutical composition of sevelamer carbonate is tablets.

[0027] The pharmaceutical composition of the present application can be used to obtain sevelamer carbonate tablets in the process of wet granulation and tableting.

[0028] The present application provides a pharmaceutical composition of sevelamer carbonate and a preparation method thereof, which is used for treating hyperphosphatemia of patients with end-stage renal disease. The present application uses sucralose as a stabilizer, so that the disintegration time of sevelamer carbonate tablets does not change significantly after a period of time. Meanwhile, it is found that the pharmaceutical composition of sevelamer carbonate can obtain good compressibility by using the preferred prescription.

[0029] Beneficial effects: The sevelamer carbonate tablet provided by the application has more stable disintegration time, better compressibility, and can better exert the effect of the active pharmaceutical ingredient. The active pharmaceutical ingredient has better effectiveness for patients. DETAILED DESCRIPTION

[0030] The application will be described in detail below with reference to examples and drawings, but the following examples should not be regarded as limiting the scope of the application.

[0031] Example 1

[0032] Prescription composition:

[0033]

[0034] Preparation process:

[0035] The tablet is prepared according to the prescription and the following process: the prescription amount of sevelamer carbonate is uniformly mixed with microcrystalline cellulose and sucralose, water is added, granulation is performed by stirring, soft material is obtained, the soft material is passed through a 24-mesh screen to obtain granules, the granules are mixed with the prescription amount of stearic acid, and the tablet is pressed to obtain the tablet.

[0036] The obtained product is a milky white oval tablet with a smooth surface and no obvious defects.

[0037] The average disintegration time of the tablet in a medium with a pH value of 1.2 is measured after the above prescription element tablet is stored at 60°C for 0, 1, 4 weeks. The results are shown in Table 1 below.

[0038] Table 1

[0039]

[0040] As can be seen from Table 1, when sucralose is used as a stabilizer, the disintegration time limit of the preparation does not become longer with the storage time, i.e., sucralose can play the role of a stabilizer to maintain the stable disintegration time limit within the shelf life. At the same time, both prescriptions can prepare defect-free tablets, indicating that sucralose as a stabilizer does not significantly affect the compressibility of the preparation.

[0041] Example 2

[0042] Prescription composition:

[0043]

[0044] Preparation process:

[0045] The tablet is prepared according to the prescription and the following process: the prescription amount of sevelamer carbonate is uniformly mixed with microcrystalline cellulose and sucralose, water is added, granulation is performed by stirring, soft material is obtained, the soft material is passed through a 24-mesh screen to obtain granules, the granules are mixed with the prescription amount of stearic acid, and the tablet is pressed to obtain the tablet.

[0046] The hardness and properties of the tablets of the above prescription are shown in Table 2.

[0047] Table 2

[0048]

[0049] As can be seen from Table 2, different lubricants will affect the hardness of the tablets and the preparation process. When stearic acid is used as a lubricant, the tablet hardness is the largest, and the prepared tablets have no obvious defects; when PEG4000, PEG6000 is used as a lubricant, the hardness is slightly lower, but abnormal sound appears during the preparation process, the punch and the die rub larger, indicating that the lubrication effect is not ideal; when magnesium stearate is used as a lubricant, the tablet hardness is lower, and the tablet surface is not smooth, indicating that magnesium stearate affects the compressibility of the prescription. The above shows that stearic acid is a more preferred disintegrating agent.

[0050] Example 3

[0051] Prescription composition:

[0052]

[0053] Preparation process:

[0054] Tablets are prepared according to the prescription in the table and the following process: the prescription amount of sevelamer carbonate is mixed uniformly with microcrystalline cellulose and sucralose, water is added, stirring granulation is performed, and soft material is obtained. The soft material is passed through a 24-mesh screen to obtain granules, the granules are mixed with the prescription amount of stearic acid, and the tablets are pressed to obtain the tablets.

[0055] The hardness and properties of the tablets of the above prescription are shown in Table 3.

[0056] Table 3

[0057]

[0058] As can be seen from Table 3, the amount of water used as a wetting agent will affect the hardness of the tablets. With the increase of the amount of water, the hardness of the tablets gradually increases. When the amount of water is increased to the amount of prescription 1, the tablets have no obvious defects and the hardness is larger. When the amount of water is further increased to the amount of prescription 8, the hardness does not increase significantly, but the moisture content is higher and the risk of microbial indicators increases, so the amount of water in prescription 1 is the preferred prescription.

[0059] Example 4

[0060] Prescription composition:

[0061]

[0062] Preparation process:

[0063] Tablet was prepared according to the prescription and the following process, the prescription amount of sevelamer carbonate was mixed with microcrystalline cellulose or lactose or mannitol, sucralose, stirred granulation, obtained soft material, the soft material was passed through 24 mesh screen, the granules were mixed with the prescription amount of stearic acid, and then the tablet was obtained.

[0064] The average time of tablet disintegration in the medium with pH value of 1.2, hardness of the above prescription tablet was determined. The results are shown in Table 4.

[0065] Table 4

[0066]

[0067]

[0068] As can be seen from Table 4, the effect of using microcrystalline cellulose in prescription 1 is the best during the tabletting process, so microcrystalline cellulose is preferred as an excipient.

[0069] Example 5

[0070] Prescription composition:

[0071]

[0072] Preparation process:

[0073] Tablet was prepared according to the prescription and the following process, the prescription amount of sevelamer carbonate was mixed with microcrystalline cellulose or lactose or mannitol, sucralose, stirred granulation, obtained soft material, the soft material was passed through 24 mesh screen, the granules were mixed with the prescription amount of stearic acid, and then the tablet was obtained.

[0074] Example 6

[0075] Prescription composition:

[0076]

[0077] Preparation process:

[0078] Tablet was prepared according to the prescription and the following process, the prescription amount of sevelamer carbonate was mixed with microcrystalline cellulose or lactose or mannitol, sucralose, stirred granulation, obtained soft material, the soft material was passed through 24 mesh screen, the granules were mixed with the prescription amount of stearic acid, and then the tablet was obtained.

Claims

1. A pharmaceutical composition of sevelamer carbonate, comprising sevelamer carbonate, a stabilizer, an excipient, a wetting agent and a lubricant, characterized in that: The stabilizer is sucralose, the excipient is microcrystalline cellulose, the wetting agent is water, the weight ratio of sevelamer carbonate to the wetting agent is 1:(0.1-0.125), the lubricant is stearic acid, the weight ratio of sevelamer carbonate to the stabilizer is 1:(0.002-0.02), the weight ratio of sevelamer carbonate to the excipient is 1:(0.02-1), and the weight ratio of sevelamer carbonate to the lubricant is 1:(0.001-0.01).

2. The composition according to claim 1, characterized in that The weight ratio of sevelamer carbonate to the stabilizer is 1:(0.002-0.012).

3. The composition according to claim 2, characterized in that The weight ratio of sevelamer carbonate to the stabilizer is 1:(0.002-0.008).

4. The composition according to claim 1, characterized in that The weight ratio of sevelamer carbonate to the excipient is 1:(0.1-0.4).

5. The composition according to claim 4, characterized in that The weight ratio of sevelamer carbonate to excipients is 1:(0.2-0.4).

6. The composition according to claim 1, characterized in that The weight ratio of sevelamer carbonate to the lubricant is 1:(0.001-0.004).

7. The composition according to claim 6, characterized in that The weight ratio of sevelamer carbonate to the lubricant is 1:(0.002-0.003).

8. The composition according to claim 1, characterized in that The invention is composed of sevelamer carbonate, sucralose, microcrystalline cellulose, stearic acid and water, wherein the weight ratio of sevelamer carbonate, sucralose, microcrystalline cellulose, stearic acid and water is 1: (0.002-0.008): (0.2-0.4): (0.002-0.003): (0.1-0.125).

9. The method for preparing the pharmaceutical composition of sevelamer carbonate according to claim 1, wherein: The following steps are involved: Sevelamer carbonate is mixed evenly with an excipient and a stabilizer, a wetting agent is added, and the mixture is stirred and granulated to obtain a soft material, and the soft material is sieved to obtain granules.

10. The method according to claim 9, characterized in that The sieve mesh aperture is 550 μm to 830 μm.

11. The method according to claim 9, characterized in that The granules are mixed with a lubricant and compressed to obtain tablets.

12. The preparation made from the pharmaceutical composition of sevelamer carbonate according to claim 1, characterized in that: Its dosage form is tablet.

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