Sevelamer carbonate dry suspension and preparation method thereof

Abstract

The invention discloses a sevelamer carbonate dry suspension and a preparation method thereof.The sevelamer carbonate dry suspension is prepared from, by mass, 94.81%-95.07% of a sevelamer carbonate raw material, 0.11%-1.30% of a suspending aid and other auxiliary materials, and the suspending aid is selected from one or more of sodium carboxymethyl cellulose, a microcrystalline cellulose-sodium carboxymethyl cellulose compound, xanthan gum and hydroxypropyl methylcellulose. Compared with the prior art, the sevelamer carbonate dry suspension has the advantages that the sevelamer carbonate raw material in the sevelamer carbonate dry suspension is high in proportion, and the suspending aid in the sevelamer carbonate dry suspension is low in proportion, so that grit feeling caused by oral administration of the suspension is effectively reduced, the stability and taste of the suspension are improved, the deposition speed of the medicine suspension is reduced, and a patient can uniformly take in the medicine when taking the sevelamer carbonate dry suspension; the method is particularly important for patients suffering from dysphagia or oral sensitivity.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically, it relates to a sevelamer carbonate dry suspension and its preparation method. Background Technology

[0002] Sevelamer carbonate is a non-absorbable phosphate-bound cross-linked polymer, free of calcium or other metals, and is a cross-linked product of polyallylamine and epichlorohydrin. Its structure contains multiple amino groups that can be partially protonated in the small intestine and bind to phosphate ions via ionic and hydrogen bonds. Sevelamer carbonate promotes phosphorus excretion by binding to phosphate ions in the gastrointestinal tract, thereby reducing the concentration of phosphorus in the blood. Sevelamer carbonate tablets and dry suspensions are currently available on the market, with the dry suspension providing an alternative dosage form for patients unable to take oral solid dosage forms.

[0003] Sevelamer carbonate is a water-insoluble drug that swells upon contact with water, resulting in a gritty texture when taken, affecting the taste for patients. Although the original product added propylene glycol alginate, the improvement in taste was not ideal, and the taste remained unpleasant.

[0004] The oral suspensions listed in the General Chapters of the Chinese Pharmacopoeia refer to oral suspensions made by dispersing poorly soluble solid drug raw materials in a liquid medium, including concentrated suspensions and dry suspensions. The main issue with suspensions is physical stability. The high dispersion of drug particles in suspensions results in high surface free energy, making the particles unstable. The higher the sedimentation velocity of the suspension particles, the lower the dynamic stability. To ensure the stability of suspensions, the Chinese Pharmacopoeia stipulates that the sedimentation volume ratio of oral suspensions should not be less than 0.90. However, the sedimentation volume ratio of the original product does not meet the requirements of the Chinese Pharmacopoeia for oral suspensions; therefore, the sedimentation volume ratio of sevelamer carbonate dry suspension needs further improvement.

[0005] Chinese patent CN 104800165 A provides a dry suspension of sevelamer carbonate and its preparation method. The formulation includes raw materials, fillers, flavoring agents, suspending agents and flocculants. The flocculant is anhydrous disodium hydrogen phosphate. After entering the body, this flocculant introduces additional phosphorus elements, which will consume the effective components of the suspension itself and cannot be used as a good option for reducing phosphorus levels.

[0006] Chinese patent CN 116270722 A discloses a sevelamer carbonate dry suspension and its preparation method. The formulation includes raw materials, a suspending agent, a flocculant, lactulose, and a flavoring agent. The suspending agent and flocculant are consistent with propylene glycol alginate and sodium chloride in the original product. This sevelamer carbonate dry suspension improves the sedimentation volume ratio, and the addition of lactulose improves its gastrointestinal side effects. However, it does not improve the grainy texture during administration, and the wet granulation process is more complex than the direct mixing process, increasing production difficulty.

[0007] Chinese patent CN 116869941 A discloses a dry suspension of sevelamer carbonate and its preparation method. The formulation includes raw materials, a suspending agent, a filler, and a flavoring agent, wherein the suspending agent is a combination of Bletilla striata gum and deacetylated chitosan. However, Bletilla striata gum and deacetylated chitosan are not commonly used pharmaceutical suspending agents, which limits the commercialization of the product.

[0008] In view of this, the present invention is hereby proposed. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a sevelamer carbonate dry suspension and its preparation method, so as to reduce the gritty feeling of oral suspension, improve the taste, increase the sedimentation volume ratio of the suspension after water dispersion, and improve the stability of the suspension.

[0010] To solve the above-mentioned technical problems, the basic concept of the technical solution adopted by the present invention is as follows:

[0011] A sevelamer carbonate dry suspension, by mass fraction, comprises: 94.81% to 95.07% sevelamer carbonate raw material, 0.11% to 1.30% suspending agent, and other excipients, wherein the suspending agent is selected from one or more of sodium carboxymethyl cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose complex, xanthan gum, and hydroxypropyl methylcellulose.

[0012] In this invention, the sevelamer carbonate dry suspension contains a high proportion of sevelamer carbonate raw material, while the proportion of suspending agent is relatively low. However, they play a crucial role in improving the stability and taste of the suspension, effectively reducing the gritty feeling caused by sevelamer carbonate raw material in oral suspensions, improving the stability and taste of the suspension, reducing the deposition rate of drug suspension, and ensuring that patients can ingest the drug evenly when taking it. This is especially important for patients with dysphagia or oral sensitivity.

[0013] Furthermore, the suspending agent includes sodium carboxymethyl cellulose and xanthan gum.

[0014] Furthermore, the mass ratio of sodium carboxymethyl cellulose to xanthan gum is 1:1 to 3:1.

[0015] Furthermore, the mass ratio of sodium carboxymethyl cellulose to xanthan gum is 2:1.

[0016] In this invention, sodium carboxymethyl cellulose and xanthan gum, when used as suspending agents, have good viscosity and can form a suitable viscosity in oral suspensions, improving the taste of the suspension, making it smoother, and reducing discomfort caused by sevelamer carbonate raw material particles. Furthermore, this suspending agent can increase the viscosity and stability of the suspension, slow down the sedimentation rate of sevelamer carbonate raw material particles, prevent particles from settling or separating in the suspension, maintain the uniform dispersion of the suspension, and thus help ensure that patients receive a uniform drug dose when taking the suspension, improving the bioavailability and therapeutic effect of the drug.

[0017] Furthermore, by mass fraction, it includes 94.98% sevelamer carbonate and 0.32% suspending agent.

[0018] Further, by mass fraction, the excipients include: 0.60% to 2.00% filler, 1.0% to 5.0% flavoring agent, and 0.006% to 0.02% coloring agent;

[0019] Preferably, it includes 1.68% filler, 3.01% flavoring agent, and 0.02% coloring agent;

[0020] Preferably, the colorant is ferric oxide.

[0021] Furthermore, the filler is selected from one or more of lactose, mannitol, and microcrystalline cellulose;

[0022] The flavoring agent is selected from one or more of aspartame, sucralose, sweet orange flavor, and saccharin;

[0023] Preferably, the flavoring agent comprises sucralose and sweet orange flavoring, and the mass ratio of sucralose to sweet orange flavoring is 1:6.5.

[0024] This invention also provides a method for preparing sevelamer carbonate dry suspension as described in any of the above technical solutions, comprising:

[0025] (1) Take sevelam carbonate raw material, suspending agent and other excipients respectively;

[0026] (2) First, mix part of the sevelam carbonate raw material with the suspending agent and other excipients, and then mix it with the remaining sevelam carbonate raw material to obtain sevelam carbonate dry suspension.

[0027] In traditional one-step mixing processes, due to variations in raw material ratios, material flowability, and the uniformity of mixing effects, some raw materials may not be fully mixed or may remain in the equipment. This invention employs a two-step mixing process: first, a portion of the sevelamer carbonate raw material is mixed with a suspending agent and other excipients; then, it is mixed with the remaining sevelamer carbonate raw material. This allows for more precise control over the degree and uniformity of mixing, reducing waste and loss of raw materials.

[0028] Further, in step (2), the total mass of the suspending agent and other excipients is weighed, and the same mass of sevelam carbonate raw material is taken and mixed with the suspending agent and other excipients. After mixing, it is then mixed with the remaining sevelam carbonate raw material.

[0029] The present invention involves weighing the total mass of the suspending agent and other excipients, then taking the same mass of sevelamer carbonate raw material and mixing it with the suspending agent and other excipients, and then mixing it with the remaining sevelamer carbonate raw material. This process can improve the utilization rate of raw materials, improve the uniformity of raw material mixing, accurately control the production process, and further improve the quality stability of the product.

[0030] Furthermore, the sevelam carbonate raw material is passed through a 20-100 mesh sieve, preferably a 40 mesh sieve. In step (2), a portion of the sevelam carbonate raw material is mixed with a suspending agent and other excipients and then passed through a 40-80 mesh sieve, preferably a 60 mesh sieve.

[0031] By adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art.

[0032] In this invention, the sevelamer carbonate dry suspension contains a high proportion of sevelamer carbonate raw material. Thus, when taking the same weight of sevelamer carbonate dry suspension, the higher proportion of the active ingredient sevelamer carbonate raw material results in a more significant effect on promoting phosphorus excretion. Although the proportion of suspending agents is lower, they play a crucial role in improving the stability and palatability of the suspension. They effectively reduce the gritty feeling caused by sevelamer carbonate raw material in oral suspensions, improve the stability and palatability of the suspension, and reduce the deposition rate of the drug suspension, ensuring that patients can ingest the drug evenly. This is especially important for patients with dysphagia or oral sensitivity.

[0033] The specific embodiments of the present invention will now be described in further detail with reference to the accompanying drawings. Attached Figure Description

[0034] The accompanying drawings, as part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention, but do not constitute an undue limitation of the invention. Obviously, the drawings described below are merely some embodiments, and those skilled in the art can obtain other drawings based on these drawings without creative effort. In the drawings:

[0035] Figure 1 The dynamic phosphorus binding force curve under pH 4.0 conditions in this invention.

[0036] It should be noted that these accompanying drawings and textual descriptions are not intended to limit the scope of the invention in any way, but rather to illustrate the concept of the invention to those skilled in the art by referring to specific embodiments. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments will be clearly and completely described below with reference to the accompanying drawings. The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0038] Example 1

[0039] This embodiment provides a sevelamer carbonate dry suspension, the components of which include:

[0040]

[0041] The preparation method is as follows:

[0042] (1) Weigh out the following ingredients according to the above dosages: sevelam carbonate raw material, microcrystalline cellulose, sodium carboxymethyl cellulose, sucralose, sweet orange powder flavoring, and yellow iron oxide; pass the sevelam carbonate raw material through a 40-mesh sieve.

[0043] (2) First, mix microcrystalline cellulose, sodium carboxymethyl cellulose, sucralose, sweet orange powder flavoring, yellow iron oxide, and 50.24 mg of sevelamer carbonate raw materials, and then pass the mixture through a 60-mesh sieve.

[0044] (3) Place the remaining 899.52 mg sevelam carbonate raw material and the mixture obtained in step (2) into a mixer and mix them evenly;

[0045] (4) After mixing evenly, the product is filled into bags to obtain the finished product of sevelamer carbonate dry suspension.

[0046] Example 2

[0047] This embodiment provides a sevelamer carbonate dry suspension, the components of which include:

[0048]

[0049] The preparation method is as follows:

[0050] (1) Weigh out the following ingredients according to the above dosage: sevelam carbonate raw material, microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, sucralose, sweet orange powder flavoring, and yellow iron oxide; pass the sevelam carbonate raw material through a 40-mesh sieve.

[0051] (2) First, mix microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, sucralose, sweet orange powder flavoring, yellow iron oxide, and 50.24 mg of sevelamer carbonate raw materials, and then pass the mixture through a 60-mesh sieve.

[0052] (3) Place the remaining 899.52 mg sevelam carbonate raw material and the mixture obtained in step (2) into a mixer and mix them evenly;

[0053] (4) After mixing evenly, the product is filled into bags to obtain the finished product of sevelamer carbonate dry suspension.

[0054] Example 3

[0055] This embodiment provides a sevelamer carbonate dry suspension, the components of which include:

[0056]

[0057] The preparation method is as follows:

[0058] (1) Weigh out the following ingredients according to the above dosages: sevelam carbonate raw material, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sucralose, sweet orange powder flavoring, and yellow iron oxide; pass the sevelam carbonate raw material through a 40-mesh sieve.

[0059] (2) First, mix microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, sucralose, sweet orange powder flavoring, yellow iron oxide, and 50.24 mg of sevelamer carbonate raw materials, and then pass the mixture through a 60-mesh sieve.

[0060] (3) Place the remaining 899.52 mg sevelam carbonate raw material and the mixture obtained in step (2) into a mixer and mix them evenly;

[0061] (4) After mixing evenly, the product is filled into bags to obtain the finished product of sevelamer carbonate dry suspension.

[0062] Example 4

[0063] This embodiment provides a sevelamer carbonate dry suspension, the components of which include:

[0064]

[0065] The preparation method is as follows:

[0066] (1) Weigh out the following ingredients according to the above dosages: sevelam carbonate raw material, microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, sucralose, sweet orange powder flavoring, and yellow iron oxide; pass the sevelam carbonate raw material through a 20-mesh sieve.

[0067] (2) First, mix microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, sucralose, sweet orange powder flavoring, yellow iron oxide, and 51.9 mg of sevelamer carbonate raw materials, and then pass the mixture through a 40-mesh sieve.

[0068] (3) Place the remaining 896.2 mg sevelam carbonate raw material and the mixture obtained in step (2) into a mixer and mix them evenly;

[0069] (4) After mixing evenly, the product is filled into bags to obtain the finished product of sevelamer carbonate dry suspension.

[0070] Example 5

[0071] This embodiment provides a sevelamer carbonate dry suspension, the components of which include:

[0072]

[0073] The preparation method is as follows:

[0074] (1) Weigh out the following ingredients according to the above dosages: sevelam carbonate raw material, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sucralose, sweet orange powder flavoring, and yellow iron oxide; pass the sevelam carbonate raw material through a 100-mesh sieve.

[0075] (2) First, mix microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, sucralose, sweet orange powder flavoring, yellow iron oxide, and 49.3 mg of sevelamer carbonate raw materials, and then pass the mixture through an 80-mesh sieve.

[0076] (3) The remaining 901.4 mg of sevelamer carbonate raw material and the mixture obtained in step (2) are placed in a mixer and mixed evenly;

[0077] (4) After mixing evenly, the product is filled into bags to obtain the finished product of sevelamer carbonate dry suspension.

[0078] Example 6

[0079] This embodiment provides a sevelamer carbonate dry suspension, the components of which include:

[0080]

[0081] The preparation method is as follows:

[0082] (1) Weigh out the following ingredients according to the above dosages: sevelam carbonate raw material, microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, sucralose, sweet orange powder flavoring, and yellow iron oxide; pass the sevelam carbonate raw material through a 50-mesh sieve.

[0083] (2) First, mix microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, sucralose, sweet orange powder flavoring, yellow iron oxide, and 51.3 mg sevelamer carbonate raw materials, and then pass the mixture through a 60-mesh sieve.

[0084] (3) The remaining 897.4 mg of sevelam carbonate raw material and the mixture obtained in step (2) are placed in a mixer and mixed evenly;

[0085] (4) After mixing evenly, the product is filled into bags to obtain the finished product of sevelamer carbonate dry suspension.

[0086] Example 7

[0087] This embodiment provides a method for preparing sevelamer carbonate dry suspension, specifically including the following steps:

[0088] (1) Weigh out the following ingredients: sevelam carbonate raw material, microcrystalline cellulose, microcrystalline cellulose-carboxymethyl cellulose sodium complex, xanthan gum, sucralose, sweet orange powder flavoring, and yellow iron oxide; pass the sevelam carbonate raw material through a 50-mesh sieve.

[0089] (2) Mix microcrystalline cellulose, sodium carboxymethyl cellulose, xanthan gum, sucralose, sweet orange powder flavoring, and yellow iron oxide, and then pass the mixture through a 60-mesh sieve.

[0090] (3) Place the sevelam carbonate raw material from step (1) and the mixture obtained in step (2) in a mixer and mix them evenly;

[0091] (4) After mixing evenly, the product is filled into bags to obtain the finished product of sevelamer carbonate dry suspension.

[0092] Experimental Example 1

[0093] This experimental example compares the taste and sedimentation volume ratio of the sevelamer carbonate dry suspensions from Examples 1 to 3, as detailed below:

[0094] (1) Taste comparison

[0095] Referring to the instructions for use of the original marketed sevelamer carbonate dry suspension, 30 ml of water was added to every 800 mg of sevelamer carbonate dry suspension, and the mixture was stirred and dispersed to prepare a suspension. Six R&D personnel conducted a small-sample taste comparison of the suspension, comparing the differences between Example 1, Example 2, and Example 3, and scoring the gritty feeling according to a scoring system. The scoring system is shown in Table 1, and the summary of the gritty feeling scoring results is shown in Table 2.

[0096] Table 1:

[0097]

[0098]

[0099] Table 2:

[0100]

[0101] As shown in the table above, in Examples 1 and 3, 4 people felt a slight gritty sensation; 1 person felt no gritty sensation; and 1 person felt a noticeable gritty sensation. In Example 2, 3 people felt a slight gritty sensation; and 3 people felt no gritty sensation. It is evident that using sodium carboxymethyl cellulose and xanthan gum in combination as suspending agents can mask the gritty sensation of sevelamer carbonate itself.

[0102] (2) Comparison of sedimentation volume ratio

[0103] Measure 50 ml of the test sample using a stoppered graduated cylinder, seal it tightly, shake vigorously for 1 minute, and record the initial height H0 of the suspension. Let it stand for 3 hours and record the final height H of the suspension. Calculate the sedimentation volume ratio according to H0 / H. The test samples are sevelamer carbonate dry suspensions from Examples 1, 2, and 3, respectively. The sedimentation volume ratios of the samples from Examples 1 to 3 are shown in Table 3.

[0104] Table 3:

[0105]

[0106] As shown in the table above, the combined use of sodium carboxymethyl cellulose and xanthan gum as suspending agents in Example 2 of this invention can ensure that the sedimentation volume ratio of the oral suspension meets the requirements of the Chinese Pharmacopoeia.

[0107] Experiment Example 2

[0108] This experimental example verifies the effects of sodium carboxymethyl cellulose and xanthan gum as suspending agents on the sedimentation volume ratio and residual amount of sevelamer carbonate dry suspension, as detailed below:

[0109] Experimental Group 1: The components of sevelamer carbonate dry suspension include:

[0110]

[0111] Experimental Group 2: The components of sevelamer carbonate dry suspension include:

[0112]

[0113] Experimental Group 3: The components of sevelamer carbonate dry suspension include:

[0114]

[0115] Experimental Group 4: The components of sevelamer carbonate dry suspension include:

[0116]

[0117]

[0118] Measure 50 ml of the test sample into a stoppered graduated cylinder, seal it tightly, shake vigorously for 1 minute, and record the initial height H0 of the suspension. Let it stand for 3 hours, and record the final height H of the suspension. Calculate the sedimentation volume ratio according to H0 / H. Measure 50 ml of the test sample into a stoppered graduated cylinder, and record the mass of the empty graduated cylinder M0 and the mass of the test sample M1. Seal it tightly, shake vigorously for 1 minute, pour out the test sample, and record the total mass M2 of the graduated cylinder and residue. Calculate the residual mass percentage according to (M2-M0) / M1. The sedimentation volume ratio and residual percentage of samples in Example 2, Experimental Groups 1-4 are shown in Table 4.

[0119] Table 4:

[0120] % of suspending agent by mass Settlement volume ratio Percentage of residual mass after pouring (%) Example 2 0.321 0.98 2.31％ Experimental group 1 0.071 0.85 0.65％ Experimental group 2 0.111 0.90 1.05％ Experimental group 3 1.302 1.00 3.79％ Experimental group 4 1.390 1.00 4.22％

[0121] As shown in the table above, in sevelamer carbonate dry suspension, the sedimentation volume ratio gradually increases with the increase of the mass fraction of the suspending agent. Except for experimental group 1, the sedimentation volume ratios of the oral suspensions in Examples 2 and Experimental groups 2-3 all meet the requirements of the Chinese Pharmacopoeia. Furthermore, the higher the mass fraction of the suspending agent, the higher the percentage of residual mass after decanting the oral suspension. Specifically, the sedimentation volume ratio of experimental group 2 just meets the requirements of the Chinese Pharmacopoeia, while the percentage of residual mass after decanting in experimental groups 3 and 4 is relatively high, failing to meet the accuracy requirements for dosage. Therefore, in summary, controlling the mass fraction of the suspending agent in sevelamer carbonate dry suspension to 0.11%–1.30% not only ensures that the sedimentation volume ratio meets the requirements of the Chinese Pharmacopoeia but also results in a low residual amount after decanting the suspension.

[0122] Experimental Example 3

[0123] This experimental example verifies the effect of the mass ratio of sodium carboxymethyl cellulose and xanthan gum on the sedimentation volume ratio, post-pour residue, and taste of sevelamer carbonate dry suspension; details are as follows:

[0124] Experimental Group 1: The only difference between this experimental group and Example 2 is that sodium carboxymethyl cellulose 1.605 mg and xanthan gum 1.605 mg were used; that is, the mass ratio of sodium carboxymethyl cellulose to xanthan gum was 1:1.

[0125] Experimental Group 2: The only difference between this experimental group and Example 2 is that sodium carboxymethyl cellulose 2.4 mg and xanthan gum 0.8 mg were used; that is, the mass ratio of sodium carboxymethyl cellulose to xanthan gum was 3:1.

[0126] Experimental Group 3: The only difference between this experimental group and Example 2 is that sodium carboxymethyl cellulose 1.07 mg and xanthan gum 2.14 mg; that is, the mass ratio of sodium carboxymethyl cellulose to xanthan gum is 0.5:1.

[0127] Experimental Group 4: The only difference between this experimental group and Example 2 is that sodium carboxymethyl cellulose 2.568 mg and xanthan gum 0.642 mg are used; that is, the mass ratio of sodium carboxymethyl cellulose to xanthan gum is 4:1.

[0128] (1) Taste comparison

[0129] Referring to the instructions for use of the original marketed sevelamer carbonate dry suspension, 30 ml of water was added to every 800 mg of sevelamer carbonate dry suspension, and the mixture was stirred and dispersed to prepare a suspension. Six R&D personnel conducted a small-sample taste comparison of the suspension, comparing the differences between Example 2 and Experimental Groups 1 to 4, and scoring the gritty sensation according to a scoring system. The scoring system is shown in Table 5, and the summary of the gritty sensation scoring results is shown in Table 6.

[0130] Table 5:

[0131]

[0132] Table 6:

[0133]

[0134] As shown in the table above, no one in experimental groups 1-4 reported a noticeable gritty texture, consistent with Example 2. This indicates that different ratios of sodium carboxymethyl cellulose and xanthan gum did not significantly affect the taste.

[0135] (2) Settlement volume ratio

[0136] Measure 50 ml of the test sample into a stoppered graduated cylinder, seal it tightly, shake vigorously for 1 minute, and record the initial height H0 of the suspension. Let it stand for 3 hours, and record the final height H of the suspension. Calculate the sedimentation volume ratio according to H0 / H. Measure 50 ml of the test sample into a stoppered graduated cylinder, and record the mass of the empty graduated cylinder M0 and the mass of the test sample M1. Seal it tightly, shake vigorously for 1 minute, pour out the test sample, and record the total mass M2 of the graduated cylinder and residue. Calculate the residual mass percentage according to (M2-M0) / M1. The sedimentation volume ratio and residual percentage of the test samples from Example 2, Experimental Groups 1 to 4 are shown in Table 7 below.

[0137] Table 7:

[0138]

[0139] As shown in the table above, when the ratio of sodium carboxymethyl cellulose to xanthan gum is between 0.5 and 4, the sedimentation volume ratio of the suspension meets the requirements of the Chinese Pharmacopoeia. However, when the mass ratio of sodium carboxymethyl cellulose to xanthan gum is less than 1:1 to 3:1, the percentage of residual mass after the suspension is poured will increase significantly; a large amount of drug residue in the container may prevent patients from receiving the correct dosage, thus leading to poor treatment efficacy.

[0140] Conversely, when the mass ratio of sodium carboxymethyl cellulose to xanthan gum is greater than 1:1 to 3:1, the sedimentation volume ratio of the suspension will be significantly reduced, and drug particles are prone to precipitation. This will lead to uneven suspension, and excessive precipitation of sevelamer carbonate raw material particles in the suspension will result in poor taste. Furthermore, the presence of a large amount of sevelamer carbonate raw material precipitate in the suspension will cause the suspension to have a noticeable particle texture, reducing patient medication compliance.

[0141] Experiment Example 4

[0142] This experimental example verifies the effect of the sevelamer carbonate dry suspension of the present invention in reducing blood phosphorus concentration, as detailed below:

[0143] Because sevelamer carbonate dry suspension is not absorbed by the body after oral administration, it is mainly excreted by binding with phosphorus in the intestines, thereby reducing the concentration of phosphorus in the blood. The Food and Drug Administration (FDA) recommends conducting in vitro phosphorus-binding capacity studies instead of in vivo studies in its bioequivalence guidelines for this product.

[0144] In vitro phosphorus binding capacity studies include static phosphorus binding capacity studies and dynamic phosphorus binding capacity studies. The similarity of the dynamic phosphorus binding capacity between the self-developed formulation and the reference formulation is evaluated by comparing the F2 value of the percentage of bound phosphorus in the sevelamer carbonate dry suspension of this invention with that of the reference formulation.

[0145] The sevelamer carbonate dry suspension prepared in Example 2 above and the original commercially available formulation ( The static and dynamic phosphorus binding forces of the dry suspension were compared. The static equilibrium phosphorus binding force at pH 4.0 is shown in Table 8 below; the dynamic equilibrium phosphorus binding force at pH 4.0 is shown in Table 9 below.

[0146] Table 8:

[0147]

[0148] *1: The K1 value is the affinity binding constant, which is related to the magnitude of the force involved in the binding process;

[0149] *2: K2 is Langmuir capacity constant, which represents the maximum amount of phosphate that can bind per unit weight of drug.

[0150] Table 9:

[0151] Time (min) 5 10 15 20 30 45 60 90 F2 value Commercially available formulations (%) 64 63 64 63 63 63 63 62 / Example 2 (%) 67 66 66 67 67 66 66 66 73

[0152] As shown in Table 8 above, the 90% confidence intervals of the static equilibrium phosphorus binding capacity K2 values ​​of Example 2 and the commercially available formulation at pH 4.0 are both within the range of 80% to 120%. This indicates that the sevelamer carbonate dry suspension of the present invention has essentially the same in vitro phosphorus binding capacity as the commercially available formulation, and is bioequivalent. The percentage of dynamic phosphorus binding capacity of the sevelamer carbonate dry suspension of the present invention and the commercially available formulation at pH 4.0 is shown in Table 9, and its curve is as follows: Figure 1 As shown, the similarity factor F2 value between the curve corresponding to the commercially available formulation and the curve corresponding to Example 2 of the present invention is 73, which is greater than 50. That is, the two curves are similar, and the dynamic phosphorus binding force of the sevelamer carbonate dry suspension of the present invention is similar to that of the commercially available formulation.

[0153] In summary, the sevelamer carbonate dry suspension of the present invention is similar to the original commercially available formulation ( In vivo, these drugs exhibit similar pharmacodynamic effects and safety profiles, while the original commercially available formulations ( The sedimentation volume ratio of the dry suspension of the present invention was 0.6, while that of Example 2 of the present invention was 0.98, which is significantly higher than that of commercially available formulations. The sedimentation volume ratio of the dry suspension means that the dry suspension of the present invention has advantages in suspension stability, which improves the quality of the suspension and the user experience.

[0154] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A dry suspension of sevelamer carbonate, characterized in that: By mass fraction, it includes: 94.81% to 95.07% sevelamer carbonate raw material, 0.11% to 1.30% suspending agent and other excipients, wherein the suspending agent is selected from one or more of sodium carboxymethyl cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose complex, xanthan gum and hydroxypropyl methylcellulose.

2. The sevelamer carbonate dry suspension according to claim 1, characterized in that: The suspending agent includes sodium carboxymethyl cellulose and xanthan gum.

3. The sevelamer carbonate dry suspension according to claim 2, characterized in that: The mass ratio of sodium carboxymethyl cellulose to xanthan gum is 1:1 to 3:

1.

4. The sevelamer carbonate dry suspension according to claim 3, characterized in that: The mass ratio of sodium carboxymethyl cellulose to xanthan gum is 2:

1.

5. A sevelamer carbonate dry suspension according to any one of claims 1 to 4, characterized in that: By mass fraction, it includes 94.98% sevelamer carbonate and 0.32% suspending agent.

6. A sevelamer carbonate dry suspension according to any one of claims 1 to 5, characterized in that: The excipients, by mass fraction, include: 0.60%–2.00% filler, 1.0%–5.0% flavoring agent, and 0.006%–0.02% coloring agent; Preferably, it includes 1.68% filler, 3.01% flavoring agent, and 0.02% coloring agent; Preferably, the colorant is ferric oxide.

7. A sevelamer carbonate dry suspension according to claim 6, characterized in that: The filler is selected from one or more of lactose, mannitol, and microcrystalline cellulose; The flavoring agent is selected from one or more of aspartame, sucralose, sweet orange flavor, and saccharin; Preferably, the flavoring agent comprises sucralose and sweet orange flavoring, and the mass ratio of sucralose to sweet orange flavoring is 1:6.

5.

8. A method for preparing a sevelamer carbonate dry suspension as described in any one of claims 1 to 7, characterized in that: include: (1) Take sevelam carbonate raw material, suspending agent and other excipients respectively; (2) First, mix part of the sevelam carbonate raw material with the suspending agent and other excipients, and then mix it with the remaining sevelam carbonate raw material to obtain sevelam carbonate dry suspension.

9. The method for preparing sevelamer carbonate dry suspension according to claim 8, characterized in that: In step (2), the total mass of the suspending agent and other excipients is weighed, and the same mass of sevelam carbonate raw material is taken and mixed with the suspending agent and other excipients. After mixing, it is then mixed with the remaining sevelam carbonate raw material.

10. The method for preparing sevelamer carbonate dry suspension according to claim 8 or 9, characterized in that: The sevelam carbonate raw material is passed through a 20-100 mesh sieve, preferably a 40 mesh sieve. In step (2), a portion of the sevelam carbonate raw material is mixed with a suspending agent and other excipients and then passed through a 40-80 mesh sieve, preferably a 60 mesh sieve.

Images