Sevelamer Carbonate for Oral Suspension and Its Preparation Method

Abstract

The present invention relates to the field of pharmaceutical preparations, and in particular, to a sevelamer carbonate dry suspension and a preparation method thereof. In the sevelamer carbonate dry suspension, the dosage of the suspending agent is 0.13 - 0.33% of the total mass, the dosage of the flocculant is 0.05 - 0.39% of the total mass, the dosage of lactulose is 72.53 - 86.90% of the total mass, the dosage of the flavoring agent is 0.34 - 0.72% of the total mass, and the dosage of the sevelamer carbonate crude drug is 12.51 - 26.20% of the total mass. This sevelamer carbonate dry suspension not only has excellent dispersibility, but also can improve its gastrointestinal side effects.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular, to a sevelamer carbonate for oral suspension and a preparation method thereof. Background Art

[0002] Sevelamer carbonate is a non-absorbable phosphate-binding cross-linked polymer, which does not contain calcium or other metals; it contains multiple amine groups, all of which are connected to the polymer backbone through a carbon atom. The amine groups exist in the intestine in a partially protonated form and bind to negatively charged phosphorus through ionic bonds and hydrogen bonds. Sevelamer carbonate can reduce the serum phosphate concentration by binding phosphate in the digestive tract and reducing its absorption. Sevelamer carbonate itself is not absorbed, so its common side effects include constipation, dyspepsia, intestinal hypomotility, intestinal obstruction, and incomplete intestinal obstruction. In the prior art, sevelamer carbonate is generally mixed with excipients such as flocculants, suspending agents, and fillers to prepare a dry suspension. Preparing it into a dry suspension can improve its redispersibility, but it cannot improve the side effects of sevelamer carbonate. Summary of the Invention

[0003] The present invention provides a sevelamer carbonate for oral suspension and a preparation method thereof. The sevelamer carbonate for oral suspension not only has excellent dispersibility, but also can improve its gastrointestinal side effects.

[0004] The present invention is implemented as follows:

[0005] In a first aspect, an embodiment of the present invention provides a sevelamer carbonate for oral suspension, the raw materials of which include sevelamer carbonate raw drug, suspending agent, flocculant, lactulose, and flavoring agent. Among them, the dosage of the suspending agent is 0.13-0.33% of the total mass, the dosage of the flocculant is 0.05-0.39% of the total mass, the dosage of the lactulose is 72.53-86.90% of the total mass, the dosage of the flavoring agent is 0.34-0.72% of the total mass, and the dosage of the sevelamer carbonate raw drug is 12.51-26.20% of the total mass.

[0006] Further, in a preferred embodiment of the present invention, the suspending agent is selected from any one of sodium alginate, xanthan gum, and propylene glycol alginate, and preferably propylene glycol alginate.

[0007] Further, in a preferred embodiment of the present invention, the flavoring agent is a water-soluble essence; preferably orange essence, strawberry essence, and lemon essence.

[0008] Further, in a preferred embodiment of the present invention, the flocculant includes sodium chloride.

[0009] Further, in a preferred embodiment of the present invention, the raw materials include sevelamer carbonate bulk drug, propylene glycol alginate, sodium chloride, lactulose and essence. Among them, the dosage of lactulose is 72.53 - 86.90% of the total mass, the dosage of essence is 0.34 - 0.72% of the total mass, the dosage of sevelamer carbonate bulk drug is 12.51 - 26.20% of the total mass, the dosage of propylene glycol alginate is 0.05 - 0.39% of the total mass, and the dosage of sodium chloride is 0.13 - 0.33% of the total mass.

[0010] Further, in a preferred embodiment of the present invention, the dosage of lactulose is 72.62% of the total mass, the dosage of essence is 0.72% of the total mass, the dosage of sevelamer carbonate bulk drug is 26.14% of the total mass, the dosage of propylene glycol alginate is 0.26% of the total mass, and the dosage of sodium chloride is 0.26% of the total mass.

[0011] In a second aspect, an embodiment of the present invention provides a method for preparing the above sevelamer carbonate dry suspension, including: mixing sevelamer carbonate bulk drug, suspending agent, flocculant, lactulose and flavoring agent and then making a preparation.

[0012] Further, in a preferred embodiment of the present invention, it includes: mixing the sevelamer carbonate bulk drug, the suspending agent, the flocculant, the lactulose and the flavoring agent to form a mixture, then screening the mixture, then making a soft material, screening again to make granules to form wet granules, and then drying to form dry granules.

[0013] Further, in a preferred embodiment of the present invention, it includes: after the mixture passes through a 40 - mesh sieve, it is added to a wet granulator, and then water is added while stirring to make a soft material. Among them, the time for making the soft material is 100 - 120 s, the rotation speed of the stirring paddle is 500 - 600 rpm, and the rotation speed of the cutter is 600 - 800 rpm; then, the soft material passes through a 16 - mesh sieve, the wet granules are dried under the condition of 60 °C, and then pass through a 24 - mesh sieve to form dry granules.

[0014] Further, in a preferred embodiment of the present invention, the dry granules are sub - packed to obtain the sevelamer carbonate dry suspension.

[0015] The beneficial effects of the present invention are as follows: By using lactulose as a sweetener as described above, the present invention can not only improve the taste of the sevelamer carbonate dry suspension, but also improve the gastrointestinal side effects of the sevelamer carbonate dry suspension. At the same time, by selecting a suspending agent, a flocculant, lactulose and a flavoring agent and controlling their contents, the sevelamer carbonate dry suspension has good redispersibility. Specific Embodiments

[0016] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. For those not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments not specified by the manufacturer are all conventional products that can be obtained through commercial purchase.

[0017] The embodiments of the present invention provide a sevelamer carbonate dry suspension, which is specifically as follows:

[0018] The raw materials of the sevelamer carbonate dry suspension include sevelamer carbonate raw drug, suspending agent, flocculant, lactulose, and flavoring agent. Among them, the dosage of the suspending agent is 0.13 - 0.33% of the total mass, the dosage of the flocculant is 0.05 - 0.39% of the total mass, the dosage of lactulose is 72.53 - 86.90% of the total mass, the dosage of the flavoring agent is 0.34 - 0.72% of the total mass, and the dosage of the sevelamer carbonate raw drug is 12.51 - 26.20% of the total mass.

[0019] The dosages of the above-mentioned various raw and auxiliary materials are relative to the total mass of the sevelamer carbonate dry suspension formed. This raw material does not include water, which will be greatly lost during the preparation process and is almost absent in the finished sevelamer carbonate dry suspension.

[0020] In the embodiments of the present invention, lactulose can be converted into organic acids by the digestive tract flora in the colon, resulting in a decrease in the intestinal pH value and increasing the fecal volume by retaining water. The above effects stimulate colonic peristalsis, keep the stool unobstructed, relieve constipation, and at the same time restore the physiological rhythm of the colon. At the same time, the above effects promote the growth of intestinal acidophilic bacteria (such as Lactobacillus), inhibit proteolytic bacteria, and convert ammonia into an ionic state: by reducing the colon pH value, exerting an osmotic effect, and improving bacterial nitrogen metabolism, thereby exerting a laxative effect. Therefore, lactulose is used as a sweetening agent in the sevelamer carbonate dry suspension to keep the suspension with a good taste. At the same time, lactulose can reduce the side effects such as constipation, indigestion, insufficient intestinal motility, intestinal obstruction, and incomplete intestinal obstruction caused by taking sevelamer carbonate.

[0021] At the same time, the embodiments of the present invention select a suspending agent, a flocculant, lactulose, and a flavoring agent, and control their contents to make the sevelamer carbonate dry suspension have good redispersibility.

[0022] Specifically, the dosage of the suspending agent is 0.13 - 0.33% of the total mass, such as 0.13%, 0.15%, 0.17%, 0.20%, 0.21%, 0.24%, 0.25%, 0.28%, 0.30%, 0.33% and any value between 0.13 - 0.33%. The suspending agent is selected from any one of sodium alginate, xanthan gum and propylene glycol alginate, and preferably propylene glycol alginate.

[0023] The dosage of the flocculant is 0.05 - 0.39% of the total mass, such as 0.05%, 0.13%, 0.15%, 0.17%, 0.20%, 0.21%, 0.24%, 0.25%, 0.28%, 0.30%, 0.39% and any value between 0.05 - 0.39%. The flocculant includes sodium chloride.

[0024] The dosage of lactulose is 72.53 - 86.90% of the total mass, such as 72.53%, 73%, 74%, 75%, 80%, 85%, 86% and any value between 72.53 - 86.90%.

[0025] The dosage of the flavoring agent is 0.34 - 0.72% of the total mass, such as 0.34%, 0.5%, 0.6%, 0.7% and any value between 0.34 - 0.72%. The flavoring agent is a water-soluble essence; preferably orange flavor essence, strawberry flavor essence and lemon flavor essence.

[0026] The dosage of sevelamer carbonate bulk drug is 12.51 - 26.10% of the total mass, such as 12.51%, 15%, 20%, 23%, 24%, 25%, 26% and any value between 12.51 - 26.1%.

[0027] Furthermore, its raw materials include sevelamer carbonate bulk drug, propylene glycol alginate, sodium chloride, lactulose and essence. Among them, the dosage of lactulose is 72.53 - 86.90% of the total mass, the dosage of the essence is 0.34 - 0.72% of the total mass, the dosage of sevelamer carbonate bulk drug is 12.51 - 26.20% of the total mass, the dosage of propylene glycol alginate is 0.05 - 0.39% of the total mass, and the dosage of sodium chloride is 0.13 - 0.33% of the total mass.

[0028] Preferably, the dosage of lactulose is 72.62% of the total mass, the dosage of the essence is 0.72% of the total mass, the dosage of the sevelamer carbonate raw drug is 26.14% of the total mass, the dosage of the propylene glycol alginate is 0.26% of the total mass, and the dosage of the sodium chloride is 0.26% of the total mass.

[0029] Second, the embodiment of the present invention provides a preparation method of the above sevelamer carbonate dry suspension, including: mixing the sevelamer carbonate raw drug, suspending agent, flocculant, lactulose and flavoring agent and then making a preparation. Specifically as follows:

[0030] Weigh the sevelamer carbonate raw drug, suspending agent, flocculant, lactulose and flavoring agent according to the amount, add them to a three-dimensional mixer for mixing, then use a swing granulator to screen the mixture through a 40-mesh sieve, use a wet granulator to premix the mixture for 5 min, start the stirring paddle and cutter of the wet granulator, add 153 g of water to make soft materials, pass the prepared soft materials through a 16-mesh sieve to obtain wet granules, dry the wet granules in an oven at 60 °C, take them out when the moisture content of the granules is lower than 4%, pass them through a 24-mesh sieve to obtain dry granules, and use a granule filling machine to perform small-bag packaging and sealing at 3.061 g / bag.

[0031] The following specifically describes a sevelamer carbonate dry suspension and its preparation method provided by the present invention in combination with specific embodiments.

[0032] Example 1

[0033] The present embodiment provides a preparation method of a sevelamer carbonate dry suspension, including:

[0034] Weigh 800 g of sevelamer carbonate raw drug (calculated as dry product), 8 g of propylene glycol alginate, 22 g of orange flavor essence, 8 g of sodium chloride and 2223 g of lactulose, add them to a three-dimensional mixer and mix at 15 rpm for 5 min, and pass the mixture through a 40-mesh sieve using a swing granulator; transfer the mixed materials to a wet granulator, start the stirring paddle at 400 rpm for dry mixing for 5 min, then add purified water to prepare soft materials, stir while adding, the stirring paddle speed is 500 rpm, the cutter speed is 800 rpm, the soft material preparation time is 120 s, pass the soft materials through a 16-mesh sieve to granulate, dry the wet granules completely at 60 °C and then pass them through a 24-mesh sieve to obtain dry granules, and pack the dry granules into small bags at a loading amount of 3061 mg / bag and seal them to obtain the sevelamer carbonate dry suspension.

[0035] Example 2

[0036] The present embodiment provides a preparation method of a sevelamer carbonate dry suspension, including:

[0037] Weigh 800 g of sevelamer carbonate raw drug (calculated as dry product), 4 g of sodium alginate, 22 g of strawberry flavor essence, 8 g of sodium chloride, and 2223 g of lactulose. Add them to a three-dimensional mixer and mix at 15 rpm for 5 min. Pass the mixture through a 40-mesh sieve using a rocking granulator. Transfer the mixed materials to a wet granulator, start the stirring paddle at 400 rpm and dry-mix for 5 min, then add purified water to prepare soft materials while stirring. The stirring paddle speed is 500 rpm, the cutter speed is 600 rpm, and the soft material preparation time is 100 s. Pass the soft materials through a 16-mesh sieve to granulate. After drying the wet granules completely at 60 °C, pass them through a 24-mesh sieve to obtain dry granules. Divide the dry granules into small bags according to the filling amount of 3054 mg / bag, seal them, and obtain the sevelamer carbonate dry suspension.

[0038] Example 3

[0039] This example provides a preparation method for sevelamer carbonate dry suspension, including:

[0040] Weigh 800 g of sevelamer carbonate raw drug (calculated as dry product), 8 g of sodium alginate, 22 g of strawberry flavor essence, 8 g of sodium chloride, and 5557 g of lactulose. Add them to a three-dimensional mixer and mix at 15 rpm for 5 min. Pass the mixture through a 40-mesh sieve using a rocking granulator. Transfer the mixed materials to a wet granulator, start the stirring paddle at 400 rpm and dry-mix for 5 min, then add purified water to prepare soft materials while stirring. The stirring paddle speed is 600 rpm, the cutter speed is 800 rpm, and the soft material preparation time is 120 s. Pass the soft materials through a 16-mesh sieve to granulate. After drying the wet granules completely at 60 °C, pass them through a 24-mesh sieve to obtain dry granules. Divide the dry granules into small bags according to the filling amount of 6395 mg / bag, seal them, and obtain the sevelamer carbonate dry suspension.

[0041] Process optimization

[0042] (1) Suspending agent screening

[0043] Prepare sevelamer carbonate dry suspension according to the prescriptions in Table 1, and investigate the sedimentation volume ratio and pourability. The preparation process is the same, referring to Example 1.

[0044] Table 1 Suspending agent screening

[0045]

[0046] The sedimentation volume ratio of sevelamer carbonate dry suspension for each prescription was investigated. Weigh a bag of dry suspension powder and put it into a stoppered measuring cylinder. Add 30 ml of water and shake vigorously to form a suspension. Record the initial height H0 of the suspension. Record the height H of the suspension at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min of standing respectively. Calculate the sedimentation volume ratio at different time points according to the following formula: Sedimentation volume ratio = H / H0. The results of the sedimentation volume ratio investigation for prescription screening are shown in Table 2:

[0047] Table 2 Test results of sedimentation volume ratio

[0048]

[0049] According to the above table, when the dosage of propylene glycol alginate as a suspending agent increased from 4 mg to 8 mg, the sedimentation trend of the suspension slowed down and the suspendability of the suspension increased. When the dosage of propylene glycol alginate as a suspending agent was 8 mg and 10 mg, the sedimentation volume ratios of the suspension were similar. Therefore, it is considered that a dosage of 8 mg of propylene glycol alginate as a suspending agent can meet the requirements of the suspendability of the suspension.

[0050] Pouring property inspection: The results of the residue after pouring and the residue after washing for 4 prescriptions are shown in Table 3:

[0051] Table 3 Test results of pouring property inspection

[0052]

[0053]

[0054] According to the above table, (1) when the same volume of water was added, when the dosage increased, the ability of the suspension to be completely poured and washed showed a deteriorating trend; (2) at the same water addition ratio, when the dosage of propylene glycol alginate increased, the ability of the suspension to be completely poured and washed showed a deteriorating trend. Especially for Prescription 4, when the dosage of propylene glycol alginate was 10 mg, the mass percentage of the residue after pouring reached 7.05%, and the percentage of the residue after washing with water was still as high as 3.42%, which could not meet the accuracy requirements of the drug dosage.

[0055] (2) Screening of flocculants

[0056] Prepare sevelamer carbonate dry suspension according to the prescriptions in Table 4, and investigate the sedimentation volume ratio and pouring property. The preparation process is the same as that in Example 1.

[0057] Table 4 Flocculant screening

[0058]

[0059] The results of the sedimentation volume ratio screening investigation are shown in Table 5:

[0060] Table 5 Sedimentation Volume Ratio Test Results

[0061]

[0062] According to the above table, as the amount of sodium chloride gradually increases, the sedimentation trend of the suspension slows down. When the amount of sodium chloride added is 8 mg, the suspension has the best suspension property. When the amount of sodium chloride added is 12 mg, its suspension property is slightly worse than that when the amount of sodium chloride added is 8 mg.

[0063] The results of the pourability test are shown in Table 6:

[0064] Table 6 Pourability Test Results

[0065]

[0066] According to the above table, as the amount of sodium chloride gradually increases, the ability of the suspension to be completely poured and washed shows a slightly deteriorating trend. However, when the amount of sodium chloride added is 8 - 12 mg, the ability of the suspension to be completely poured and washed tends to be stable.

[0067] (3) Screening of the Dosage of Lactulose

[0068] Prepare sevelamer carbonate dry suspension according to the prescriptions in Table 7, and investigate the sedimentation volume ratio and pourability. The preparation process of Prescription 3 refers to Example 1, and the preparation processes of Prescriptions 8 and 9 refer to Example 3.

[0069] Table 7 Screening of the Dosage of Lactulose

[0070]

[0071] The results of the sedimentation volume ratio investigation are shown in Table 8:

[0072] Table 8 Sedimentation Volume Ratio Test Results

[0073]

[0074] According to the above table, within the range of 2223 mg - 5557 mg of lactulose added, the suspension property of the suspension is good.

[0075] The results of the pourability test are shown in Table 9:

[0076] Table 9 Pourability Test Results

[0077]

[0078] According to the above table, as the amount of lactulose gradually increases, the viscosity of the suspension increases, and the ability to be completely poured and washed shows a deteriorating trend.

[0079] In vitro bioequivalence test

[0080] According to the individual drug guidance of sevelamer carbonate by the FDA, an in vitro bioequivalence test needs to be designed independently. The in vitro equilibrium binding test is a key study for evaluating bioequivalence. The self-developed tablets and the reference tablets are incubated with at least 8 different concentration levels of phosphate. Based on the concentration of total phosphate binding, the binding constant k1 and the capacity constant k2 are calculated through the Langmuir equation. The bioequivalence is evaluated by the confidence interval of the k2 ratio between the self-developed tablets and the reference tablets. The data of the in vitro equilibrium binding test are shown in Table 10 - Table 13:

[0081] Table 10 Data of phosphate equilibrium binding experiment (without acid treatment, pH4 medium)

[0082]

[0083]

[0084] Table 11 Data of phosphate equilibrium binding experiment (with acid treatment, pH4 medium)

[0085]

[0086] Table 12 Data of phosphate equilibrium binding experiment (without acid treatment, pH7 medium)

[0087]

[0088] Table 13 Data of phosphate equilibrium binding experiment (with acid treatment, pH7 medium)

[0089]

[0090]

[0091] According to the above tables, it can be seen that the k2 values obtained from the in vitro phosphate equilibrium binding experiments under four different conditions are all close to those of the reference, indicating that the phosphate adsorption ability of the self-prepared products is similar to that of the reference, and different dosages of lactulose have no effect on the phosphate adsorption of sevelamer carbonate.

[0092] In vivo experiment

[0093] A pre - test of post - meal administration was carried out using the reference (800mg specification) and the suspension prepared according to Prescription 3. A single - center, randomized, open - label, two - formulation, two - period, double - crossover trial was adopted. The sample size was 24 cases, and the safety in healthy subjects was observed. The statistical results of the number of patients with constipation and abdominal distension are shown in Table 14:

[0094] Table 14 Statistical results of the number of patients with constipation and abdominal distension

[0095]

[0096] According to the above table, the sevelamer carbonate for oral suspension provided by the embodiments of the present invention can effectively avoid the side effects of constipation and abdominal distension caused by taking medicine compared with the original research dry suspension.

[0097] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A sevelamer carbonate for oral suspension, characterized in that, Its raw materials include sevelamer carbonate bulk drug, suspending agent, flocculant, lactulose and flavoring agent. Among them, the dosage of the suspending agent is 0.13 - 0.26% of the total mass, the dosage of the flocculant is 0.05 - 0.39% of the total mass, the dosage of lactulose is 72.53 - 86.90% of the total mass, the dosage of the flavoring agent is 0.34 - 0.72% of the total mass, and the dosage of sevelamer carbonate bulk drug is 12.51 - 26.20% of the total mass; among them, the suspending agent is selected from propylene glycol alginate; the flocculant includes sodium chloride.

2. The sevelamer carbonate dry suspension according to claim 1, wherein The flavoring agent is water-soluble essence.

3. The sevelamer carbonate dry suspension according to claim 1, characterized in that, The flavoring agent is orange flavor essence, strawberry flavor essence and lemon flavor essence.

4. The sevelamer carbonate dry suspension according to claim 1 or 2, characterized in that, Its raw materials include sevelamer carbonate bulk drug, propylene glycol alginate, sodium chloride, lactulose and essence. Among them, the dosage of lactulose is 72.53 - 86.90% of the total mass, the dosage of the essence is 0.34 - 0.72% of the total mass, the dosage of sevelamer carbonate bulk drug is 12.51 - 26.20% of the total mass, the dosage of propylene glycol alginate is 0.05 - 0.39% of the total mass, and the dosage of sodium chloride is 0.13 - 0.33% of the total mass.

5. The sevelamer carbonate for oral suspension according to claim 4, wherein The dosage of lactulose is 72.62% of the total mass, the dosage of the essence is 0.72% of the total mass, the dosage of sevelamer carbonate bulk drug is 26.14% of the total mass, the dosage of propylene glycol alginate is 0.26% of the total mass, and the dosage of sodium chloride is 0.26% of the total mass.

6. A preparation method of the sevelamer carbonate dry suspension according to claim 1, characterized in that, It includes: Mix sevelamer carbonate bulk drug, suspending agent, flocculant, lactulose and flavoring agent and then carry out formulation.

7. The preparation method according to claim 6, wherein It includes: Mix the sevelamer carbonate bulk drug, the suspending agent, the flocculant, the lactulose and the flavoring agent to form a mixture, then sieve the mixture, then make soft material, sieve again to make granules to form wet granules, and then dry to form dry granules.

8. The preparation method according to claim 7, characterized in that, It includes: After the mixture passes through a 40-mesh sieve, add it to a wet granulator, and then add water while stirring to make soft material. Among them, the time for making soft material is 100 - 120 s, the rotation speed of the stirring paddle is 500 - 600 rpm, and the rotation speed of the cutter is 600 - 800 rpm; then, the soft material passes through a 16-mesh sieve, the wet granules are dried under the condition of 60 °C, and then pass through a 24-mesh sieve to form dry granules.

9. The preparation method according to claim 7 or 8, characterized in that, Carry out sub-packaging on the dry granules to obtain the sevelamer carbonate dry suspension.

Images