An oral suspension of sodium zirconium cyclosilicate and its preparation method

Abstract

The present invention discloses a sodium zirconium cyclosilicate oral suspension and a preparation method thereof, which comprise the following components in mass percentages: 10-30% of sodium zirconium cyclosilicate, 0.1-2.0% of cellulose, 0.01-0.30% of suspending agent, 0-10% of flavoring agent, 0-1.0% of preservative, and purified water; the suspending agent is a mixture of xanthan gum and locust bean gum. The potassium ion exchange capacity of the sodium zirconium cyclosilicate oral suspension of the present invention is equivalent to that of the commercially available powder and has good dispersion stability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a sodium zirconium cyclosilicate oral suspension and a preparation method thereof. Background Art

[0002] Hyperkalemia is a common state of electrolyte disorder in the body, which can be life-threatening in severe cases and mostly occurs in patients with chronic kidney disease (CKD) and heart failure. Currently, CKD has a relatively high incidence rate worldwide, and elevated blood potassium in the body will accelerate the disease progression of CKD patients, leading to many adverse consequences such as emergency hospitalization, increasing the risk of death. Moreover, hyperkalemia is prone to occur repeatedly and continuously, bringing psychological pressure and economic burden to patients and their families.

[0003] The drugs used for reducing blood potassium in the maintenance period of hyperkalemia patients are only polystyrene sulfonate and sodium zirconium cyclosilicate. Among them, polystyrene sulfonate is an adsorbent resin type potassium-lowering drug, which was first marketed in 1958 and belongs to organic polymer type; while sodium zirconium cyclosilicate belongs to inorganic crystal type and is a potassium-lowering drug marketed in the recent 5 years (launched in the United States and China in 2018 and 2019 respectively). It has a unique cubic crystal structure and has a high binding force for potassium ions. After taking it, it binds to potassium ions in the gastrointestinal tract and is excreted through feces, thereby reducing the blood potassium level.

[0004] Potassium-lowering resin drugs absorb water in the intestine after taking, swell and are prone to cause constipation. Therefore, patients need to take laxatives simultaneously during the medication process. While sodium zirconium cyclosilicate is an inorganic crystal, insoluble in water, does not swell when encountering water, and has good gastrointestinal tolerance.

[0005] Currently, the dosage form of the inorganic crystal type potassium-lowering drug sodium zirconium cyclosilicate sold on the market is powder (trade name: Lixuezhuo )). This preparation is directly filled with the active ingredient, with each small bag being 5 grams or 10 grams, without adding any excipients. The usage and dosage section in its drug instruction manual describes the use of this drug as follows: "Pour each small bag completely into a water cup containing about 45 ml of water and stir well. The powder will not dissolve. This odorless liquid should be taken while it is still turbid. If the powder precipitates, it should be stirred again to ensure that all the drug is taken."

[0006] Experiments found that according to this method, the powder sinks rapidly after being added to water. Especially when the particle size is larger or there are large particle size powders due to uneven crystallization in the production process, even with stirring, there are still a few deposits at the bottom of the water cup. Once the stirring stops, the powder sinks rapidly, resulting in patients being unable to take all the powder completely, or having to add water and stir it up several times before drinking. And patients with kidney disease, especially those in the late stage of kidney disease, need to strictly control the water intake to reduce the burden on the kidneys.

[0007] In addition, during the process of pouring into the mouth and swallowing, if the amount of powder is too much (5 - 10 g per time), fine powder is likely to remain in the mouth, with an obvious gritty feeling. Since this drug needs to be taken for a long time, especially for pediatric patients, low compliance may cause patients to refuse to take or take less of the drug, resulting in unstable blood potassium levels in patients and increasing the risk of patient death. Therefore, it is very important to develop a preparation that is convenient for patients to take, reduces the gritty feeling during taking, and improves the compliance of patients taking the drug.

[0008] For poorly soluble drugs, oral suspension is a relatively good dosage form. The sedimentation of the drug can be solved by adding a suspending agent, the wetting of the drug can be solved by adding an appropriate amount of surfactant, and the taste can be improved by adding an appropriate amount of flavoring agent. However, in our experimental research, we found that organic resin potassium-lowering drugs such as calcium polystyrene sulfonate have a small specific gravity (1.33 g / cm 3 ) and expand when encountering water (it can expand to 80% - 100% of the original volume after absorbing water), and its suspension performance is relatively easy to solve. While sodium zirconium cyclosilicate is an inorganic salt, its density is as high as 2.18 g / cm 3 , with a specific gravity much greater than that of water, and it will not absorb water and expand. It settles rapidly in water, and the powder deposited at the bottom can form a very tight precipitate, making it very difficult to redisperse.

[0009] After retrieval, there are very few literature reports on the preparation research of sodium zirconium cyclosilicate. Chinese Patent ZL201480072530.5 reported its tablet formulation, which consists of hydroxypropyl cellulose, silicified microcrystalline cellulose, crospovidone, and magnesium stearate, with specifications of 500 mg and 1000 mg. The tablets are large, and the dosage per administration requires 10 - 20 tablets, not meeting the requirements for clinical use.

[0010] European Patent Document with Publication Number WO2019 / 092179A1 discloses an oral suspension dosage form. However, its potassium ion exchange capacity is only 2.50 mEq / g (while the potassium ion exchange capacity requirement for medicinal sodium zirconium cyclosilicate is above 3.0 mEq / g). The low potassium ion exchange capacity of this suspension may be due to the low purity of this inorganic crystal. In addition, this suspension formulation selects xanthan gum alone as the suspending agent and Tween 20 - poloxamer 188 as the surfactant. Since the specific gravity of sodium zirconium cyclosilicate is large, to meet the requirements of the sedimentation rate standard for the suspension, the usage amount of xanthan gum in the formulation reaches 0.65%, and the usage amount of poloxamer 188 reaches 7%, making the liquid material very viscous and increasing the difficulty of production and filling. Moreover, to enable the drug to be released from a large amount of xanthan gum in the gastrointestinal tract, the surfactant Tween 20 is used at 2%. Since Tween 20 has a special odor and bitterness, and poloxamer has a weak odor, it will also affect the compliance of taking the drug for people with sensitive taste or children.

[0011] The best way to slow down the sedimentation rate of microparticles is to reduce their particle size. However, during the physical pulverization process of sodium zirconium cyclosilicate using a pulverizer or colloid mill, particles with a particle size below 3 μm are easily generated. Since the powder with a size less than 3 μm will be absorbed by the human body, resulting in an increase in the zirconium content in the body and thus damaging the health of patients. Therefore, if sodium zirconium cyclosilicate is to maintain suspension stability, theoretically a more viscous system is required, that is, more suspending agents are used. However, the use of excessive suspending agents has two problems. First, the liquid material becomes very viscous, making production and filling difficult or infeasible. Second, the powder encapsulated by the colloid after the drug enters the human body cannot be released. A large amount of colloid blocks the channel for the exchange of sodium ions in the drug sodium zirconium cyclosilicate with potassium ions in intestinal fluid, thereby affecting the exchange of sodium ions in the drug with potassium ions in intestinal fluid and further affecting the drug efficacy.

[0012] Therefore, it is necessary to select a suitable suspending agent to enable the oral suspension of sodium zirconium cyclosilicate to remain uniformly stable during long-term storage and to quickly disintegrate after entering the human body. Summary of the Invention

[0013] The present invention provides an oral suspension of sodium zirconium cyclosilicate and a preparation method thereof. The potassium ion exchange capacity of the oral suspension of sodium zirconium cyclosilicate is equivalent to that of a commercially available powder and has good dispersion stability.

[0014] The technical solution of the present invention is as follows:

[0015] An oral suspension of sodium zirconium cyclosilicate, comprising the following components in mass percentages: 10 - 30% of sodium zirconium cyclosilicate, 0.1 - 2.0% of cellulose, 0.01 - 0.30% of suspending agent, 0 - 10% of flavoring agent, 0 - 1.0% of preservative, and purified water;

[0016] The suspending agent is a mixture of xanthan gum and locust bean gum.

[0017] Common suspending agents in oral suspensions, such as xanthan gum and locust bean gum, are insoluble in water, and their conventional dosages are 0.3% - 3.0% and 0.4% - 2.5% (Pharmaceutics, 4th Edition, People's Medical Publishing House). The colloid formed after they swell in water easily encapsulates the active ingredient sodium zirconium cyclosilicate, making it unable to perform sodium-potassium exchange with potassium ions in intestinal fluid after entering the human body, thus unable to capture potassium ions and further reducing its drug efficacy. Therefore, when the suspension contains a large amount of colloid suspending agents, to ensure its drug efficacy, a large amount of surfactant also needs to be added.

[0018] In the present invention, the inventors surprisingly found that when the suspending agent is replaced from a single xanthan gum to a mixed colloid of xanthan gum and locust bean gum, only a very small amount (0.01 - 0.30%) is needed, and when combined with cellulose, the suspension can reach a long-term stable dispersion state, without stratification and precipitation at the bottom after standing for at least 30 days, and it can quickly disintegrate without adding surfactants, which can further reduce the application of excipients with toxic and side effects. The potassium ion exchange capacity of the sodium zirconium cyclosilicate oral suspension of the present invention is equivalent to that of the commercially available powder, which is 3.0 - 3.8 mEq / g, indicating that this dosage form does not affect the efficacy of sodium zirconium cyclosilicate.

[0019] At the same time, after reducing the dosage of the gum suspending agent, the state of the suspension is thinner when it is just prepared, which is convenient for filling. After standing, its viscosity will increase significantly, maintaining its suspension stability, and the content of sodium zirconium cyclosilicate can be further increased to 30% while still maintaining suspension stability. In addition, when the suspension of the present invention is heated to 50 - 60 °C, its viscosity will decrease and the state will become thinner, and it will become thicker again after cooling to room temperature, which reduces the difficulty of filling during production.

[0020] The disintegration time of the oral suspension of the present invention in water does not exceed 30 min, preferably does not exceed 20 min, and most preferably does not exceed 15 min.

[0021] When a relatively large amount of the suspending agent is used, although the dispersion stability of the suspension will increase to a certain extent, the viscosity of the suspension will also become too large, which is not conducive to swallowing, the difficulty of dispersing the active pharmaceutical ingredient during production will increase, and the redispersibility after long-term storage will also be weakened, which is disadvantageous. If the state of the suspension is thinner, aspiration may occur when the patient takes it, choking into the trachea, which is not safe, and the sodium zirconium cyclosilicate in it is likely to settle, reducing the suspension dispersion stability. Therefore, it is necessary to strictly control the dosage of the suspending agent to make the final state of the oral suspension appropriate.

[0022] At the same time, the used suspending agent is insoluble in water, and the colloid formed after swelling is easy to wrap the sodium zirconium cyclosilicate powder, affecting its potassium ion exchange capacity. Therefore, its dosage should be as small as possible while ensuring the appropriate state of the suspension. Selecting an appropriate ratio can make the suspension state thick enough with less suspending agent, which is convenient for packaging but can quickly disintegrate in the body without affecting taking and efficacy, and can be taken directly by extruding with a strip package, which is convenient and fast.

[0023] Preferably, the mass percentage content of the suspending agent is 0.01 - 0.28%; more preferably 0.01 - 0.20%; still more preferably 0.01 - 0.15%.

[0024] Preferably, in the mixture of xanthan gum and locust bean gum, the mass ratio of xanthan gum to locust bean gum is 0.4-6.5:1; most preferably, the mass ratio of xanthan gum to locust bean gum is 1:1.

[0025] A second aspect of the present invention relates to further improving the mouthfeel of the oral suspension. By adding cellulose, the mouthfeel of the oral suspension can be made softer.

[0026] Preferably, the cellulose is at least one of sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, microcrystalline cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, and guar gum / microcrystalline cellulose co-processed product.

[0027] Further preferably, the cellulose is methylcellulose. In the oral suspension of the present invention, methylcellulose not only improves the mouthfeel and makes the suspension softer, but also can synergize with xanthan gum and locust bean gum to improve the stability of the oral suspension.

[0028] Preferably, the mass percentage of the cellulose is 0.2-1.5%; more preferably 0.2-0.8%.

[0029] Preferably, the mass percentage of the sodium zirconium cyclosilicate is 15-25%, and more preferably 20-25%. A higher content of sodium zirconium cyclosilicate can reduce the amount of suspension that patients need to take each time, making it easier to take.

[0030] If the particle size of sodium zirconium cyclosilicate is less than 3 μm, it may be absorbed by the human body, thereby affecting liver and kidney function and causing certain toxic side effects. If the particle size is too large, a gritty feeling can be clearly felt when taking it, affecting the taste when taking it, and also affecting the suspension and dispersion stability of the suspension.

[0031] Therefore, preferably, the particle size D of the sodium zirconium cyclosilicate bulk drug is 90 3 to 130 μm; further preferably, the particle size D of the sodium zirconium cyclosilicate raw material 90 The particle size of the sodium zirconium cyclosilicate API is preferably less than 75 μm and less than 3 μm, and the particle size is preferably less than 3%. 90 The particle size is 10 to 30 μm and the particle size smaller than 3 μm does not exceed 3%.

[0032] In order to further improve the palatability of the oral suspension and enhance the patient's medication compliance, preferably, the sodium zirconium cyclosilicate oral suspension also includes a flavoring agent.

[0033] The flavor corrector is at least one of saccharin sodium, aspartame, sucralose, maltose, maltitol, liquid maltitol, fructose, lactose, mannitol and sucrose.

[0034] Preferably, the flavoring agent is at least one of sucralose, mannitol, and maltitol; more preferably, it is sucralose and maltitol.

[0035] Preferably, the mass percentage content of the flavoring agent is 5-10%.

[0036] To further improve the palatability of the oral suspension and enhance the patient's medication compliance, preferably, the sodium zirconium cyclosilicate oral suspension further comprises a flavor.

[0037] The flavor is strawberry flavor, apple flavor, orange flavor, cherry flavor, chocolate flavor, vanilla flavor, honeydew melon flavor, blueberry flavor, grape flavor, lemon flavor, kiwi flavor, coffee flavor, matcha flavor, etc. Considering the flavors that are easily acceptable to the public, apple flavor, orange flavor, or strawberry flavor is preferred.

[0038] The sodium zirconium cyclosilicate oral suspension contains a suspending agent of natural polysaccharides, which is prone to breeding molds, etc., causing the suspension to deteriorate. Therefore, to enable the oral suspension of the present invention to be stored for a long time, preferably, the sodium zirconium cyclosilicate oral suspension further comprises a preservative.

[0039] The preservative is at least one of sorbic acid, sodium sorbate, benzyl alcohol, benzoic acid, sodium benzoate, citric acid, sodium citrate, methylparaben, ethylparaben, propylparaben, butylparaben, chlorobutanol, benzalkonium bromide, and chitosan.

[0040] Preferably, the mass percentage content of the preservative is 0.02-0.8%; more preferably, it is 0.02-0.6%.

[0041] The present invention also provides a preparation method of the above-mentioned sodium zirconium cyclosilicate oral suspension, comprising the following steps:

[0042] (1) Preparation of liquid medicine 1: Take a part of the formulated amount of purified water, heat it to 60-90°C and keep it at a constant temperature, add a suspending agent and cellulose, and use a homogenizer to fully swell and mix them evenly.

[0043] (2) Preparation of liquid medicine 2: Take a part of the formulated amount of purified water, add a flavoring agent and a preservative, and completely dissolve them in water.

[0044] (3) Mix liquid medicine 1 and liquid medicine 2 evenly, add sodium zirconium cyclosilicate, use a homogenizer to stir to make a preliminary even mixture, then add an appropriate amount of purified water for quantification, and continue to stir to make a fully even mixture and dispersion, obtaining the sodium zirconium cyclosilicate oral suspension.

[0045] Compared with the prior art, the beneficial effects of the present invention are:

[0046] By using a very small amount of xanthan gum and locust bean gum mixed suspending agent in a certain ratio, together with methylcellulose that can make the taste mild, the sodium zirconium cyclosilicate suspension can have excellent dispersion stability, and can still maintain the stability of its dispersion performance after standing for at least 30 days, and is still much higher than the requirement of the Chinese Pharmacopoeia for the suspension that "the sedimentation ratio after standing for three hours should be greater than 0.9". It is also unexpectedly found that the xanthan gum and locust bean gum mixed suspending agent has basically no influence on the disintegration and release of the drug from the colloid, and the potassium ion exchange capacity of the prepared sodium zirconium cyclosilicate oral suspension is equivalent to that of the marketed sodium zirconium cyclosilicate powder without added excipients. Thus, the disadvantages of the current sodium zirconium cyclosilicate suspension are creatively solved. While improving the compliance of taking medicine, it does not affect the efficacy of the drug, and greatly meets the clinical requirements for the efficacy and compliance of long-term medication for patients with hyperkalemia, especially children.

[0047] The sodium zirconium cyclosilicate oral suspension of the present invention can be carried around, is convenient to take, has a suitable taste, improves the defects of the existing dosage form, and greatly increases the compliance of patients in taking medicine. Each excipient preferably uses natural excipients that are non-toxic and have no side effects on the human body, and can minimize the side effects on the bodies of patients of all ages. Description of the Drawings

[0048] Figure 1 It is a schematic structural diagram of sodium zirconium cyclosilicate. Detailed Embodiments

[0049] The following examples are only used to further illustrate the present invention, but do not limit the present invention.

[0050] The preparation method of the oral suspension in the following examples includes the following steps:

[0051] 1. Particle size D of the raw drug 90 Sodium zirconium cyclosilicate powder with a particle size of about 20 μm and D3 greater than about 3 μm; its potassium ion exchange capacity (KEC) is 3.0 - 3.8 mEq / g, and its structural formula is as Figure 1 shown;

[0052] 2. Preparation of Liquid Medicine 1: Take 50% (w / w) of the total amount of purified water in the suspension, heat it to 60 - 90 °C and keep it at a constant temperature, add the suspending agent and thickening agent, and use a homogenizer to make it fully swell and mix and disperse evenly;

[0053] 3. Preparation of Liquid Medicine 2: Take 10% (w / w) of the total amount of purified water in the suspension, add the flavoring agent and preservative, and make them completely dissolve in water;

[0054] 4. Mix Liquid Medicine 1 and Liquid Medicine 2 evenly, add sodium zirconium cyclosilicate, use a homogenizer to stir to make it preliminarily mixed evenly, then add an appropriate amount of purified water for quantification, and continue to stir to make it fully mixed and dispersed evenly.

[0055] Other physical properties of the suspension were confirmed by the following methods: appearance (by visual observation); redispersion (by manual shaking); viscosity (by digital rotational viscometer).

[0056] Example 1:

[0057] The formulation of the oral suspension - sodium zirconium cyclosilicate 20% (w / w) is shown in Table 1 as follows:

[0058] Table 1

[0059]

[0060] At room temperature, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0061] Example 2:

[0062] The formulation of the oral suspension - sodium zirconium cyclosilicate 20% (w / w) is shown in Table 2 as follows:

[0063] Table 2

[0064]

[0065] At room temperature, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0066] Example 3:

[0067] The formulation of the oral suspension - sodium zirconium cyclosilicate 20% (w / w) is shown in Table 3 as follows:

[0068] Table 3

[0069]

[0070] At room temperature, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0071] Example 4:

[0072] The formulation of the oral suspension - sodium zirconium cyclosilicate 20% (w / w) is shown in Table 4 as follows:

[0073] Table 4

[0074]

[0075]

[0076] At room temperature, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0077] Example 5:

[0078] The formulation of the oral suspension - sodium zirconium cyclosilicate 25% (w / w) is shown in Table 5 as follows:

[0079] Table 5

[0080]

[0081] Under room - temperature conditions, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0082] Example 6:

[0083] The formulation of the oral suspension - sodium zirconium cyclosilicate 25% (w / w) is shown in Table 6 as follows:

[0084] Table 6

[0085]

[0086] Under room - temperature conditions, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0087] Example 7:

[0088] The formulation of the oral suspension - sodium zirconium cyclosilicate 25% (w / w) is shown in Table 7 as follows:

[0089] Table 7

[0090]

[0091] Under room - temperature conditions, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0092] Example 8:

[0093] The formulation of the oral suspension - sodium zirconium cyclosilicate 25% (w / w) is shown in Table 8 as follows:

[0094] Table 8

[0095]

[0096] Under room - temperature conditions, the suspension can maintain stable physical properties for at least 1 month, without stratification and no precipitation at the bottom.

[0097] Comparative Examples 1 - 9

[0098] The formulations of the oral suspensions - sodium zirconium cyclosilicate in Comparative Examples 1 - 9 are shown in Table 9 (where locust bean gum is food - grade locust bean gum):

[0099] Table 9

[0100]

[0101]

[0102] It can be seen from the observation and comparison of Comparative Examples 3 to 5 that the use of hydroxypropyl methylcellulose will reduce the viscosity of the suspension, while the use of hydroxypropyl cellulose will increase the viscosity to some extent. However, after standing for two weeks, it is observed that both Comparative Example 4 and Comparative Example 5 have slight delamination and the supernatant is yellowish; it can be seen from the observation and comparison of Comparative Example 1 and Comparative Example 6 that the use of microcrystalline cellulose will reduce the viscosity of the suspension; it can be seen from the observation and comparison of Comparative Example 2 and Comparative Examples 7 to 9 that the use of high-viscosity hydroxypropyl cellulose, sodium carboxymethylcellulose, and microcrystalline cellulose-sodium carboxymethylcellulose will reduce the viscosity of the suspension. Therefore, methylcellulose is preferred.

[0103] Since it is desired to minimize the amount of macromolecular polysaccharide gum suspending agents, a variety of suspending agents can also be used to increase the stability of the suspension.

[0104] Comparative Example 10

[0105] The formulation of the oral suspension - sodium zirconium cyclosilicate is shown in Table 10:

[0106] Table 10

[0107] Component Dosage / g Sodium zirconium cyclosilicate 30.00 Methyl cellulose 0.60 Sodium carboxymethyl cellulose 0.40 Xanthan gum 0.14 Locust bean gum (INCOMA.S.) 0.14 Sucralose 0.01 Maltitol 12.00 Water Appropriate amount up to 150 g

[0108] Compared with Example 1 and Example 6, the oral suspension of Comparative Example 10 significantly delaminated after only standing for one week. Adding sodium carboxymethylcellulose additionally on the basis of methylcellulose has a negative effect on the dispersion of the suspension.

[0109] Comparative Example 11

[0110] The formulation of the oral suspension - sodium zirconium cyclosilicate 20% (w / w) is shown in Table 11:

[0111] Table 11

[0112]

[0113] Although this formulation has excellent suspension stability, its viscosity is too high, which is not conducive to production and filling. After standing, the viscosity even rises to 61609.71 cp·s, which is too viscous and not conducive to patients' taking, and also causes a certain hindrance to the release of the drug after entering the human body.

[0114] Comparative Examples 12 - 14

[0115] The formulations of the oral suspensions - sodium zirconium cyclosilicate of Comparative Examples 12 - 14 are shown in Table 12:

[0116] Table 12

[0117]

[0118]

[0119] Select D 90 is 20 μm, D 90 is 75 μm, D 90 Three batches of samples prepared from sodium zirconium cyclosilicate API with D being 130 μm. In Comparative Example 14, the particles of the obtained suspension had an obvious rough feeling, and there were visible powder particles after spreading the suspension; in Comparative Example 13, the particle feeling was not obvious and there was only a slight gritty feeling; in Comparative Example 12, it was very delicate.

[0120] Comparative Example 15

[0121] Oral suspension - 20% (w / w) sodium zirconium cyclosilicate formula is shown in Table 13:

[0122] Table 13

[0123] Component Dosage / g Sodium zirconium cyclosilicate 30.00 Methyl cellulose 0.60 Xanthan gum 0.60 Locust bean gum (INCOMA.S.) 0.40 Sucralose 0.01 Maltitol 12.00 Water Appropriate amount up to 150 g Viscosity (cp·s) 52478.18

[0124] At room temperature, the suspension can maintain physical stability for at least 1 month, without stratification and no precipitation at the bottom.

[0125] Although Comparative Example 15 can maintain suspension stability, its viscosity is too high, and the amount of the gum suspending agent used in Comparative Example 15 is relatively large, which is not conducive to production and filling, nor is it conducive to patients taking.

[0126] Comparative Example 16

[0127] Oral suspension - 20% (w / w) sodium zirconium cyclosilicate formula is shown in Table 14:

[0128] Table 14

[0129]

[0130]

[0131] At room temperature, the suspension can maintain physical stability for at least 1 month, without stratification and no precipitation at the bottom.

[0132] Comparative Example 17

[0133] Oral suspension - 20% (w / w) sodium zirconium cyclosilicate formula is shown in Table 15:

[0134] Table 15

[0135]

[0136] At room temperature, the suspension can maintain physical stability for at least 1 month, without stratification and no precipitation at the bottom.

[0137] Comparative Example 18

[0138] Oral suspension - Sodium zirconium cyclosilicate 25% (w / w) formulation is shown in Table 16 as follows:

[0139] Table 16

[0140]

[0141]

[0142] Under room temperature conditions, the suspension has stratified after standing for one week and there is precipitation at the bottom.

[0143] Comparative Example 19

[0144] Oral suspension - Sodium zirconium cyclosilicate 25% (w / w) formulation is shown in Table 17 as follows:

[0145] Table 17

[0146] Component Dosage / g Sodium zirconium cyclosilicate 30.00 Methyl cellulose 0.72 Xanthan gum 0.12 Gelatin 0.24 Pectin 0.30 Sucralose 0.012 Maltitol 12.00 Propylparaben 0.0225 Butylparaben 0.0075 Water Appropriate amount up to 120 g Viscosity (cp·s) 266.44

[0147] Under room temperature conditions, the suspension has stratified after standing for one week and there is precipitation at the bottom.

[0148] Test Example 1:

[0149] Potassium ion exchange capacity (KEC) detection method:

[0150] Accurately weigh an appropriate amount of potassium chloride of known purity, dissolve it in water and dilute to make a solution containing about 9.53 mg per 1 ml. As the potassium ion stock solution, accurately measure 1.0 ml and place it in a 100 - ml volumetric flask, dilute to the mark with water, and shake well to obtain the potassium ion reference solution.

[0151] Take about 2.5 g of this product, weigh accurately, wash it three times with water, take the precipitate, transfer it to a 100-ml volumetric flask, accurately add 40 ml of potassium ion stock solution, vortex and shake for not less than 3 hours, filter through a 0.45-μm microporous membrane, accurately measure 1.0 ml of the filtrate, place it in a 100-ml volumetric flask, dilute it to the mark with water, shake well, and use it as the test solution. Determine by ion chromatography (General Chapter 0513, Section IV, Chinese Pharmacopoeia 2020 Edition) using a cation exchange chromatographic column (Dionex IonPac CS12A 250x2 mm chromatographic column, Dionex IonPac CG12A 50x2 mm guard column; or a chromatographic column with equivalent performance): the detector is a conductivity detector (Dionex CERS 500e 2 mm), the column temperature is 35°C, 20 mmol / L methanesulfonic acid solution is used as the mobile phase, and the flow rate is 1.0 ml per minute. Inject the potassium ion reference solution continuously for 5 times, and the relative standard deviation of the peak area of potassium ion should not exceed 2.0%. Accurately measure 10 μl of the test solution and the reference solution respectively, inject them into the ion chromatograph, and record the chromatogram.

[0152] Calculate the potassium ion exchange capacity (KEC) according to the following formula, and the limit is 3.0 - 3.8 mEq / g.

[0153]

[0154] Where:

[0155] m 贮备KCl is the amount (g) of KCl in 1000 ml of the stock solution;

[0156] m 供 is the weight (mg) of the test sample;

[0157] A 标 is the peak area of potassium ion in the standard solution;

[0158] A 供 is the peak area of potassium ion in the test solution;

[0159] p is the purity of KCl;

[0160] V is the volume (ml) of the stock solution added;

[0161] 10 is the conversion factor;

[0162] 74.5513 is the molar mass of KCl (g / mol).

[0163] Compare the potassium ion exchange capacities of Examples 1 - 8 and Comparative Examples 15 - 17, and the results are shown in Table 17:

[0164] Table 17

[0165] Sample KEC (mEq / g) Example 1 3.58 Example 2 3.45 Example 3 3.55 Example 4 3.62 Example 5 3.52 Example 6 3.64 Example 7 3.72 Example 8 3.71 Comparative Example 15 3.54 Comparative Example 16 3.63 Comparative Example 17 3.60

[0166] Test Example 2:

[0167] The disintegration times of Comparative Examples 1 to 8 and Comparative Examples 15 to 17 were compared, and the results are shown in Table 18:

[0168] Table 18

[0169] Sample Whether it disintegrates within 15 min Example 1 √ Example 2 √ Example 3 √ Example 4 √ Example 5 √ Example 6 √ Example 7 √ Example 8 √ Comparative Example 15 × Comparative Example 16 √ Comparative Example 17 √ Comparative Example 19 √

[0170] Test Example 3:

[0171] The compounding effects of each gum are shown in Table 19:

[0172] Table 19

[0173]

[0174]

[0175]

[0176] The compounding of other gums could not achieve the effect of the compounding of xanthan gum and locust bean gum. The viscosity of the compound solution of xanthan gum and locust bean gum decreased when the temperature was raised to 50 - 60°C, and this change was reversible.

[0177] Test Example 4:

[0178] Comparative Examples 1, 2, 4, and 8 were compared with zirconium silicate sodium aqueous suspensions (A, B) of the same concentration (20%), and their palatabilities were evaluated.

[0179] The composition of the zirconium silicate sodium aqueous suspension is as follows:

[0180] A) Zirconium silicate sodium suspended in water (total amount 150 g)

[0181] B) Zirconium silicate sodium suspended in water containing 0.14 g of xanthan gum and 0.14 g of locust bean gum (total amount 150 g)

[0182] The evaluation is as follows:

[0183] Example 1: Good soft taste, no graininess, no powder residue in the mouth.

[0184] Example 2: Good soft taste, no graininess, no powder residue in the mouth.

[0185] Example 4: Good soft taste, no graininess, no powder residue in the mouth.

[0186] Example 8: Good soft taste, no graininess, no powder residue in the mouth.

[0187] Suspension A: Poor general taste, obvious powdery feeling, with medicinal powder adhering to the oral cavity, and it is necessary to drink water and gargle several times.

[0188] Suspension B: Better general taste, slight powdery feeling, with a little powder remaining in the oral cavity.

[0189] Industrial applicability

[0190] Even when the oral suspension of the present invention is stored for a long time, sodium zirconium cyclosilicate therein can maintain a stable suspension and dispersion state. In addition, the content of sodium zirconium cyclosilicate in its unit package is the greatest common divisor of the dosages for different medication stages, and there is no need to adopt a large packaging form, and the portability is excellent. Moreover, according to the dosage required for different medication stages, the corresponding dose can be directly taken without using a measuring cup, which is very convenient. On the other hand, generally when taking a water-insoluble drug such as sodium zirconium cyclosilicate, it is necessary to add extra water for preparation, while when taking the oral suspension of the present invention, there is no need to add extra water for preparation, nor tools such as a medicine spoon. Therefore, the steps in taking the medicine are simple and convenient, and it is a safe and effective pharmaceutical composition that meets the medication compliance.

[0191] The above-described embodiments have elaborated on the technical solutions and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the present invention. Any modifications, supplements, equivalent replacements, etc. made within the scope of the principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A sodium zirconium cyclosilicate oral suspension, characterized in that, Comprising the following components in mass percentages: sodium zirconium cyclosilicate 10 - 30%, cellulose 0.1 - 2.0%, suspending agent 0.01 - 0.30%, flavoring agent 0 - 10%, preservative 0 - 1.0%, purified water; The cellulose is methylcellulose; the suspending agent is a mixture of xanthan gum and locust bean gum; Particle size D of sodium zirconium cyclosilicate API 90 The particles with a size less than 3 μm and ≤ 75 μm do not exceed 3%.

2. The sodium zirconium cyclosilicate oral suspension according to claim 1, wherein The disintegration time in water does not exceed 30 min.

3. The sodium zirconium cyclosilicate oral suspension according to claim 1, wherein The mass percentage content of the suspending agent is 0.01 - 0.28%.

4. The sodium zirconium cyclosilicate oral suspension according to claim 1, characterized in that, In the mixture of xanthan gum and locust bean gum, the mass ratio of xanthan gum to locust bean gum is 0.4 - 6.5:

1.

5. The sodium zirconium cyclosilicate oral suspension according to claim 1, wherein The mass percentage content of the cellulose is 0.2 - 1.5%.

6. The sodium zirconium cyclosilicate oral suspension according to claim 1, wherein The mass percentage content of the sodium zirconium cyclosilicate is 15 - 25%.

7. The sodium zirconium cyclosilicate oral suspension according to claim 1, wherein Particle size D of sodium zirconium cyclosilicate bulk drug 90 is 10 - 30 μm, and the particles smaller than 3 μm do not exceed 3%.

8. A method for preparing the sodium zirconium cyclosilicate oral suspension according to any one of claims 1-7, characterized in that, Comprising the following steps: (1) Preparation of liquid medicine 1: Take a part of the formulated amount of purified water, heat it to 60 - 90 °C and keep it at a constant temperature, add the suspending agent and cellulose, and use a homogenizer to fully swell and mix them evenly; (2) Preparation of liquid medicine 2: Take a part of the formulated amount of purified water, add the flavoring agent and preservative, and completely dissolve them in water; (3) Mix liquid medicine 1 and liquid medicine 2 evenly, add sodium zirconium cyclosilicate, use a homogenizer to stir to make a preliminary even mixture, then add an appropriate amount of purified water for quantification, and continue to stir to make a fully mixed and evenly dispersed mixture to obtain the oral suspension of sodium zirconium cyclosilicate.

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