Potassium citrate sustained release tablet and preparation method thereof

Abstract

The invention relates to a potassium citrate sustained release tablet and a preparation method thereof. The potassium citrate sustained release tablet comprises potassium citrate, a waxy framework material, polyvinyl alcohol and sodium alginate. By adding a proper amount of polyvinyl alcohol and sodium alginate, the friability of the tablet is greatly improved, and the risk of ethanol dosage dumping of the product is obviously reduced.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a potassium citrate sustained-release tablet and a preparation method thereof. Background Art

[0002] The chemical name of potassium citrate, the active ingredient in potassium citrate sustained-release tablets, is potassium 2-hydroxypropane-1,2,3-tricarboxylate monohydrate, and its structural formula is as follows:

[0003]

[0004] Potassium citrate is recognized as the most important stone-inhibiting factor. Citrate can react with Ca in urine to 2+ Chelation: Citrate inhibits all stages of stone crystallization, including nucleation, growth, aggregation, and retention. Potassium citrate promotes stone excretion and inhibits stone growth. Because potassium citrate dissolves calcium oxalate crystals, it reduces aggregation. The calcium oxalate crystals become rounded, aggregation is significantly reduced, the average particle size decreases, and some crystals develop depressions on their surfaces. Finally, they are excreted in the urine. Based on the mechanism of action of these drugs, potassium citrate is highly effective in preventing and recurring stones.

[0005] Potassium citrate is currently available in sustained-release tablets and granules, with solutions occasionally available. Clinical safety trial literature on potassium citrate indicates that potassium citrate granules are rapidly released in the stomach, reaching peak concentrations quickly, but also decreasing rapidly, potentially causing short-term gastrointestinal irritation and causing unstable blood potassium levels. They require dissolution with warm water before administration. Gastrointestinal adverse reactions are predominantly reported with granules. Potassium citrate sustained-release tablets are sustained-release tablets that are absorbed from the gastrointestinal tract after oral administration. Peak blood concentrations take longer to reach peak levels, resulting in more stable blood potassium levels and fewer gastrointestinal side effects compared to granules. The active ingredient, potassium citrate, released from potassium citrate sustained-release tablets binds to calcium ions in urine to form a soluble chelate, thereby reducing urinary calcium concentrations and lowering the saturation of calcium oxalate, calcium phosphate, amino acids, and calcium urate. This not only promotes the dissolution of calcium salt crystals but also effectively inhibits stone formation and prevents stone recurrence.

[0006] For example, patents CN101791299A, CN104739794A, CN104800180A, CN102240272B, CN115364063B, and TW200829287A all report on sustained-release tablets of potassium citrate and related preparation methods. The preparation methods of potassium citrate sustained-release tablets disclosed in the above patents mainly include: wet granulation tableting, dry granulation tableting, granulation tableting combined with melt granulation and wet granulation, fluidized bed granulation tableting, and hot-jacketed ribbon mixer melt granulation tableting. Regardless of whether it is a wet granulation process or a dry granulation process, the wax skeleton sustained-release material, a key component of the product's prescription, is difficult to fully melt. Not only is the API sustained-release rate difficult to guarantee and control, but the trial product also has a large risk of ethanol dose dumping. The preparation method that combines melt granulation with wet granulation has a long heating time and high energy consumption because the whole batch of materials needs to be heated and melted at the same time. There are also problems such as material sticking to the wall and difficulty in discharging. Secondary granulation is required, the production process is complicated, and production efficiency is reduced. The fluidized bed granulation process is prone to material stratification, filter bag and air distribution plate blockage, and the production process is complex and difficult to control. The hot jacketed ribbon mixer is used for melt granulation. Since the whole batch of materials needs to be heated at the same time, the heating time is long and the energy consumption is high. There are also problems such as material sticking to the wall and difficulty in discharging, and the overall production efficiency is not high. From this point of view, the preparation process of potassium citrate sustained-release tablets needs to be further improved, optimized, developed and enriched.

[0007] Furthermore, during the development and imitation of potassium citrate sustained-release tablets, it was surprisingly discovered that the reference formulation of potassium citrate sustained-release tablets had poor friability and posed a certain risk of ethanol dose dumping. Therefore, it was necessary to further improve the potassium citrate sustained-release tablets to improve the product's friability and reduce the risk of ethanol dose dumping. Summary of the Invention

[0008] The object of the present invention is to provide a potassium citrate sustained-release tablet with reduced friability and risk of ethanol dose dumping.

[0009] Another object of the present invention is to provide a method for preparing potassium citrate sustained-release tablets that is simple, highly stable, and capable of continuous production.

[0010] To achieve the above object, the present invention adopts the following technical solutions:

[0011] An object of the present invention is to provide a potassium citrate sustained-release tablet, which comprises potassium citrate and a waxy skeleton material. The potassium citrate sustained-release tablet further comprises polyvinyl alcohol and sodium alginate.

[0012] The present invention optimizes the prescription design and greatly improves the friability of the tablet and significantly reduces the risk of ethanol dose dumping of the product by adding appropriate amounts of polyvinyl alcohol and sodium alginate during the prescription design and development optimization process.

[0013] According to some specific embodiments, the polyvinyl alcohol accounts for 0.5%-1.5% of the total mass of the potassium citrate sustained-release tablet, for example, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4% or 1.5%.

[0014] According to some specific embodiments, the sodium alginate accounts for 0.5%-1.5% of the total mass of the potassium citrate sustained-release tablet, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4% or 1.5%.

[0015] According to some specific embodiments, the mass ratio of the polyvinyl alcohol to the sodium alginate is 1:0.5-2, for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0016] According to some specific embodiments, the model of the polyvinyl alcohol is polyvinyl alcohol 4-88.

[0017] According to some specific embodiments, the mass of the potassium citrate in the potassium citrate sustained-release tablet is 0.54 g / tablet to 1.62 g / tablet.

[0018] According to some specific embodiments, the particle size of the potassium citrate is D50≤500 μm and D90≤900 μm.

[0019] Furthermore, the particle size of the potassium citrate is D50≤450 μm and D90≤850 μm.

[0020] According to some specific embodiments, the waxy skeleton material is one or more of carnauba wax, insect wax and synthetic wax.

[0021] Furthermore, the waxy skeleton material is carnauba wax.

[0022] Furthermore, the waxy skeleton material accounts for 10%-15% of the total mass of the potassium citrate sustained-release tablet, for example, 10%, 11%, 12%, 13%, 14% or 15%.

[0023] According to some specific embodiments, the potassium citrate sustained-release tablet further comprises a lubricant.

[0024] Furthermore, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide and sodium lauryl sulfate.

[0025] Furthermore, the lubricant is magnesium stearate.

[0026] Furthermore, the lubricant accounts for 0.4%-1% of the total mass of the potassium citrate sustained-release tablet, for example, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%.

[0027] According to some specific embodiments, based on the unit dosage, the potassium citrate sustained-release tablets are composed of raw materials and excipients in the following prescription ratios: 0.54g-1.62g of potassium citrate, 80mg-250mg of waxy skeleton material, 10mg-30mg of polyvinyl alcohol, 5mg-15mg of sodium alginate, and 4mg-18mg of lubricant.

[0028] According to one embodiment, each unit of potassium citrate sustained-release tablet contains the following components: 1620 mg of potassium citrate, 270 mg of carnauba wax, 27 mg of polyvinyl alcohol, 15 mg of sodium alginate, and 12 mg of magnesium stearate.

[0029] According to another embodiment, each unit of potassium citrate sustained-release tablet contains the following components: 1080 mg of potassium citrate, 180 mg of carnauba wax, 18 mg of polyvinyl alcohol, 10 mg of sodium alginate, and 8 mg of magnesium stearate.

[0030] According to another embodiment, each unit of potassium citrate sustained-release tablet contains the following components: 540 mg of potassium citrate, 90 mg of carnauba wax, 9 mg of polyvinyl alcohol, 5 mg of sodium alginate, and 4 mg of magnesium stearate.

[0031] A second aspect of the present invention provides a method for preparing the potassium citrate sustained-release tablets as described above, comprising mixing potassium citrate, polyvinyl alcohol, sodium alginate, and a waxy skeleton material, granulating the mixture using a twin-screw hot-melt extruder, and then compressing the mixture using a tablet press to obtain the potassium citrate sustained-release tablets.

[0032] The present invention adopts a twin-screw hot melt extrusion granulator to replace a fluidized bed or a mixer with a heat jacket for hot melt extrusion granulation, thereby greatly simplifying the difficulty of process control and realizing a rapid and continuous granulation process.

[0033] According to some specific embodiments, the preparation method specifically comprises the following steps:

[0034] (1) crushing the potassium citrate using a crusher or a screening granulator;

[0035] (2) adding the processed potassium citrate, polyvinyl alcohol, sodium alginate, and waxy skeleton material into a mixer for premixing;

[0036] (3) adding the premixed particles into a twin-screw hot melt extrusion granulator through a feeder for hot melt extrusion granulation;

[0037] (4) further granulating the hot-melt extruded particles using a swing granulator or a screening granulator;

[0038] (5) adding the granulated particles and lubricant into a mixer and mixing them to obtain mixed particles;

[0039] (6) The mixed granules are compressed into tablets using a fully automatic high-speed tablet press to obtain the potassium citrate sustained-release tablets.

[0040] Furthermore, the mixer is a column mixer or a three-dimensional mixer.

[0041] Furthermore, the twin-screw hot melt extrusion granulator is a Process 16 Hygienic hot melt extrusion granulator.

[0042] Furthermore, the tablet press is a fully automatic high-speed tablet press.

[0043] Furthermore, the crushing process in step (1) uses a sieve of less than 1.5 mm.

[0044] Furthermore, in step (1), the rotation speed of the granulator for granulation is controlled to be 30-50 Hz.

[0045] Furthermore, in step (2), polyvinyl alcohol, sodium alginate, and carnauba wax are first mixed and granulated to obtain mixed powder 1, and then the mixed powder 1 is mixed with potassium citrate.

[0046] Furthermore, in step (3), the extrusion speed is controlled to be 100-400 rpm and the hot melt temperature is controlled to be 105-130°C.

[0047] Furthermore, in step (4), the sieve used for granulation has an aperture of 14-18 meshes.

[0048] Due to the implementation of the above technical solution, the present invention has the following advantages compared with the prior art:

[0049] The invention greatly improves the friability of the tablet and significantly reduces the risk of ethanol dose dumping of the product by adding appropriate amounts of polyvinyl alcohol and sodium alginate.

[0050] Furthermore, the present invention adopts a hot melt extrusion granulation method to improve the traditional batch production mode into a continuous production mode, which greatly reduces the difficulty and complexity of the formulation process control, significantly improves the production efficiency, and can achieve one-time continuous and rapid granulation.

[0051] In addition, during the granulation process, the screw rotates horizontally to propel the feeding, mixing, and melt granulation, which can effectively solve the common problems of material stratification, filter bag and air distribution plate blockage in wet granulation or fluidized bed granulation processes.

[0052] The material heating method has been improved from the traditional overall heating of the entire batch of materials to continuous rolling heating of local materials, which significantly improves the melting efficiency and melting effect of the wax skeleton material (making the melting contact between the API and the wax skeleton material more complete), and to a certain extent helps to further reduce the risk of product ethanol dosage dumping.

[0053] Compared with the batch melt granulation process, the hot melt extrusion continuous granulation process further improves the heating efficiency, further optimizes the granulation process, shortens the granulation time, reduces energy consumption and product trial production costs, and is more conducive to commercial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 A hot-jacketed ribbon mixer was used for the reference preparation of Comparative Example 3;

[0055] Figure 2 The twin-screw hot melt extruder used for granulation in Example 1;

[0056] Figure 3 Comparison of dissolution curves of Example 1, Example 2, and Comparative Example 3 (pH 1.0 hydrochloric acid, paddle method 50 rpm);

[0057] Figure 4 Comparison of dissolution curves of Example 1, Example 2, and Comparative Example 3 (pH 4.5 medium, paddle method 50 rpm);

[0058] Figure 5 Comparison of dissolution curves of Example 1, Example 2, and Comparative Example 3 (pH 6.8 medium, paddle method 50 rpm);

[0059] Figure 6 The dissolution curves of Example 1, Example 2 and Comparative Example 3 are compared (aqueous medium, paddle method 50 rpm). DETAILED DESCRIPTION

[0060] In order to further improve and enhance product quality (improve product friability and reduce the risk of ethanol dose dumping), appropriate amounts of polyvinyl alcohol and sodium alginate were added during the formulation design and development optimization process, which greatly improved the friability of the tablets and significantly reduced the risk of ethanol dose dumping.

[0061] Furthermore, during the process of imitating and developing potassium citrate sustained-release tablets, it was surprisingly discovered that the trial production process of this product can significantly overcome the shortcomings of the above trial production process by selecting the hot melt extrusion granulation process, and at the same time can also achieve the expected release rate and sustained-release dissolution curve. That is, the hot melt extrusion granulation process selected for this product has comprehensive advantages that other trial production processes cannot have, and has certain technical advantages in subsequent commercial promotion. The advantages of using the hot melt extrusion granulation process for this product mainly include: ① The hot melt extrusion granulation method improves the traditional batch production mode into a continuous production mode, greatly reducing the difficulty and complexity of the formulation process control, significantly improving production efficiency, and achieving one-time rapid granulation; ② During the granulation process, the screw rotates horizontally to promote feeding, mixing, and melt granulation, which can effectively solve the common problems of easy stratification of materials, filter bag and air distribution plate blockage in wet granulation or fluidized bed granulation processes; ③ The material heating method is improved from the traditional overall heating of the entire batch of materials to continuous rolling heating of local materials, which significantly improves the wax skeleton. The melting efficiency and melting effect of the material (enabling more complete melting contact between the API and the waxy skeleton material) can, to a certain extent, further reduce the risk of ethanol dose dumping of the product; ④ The hot-melt extrusion granulation process does not involve the addition of adhesives (or wetting agents), fluidized bed or oven drying processes, which not only simplifies the preparation process but also further reduces the exposure of the material and the dissolution of the API by the wetting agent; ⑤ The hot-melt extrusion granulation process improves the heating efficiency of the melt granulation process, further optimizes the granulation process, shortens the granulation time, reduces energy consumption and product trial production costs, and is more conducive to commercial production.

[0062] The present invention will be further illustrated by specific examples below, but these examples are not intended to limit the scope of protection of the present invention. Those skilled in the art may make improvements to the preparation methods and apparatus within the scope of the claims, and such improvements should also be considered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the appended claims.

[0063] In the present invention, percentages not specified are percentages by mass.

[0064] The present invention is specifically described below by way of examples, but the present invention is not limited to these examples;

[0065] Example 1: Batch 1000 pieces / batch

[0066] The prescription of this embodiment is shown in Table 1 below.

[0067] Table 1

[0068] Element Unit dose / mg Function Remark: Potassium citrate 1620 Active ingredient / Carnauba wax 270 Frame material (sustained-release inhibitor) / polyvinyl alcohol 27 adhesives Model: 4-88 Sodium alginate 15 disintegrants / magnesium stearate 12 lubricant /

[0069] Preparation method:

[0070] Pretreatment: Use a granulator to pass potassium citrate through a 1.5 mm sieve and granulate it three times (granulator speed 30-50 Hz). Weigh other related excipients according to the prescribed amount and set aside.

[0071] Premix 1: Add polyvinyl alcohol, sodium alginate, and carnauba wax to an SHR-10 laboratory mixer in sequence, mix at 6 rpm for 15 minutes, pass through a 1.0 mm sieve granulator, and continue mixing in the SHR-10 laboratory mixer at 6 rpm for 15 minutes to obtain mixed powder 1;

[0072] Premix 2: Add potassium citrate and powder mix 1 into an SHR-10 laboratory mixer in sequence and mix at 6 rpm for 20 min to obtain powder mix 2.

[0073] Hot melt extrusion granulation: The mixed powder 2 is evenly added to the hot melt extrusion granulator through a feeder, the screw feeding speed is controlled at 100-400 rpm, the hot melt temperature is 105-130°C, and continuous hot melt extrusion granulation is performed to obtain granules 3;

[0074] Granulation: Granule 3 was granulated once using an oscillating granulator (16-mesh sieve) to obtain Granule 4;

[0075] Total mixing: Add the prepared granules 4 and magnesium stearate into an SHR-10 laboratory mixer and mix at 6 rpm for 10 min to obtain a total mixed powder;

[0076] Tablet Compression: The powder mix is ​​added to the tablet press hopper and tablets are compressed using a GZP-8 fully automatic high-speed tablet press (standard tablet weight = labeled weight / total mixed particle content). A dedicated die for potassium citrate sustained-release tablets (oval die, long diameter 20.4mm, short diameter 10.8mm) is used. After adding the materials, tableting parameters are adjusted and the machine is commissioned. Once the raw tablets meet the in-process control indicators (raw tablet intermediate quality control: pale yellow tablets, smooth surface, no discoloration, no pitting, and no defects; weight variation ±5%; average hardness range of 10 tablets: 150 ± 20N; friability loss ≤ 1.0%; no broken, cracked, or crushed tablets). Tablet compression officially begins. All indicators are monitored throughout the tableting process. The tableting speed is controlled within the range of 10,000-30,000 tablets / hour; the tableting pressure is controlled between 3 and 7 kN; and the feeding frequency is controlled between 20 and 40 Hz. The weight difference is ±5%; the average hardness of 10 tablets is 150 ± 25 N. Tabletting gives potassium citrate sustained-release tablets.

[0077] Example 2: Batch 1000 pieces / batch

[0078] The prescription of this embodiment is shown in Table 2 below.

[0079] Table 2

[0080] Element Unit dose / mg Function Remark: Potassium citrate 1620 Active ingredient / Carnauba wax 270 Frame material (sustained-release inhibitor) / polyvinyl alcohol 15 adhesives Model: 4-88 Sodium alginate 27 disintegrants / magnesium stearate 12 lubricant /

[0081] Preparation method:

[0082] Pretreatment: Use a granulator to pass potassium citrate through a 1.5 mm sieve and granulate it three times (granulator speed 30-50 Hz). Weigh other related excipients according to the prescribed amount and set aside.

[0083] Premix 1: Add polyvinyl alcohol, sodium alginate, and carnauba wax to an SHR-10 laboratory mixer in sequence, mix at 6 rpm for 15 minutes, pass through a 1.0 mm sieve granulator, and continue mixing in the SHR-10 laboratory mixer at 6 rpm for 15 minutes to obtain mixed powder 1;

[0084] Premix 2: Add potassium citrate and powder mix 1 into an SHR-10 laboratory mixer in sequence and mix at 6 rpm for 20 min to obtain powder mix 2.

[0085] Hot melt extrusion granulation: The mixed powder 2 is evenly added to the hot melt extrusion granulator through a feeder, the screw feeding speed is controlled at 100-400 rpm, the hot melt temperature is 105-130°C, and continuous hot melt extrusion granulation is performed to obtain granules 3;

[0086] Granulation: Granule 3 was granulated once using an oscillating granulator (16-mesh sieve) to obtain Granule 4;

[0087] Total mixing: Add the prepared granules 4 and magnesium stearate into an SHR-10 laboratory mixer and mix at 6 rpm for 10 min to obtain a total mixed powder;

[0088] Tabletting: The powder mix is ​​added to the tablet press hopper and compressed using a GZP-8 fully automatic high-speed tablet press (standard tablet weight = labeled weight / total mixed particle content). Use a dedicated die for potassium citrate sustained-release tablets (oval die; long diameter 20.4mm, short diameter 10.8mm). After adding the materials, adjust the tableting parameters and start the machine for commissioning. Once the tablets meet the in-process control indicators, tableting officially begins. All parameters are monitored during the tableting process. The tableting speed is controlled within a range of 10,000-30,000 tablets / hour; the tableting pressure is controlled between 3 and 7 kN; and the feed frequency is controlled between 20 and 40 Hz. Weight variation is ±5%; the average hardness of 10 tablets is 150 ± 25 N. Potassium citrate sustained-release tablets are obtained after tableting.

[0089] Example 3: Batch 1000 pieces / batch

[0090] The prescription of this embodiment is shown in Table 3 below.

[0091] Table 3

[0092] Element Unit dose / mg Function Remark: Potassium citrate 1620 Active ingredient / Carnauba wax 270 Frame material (sustained-release inhibitor) / polyvinyl alcohol 27 adhesives Model: 4-88 Sodium alginate 15 disintegrants / magnesium stearate 12 lubricant /

[0093] Preparation method:

[0094] Pretreatment: Use a granulator to pass potassium citrate through a 1.5 mm sieve and granulate it three times (granulator speed 30-50 Hz). Weigh other related excipients according to the prescribed amount and set aside.

[0095] Premix 1: Add polyvinyl alcohol, sodium alginate, and carnauba wax to an SHR-10 laboratory mixer in sequence, mix at 6 rpm for 15 minutes, pass through a 1.0 mm sieve granulator, and continue mixing in the SHR-10 laboratory mixer at 6 rpm for 15 minutes to obtain mixed powder 1;

[0096] Premix 2: Add potassium citrate and powder mix 1 into an SHR-10 laboratory mixer in sequence and mix at 6 rpm for 20 min to obtain powder mix 2.

[0097] Fluidized bed granulation: Add powder mixture 1 to the FBM-200E fluidized bed for granulation. Set the exhaust frequency conversion to 35%-70% and the inlet air temperature range to 90-120°C. When the material temperature reaches 95-105°C, continue drying and heat preservation for about 1.5 hours before discharging to obtain granules 3.

[0098] Granulation: Granule 3 was granulated once using an oscillating granulator (16-mesh sieve) to obtain Granule 4;

[0099] Total mixing: Add the prepared granules 4 and magnesium stearate into an SHR-10 laboratory mixer and mix at 6 rpm for 10 min to obtain a total mixed powder;

[0100] Tabletting: The powder mix is ​​added to the tablet press hopper and compressed using a GZP-8 fully automatic high-speed tablet press (standard tablet weight = labeled weight / total mixed particle content). Use a dedicated die for potassium citrate sustained-release tablets (oval die, long diameter 20.4mm, short diameter 10.8mm). After adding the materials, adjust the tableting parameters and start the machine for commissioning. Once the tablets meet the in-process control indicators, tableting officially begins. All parameters are monitored during the tableting process. The tableting speed is controlled within a range of 10,000-30,000 tablets / hour; the tableting pressure is controlled between 3 and 7 kN; and the feed frequency is controlled between 20 and 40 Hz. Weight variation is ±5%; the average hardness of 10 tablets is 150 ± 25 N. Potassium citrate sustained-release tablets are obtained after tableting.

[0101] Comparative Example 1: Batch 1000 pieces / batch

[0102] The prescription of this comparative example is shown in Table 4 below.

[0103] Table 4

[0104] Element Unit dose / mg Function Remark: Potassium citrate 1620 Active ingredient / Carnauba wax 312 Frame material (sustained-release inhibitor) / magnesium stearate 12 lubricant /

[0105] Preparation method:

[0106] Preparation: Potassium citrate was crushed and sieved through a 1.5 mm screen, and the other related excipients were weighed according to the prescription amount.

[0107] Premixing: Potassium citrate and carnauba wax were sequentially added to a SHR-10 experimental mixer, mixed at 6 rpm for 15 min, sieved through a 2.0 mm screen, and then mixed in the SHR-10 experimental mixer at 6 rpm for 20 min to obtain a mixed powder.

[0108] Hot melt extrusion granulation: The mixed powder was uniformly fed into a Process 16 Hygienic hot melt extrusion granulator, the screw feed speed was controlled at 100-400 rpm, and the hot melt temperature was controlled at 105-130°C, to perform continuous hot melt extrusion granulation to obtain granules 1.

[0109] Granulation: The granules 1 were sieved through a swing granulator (16 mesh screen) for one pass to obtain granules 2.

[0110] Total mixing: The prepared granules 2 and magnesium stearate were added to a SHR-10 experimental mixer, mixed at 6 rpm for 10 min to obtain a total mixed powder.

[0111] Tabletting: The total mixed powder was added to the hopper of a tablet press, and a GZP-8 type full-automatic high-speed tablet press was used for tabletting (standard tablet weight = marked amount / total mixed granule content). The die was a special mold for potassium citrate sustained-release tablets (die: oval punch; major diameter 20.4 mm, minor diameter 10.8 mm). After adding the material, the tabletting parameters were adjusted, the machine was started and debugged, and the control indicators of the blank tablets were qualified before formal tabletting. The indicators were monitored during tabletting. The tabletting speed was controlled in the range of 100,000-300,000 tablets / hour, the tabletting pressure was controlled at 3-7 kN, and the feed frequency was controlled at 20-40 Hz. The weight difference was ±5%, and the average hardness of 10 tablets was 150±25 N. The potassium citrate sustained-release tablets were obtained by tabletting.

[0112] Comparative Example 2: 1000 tablets / batch

[0113] The prescription of this comparative example is shown in Table 5 below.

[0114] Table 5

[0115] Element Unit dose / mg Function Remark: Potassium citrate 1620 Active ingredient / Carnauba wax 312 Frame material (sustained-release inhibitor) / magnesium stearate 12 lubricant /

[0116] Preparation method:

[0117] Preparation: Potassium citrate was crushed and sieved through a 1.5 mm screen, and the other related excipients were weighed according to the prescription amount.

[0118] Premixing: Potassium citrate and carnauba wax were added to an SHR-10 laboratory mixer in sequence, mixed at 6 rpm for 15 minutes, passed through a 2.0 mm sieve granulator, and then mixed in an SHR-10 laboratory mixer at 6 rpm for 20 minutes to obtain mixed powder 1;

[0119] Fluidized bed granulation: Add powder mixture 1 to the FBM-200E fluidized bed for granulation. Set the exhaust frequency conversion to 35%-70% and the inlet air temperature range to 90-120°C. When the material temperature reaches 95-105°C, continue drying and heat preservation for about 1.5 hours before discharging to obtain granules 2.

[0120] Granulation: Granule 2 was granulated once using an oscillating granulator (16-mesh sieve) to obtain Granule 3;

[0121] Total mixing: Add the prepared granules 3 and magnesium stearate into an SHR-10 laboratory mixer and mix at 6 rpm for 10 min to obtain a total mixed powder;

[0122] Tabletting: The powder mix is ​​added to the tablet press hopper and compressed using a GZP-8 fully automatic high-speed tablet press (standard tablet weight = labeled weight / total mixed particle content). Use a dedicated die for potassium citrate sustained-release tablets (oval die; long diameter 20.4mm, short diameter 10.8mm). After adding the materials, adjust the tableting parameters and start the machine for commissioning. Once the tablets meet the in-process control indicators, tableting officially begins. All parameters are monitored during the tableting process. The tableting speed is controlled within a range of 10,000-30,000 tablets / hour; the tableting pressure is controlled between 3 and 7 kN; and the feed frequency is controlled between 20 and 40 Hz. Weight variation is ±5%; the average hardness of 10 tablets is 150 ± 25 N. Potassium citrate sustained-release tablets are obtained after tableting.

[0123] Comparative Example 3: Reference preparation: Trade name: Urocit-K, batch number 22M052; specification 1.62 g; manufacturer: Mission Pharma, USA.

[0124] Relevant properties of each embodiment, comparative example and 22M052 batch of reference preparations were measured, and the measurement results are detailed in the table below. Among them, Table 6 is the particle size distribution after API pretreatment; Table 7 is a summary of the test results of the prepared potassium citrate sustained-release tablet intermediates or finished products; Table 8 is the ethanol dose dumping test results of the potassium citrate sustained-release tablets of Comparative Example 3; Table 9 is the ethanol dose dumping test results of the potassium citrate sustained-release tablets prepared in Example 1; Table 10 is the ethanol dose dumping test results of the potassium citrate sustained-release tablets prepared in Example 2; Table 11 is the ethanol dose dumping test results of the potassium citrate sustained-release tablets prepared in Comparative Example 1; Table 12 is a summary table of the dissolution of the potassium citrate sustained-release tablets of Example 1, Example 2 and Comparative Example 3 in different media.

[0125] Table 6

[0126] API particle size distribution D10(μm) D50(μm) D90(μm) Example 1 148.2 448.8 849.0 Example 2 116.0 432.5 812.9 Example 3 126.7 409.8 807.6 Comparative Example 1 125.9 438.1 821.9 Comparative Example 2 133.3 459.6 819.2

[0127] Table 7

[0128]

[0129]

[0130] Table 8

[0131]

[0132] Table 9

[0133]

[0134]

[0135] Table 10

[0136]

[0137] Table 11

[0138]

[0139]

[0140] Table 12

[0141]

[0142]

[0143]

[0144] The above test results show that in pH 1.0 medium, pH 4.5 medium, pH 6.8 medium and water, the dissolution curves of the preparations of Examples 1 and 2 and the reference preparation have F2 values ​​≥ 50, and the dissolution curves are consistent.

[0145] Selection of ethanol dose dumping dissolution conditions: dissolution medium: 0.1 mol / L hydrochloric acid; medium volume: 900 mL; dissolution method: paddle method, 50 rpm; ethanol addition concentration: 0%, 5%, 20%, 40%.

[0146] The quality standards (or in-process quality standards) based on or formulated for the examples and comparative examples are shown in Table 13.

[0147] Table 13

[0148]

[0149]

[0150] Comparing the trial production results of Example 1 (Example 2, Example 3) with those of Comparative Example 1, it was found that when polyvinyl alcohol and sodium alginate were added to the prescription, the friability of the trial-produced tablets was significantly improved (decreased from 2.79% to <1.0%, in line with the provisions of the Chinese Pharmacopoeia); Comparing the trial production results of Example 1 (Example 2) with Comparative Example 2 and Example 3, it was found that, compared with the trial production products of the fluidized bed granulation process, the trial production products of the hot melt extrusion granulation process had better mixing uniformity of the total mixed particles and greatly reduced granulation time; at the same time, comparing the trial production results of Example 1 (Example 2) with Comparative Example 3 (reference preparation), it was found that the friability of the trial-produced tablets was significantly improved (decreased from 3.97% to about 0.7%, <1.0%, in line with the provisions of the Chinese Pharmacopoeia). Comparative Example 1 (Example 2) and Comparative Example 3 sample trial-production results found that, after adjusting the formulation formula and changing the reference preparation ribbon mixer melting granulation process to hot melt extrusion granulation process, this product ethanol dosage dumping phenomenon is greatly improved, but there is still slight ethanol dosage dumping phenomenon, illustrate that hot melt extrusion granulation process can improve the melting efficiency and the melting effect of wax slow-release material to a certain extent (making API and wax slow-release material melting contact more abundant), be conducive to lower product ethanol dosage dumping risk to a certain extent, significantly improve granulation efficiency simultaneously, simplify granulation process, shorten granulation time. Comparative Example 1 (Example 2) and Comparative Example 2 and Example 3 sample trial-production results found that this product trial-production process is changed to hot melt extrusion granulation process and can greatly overcome fluidized bed granulation and have shortcomings (such as: granulation heating time is long, material easy stratification causes mixing uniformity difference, air flow distribution plate and filter bag common blocking problem). Meanwhile on the basis of hot melt extrusion granulation process, by prescription optimization, after adding (polyvinyl alcohol, sodium alginate), this product ethanol dosage dumping risk is eliminated.

[0151] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and does not limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A potassium citrate sustained-release tablet comprising potassium citrate and a waxy skeleton material, characterized in that: The potassium citrate sustained-release tablet further comprises polyvinyl alcohol and sodium alginate.

2. The potassium citrate sustained-release tablet according to claim 1, characterized in that: The polyvinyl alcohol accounts for 0.5%-1.5% of the total mass of the potassium citrate sustained-release tablet, and the sodium alginate accounts for 0.5%-1.5% of the total mass of the potassium citrate sustained-release tablet.

3. The potassium citrate sustained-release tablet according to claim 1, characterized in that: The mass ratio of the polyvinyl alcohol to the sodium alginate is 1:0.5-2.

4. The potassium citrate sustained-release tablet according to any one of claims 1 to 3, characterized in that: The model of the polyvinyl alcohol is polyvinyl alcohol 4-88.

5. The potassium citrate sustained-release tablet according to claim 1, characterized in that: The mass of the potassium citrate in the potassium citrate sustained-release tablet is 0.54 g / tablet to 1.62 g / tablet; the particle size of the potassium citrate is D50≤500 μm and D90≤900 μm.

6. The potassium citrate sustained-release tablet according to claim 1, characterized in that: The waxy skeleton material is one or more of carnauba wax, insect wax and synthetic wax; the potassium citrate sustained-release tablet also includes a lubricant.

7. The potassium citrate sustained-release tablet according to claim 7, characterized in that: The wax skeleton material is carnauba wax; the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide and sodium lauryl sulfate.

8. The potassium citrate sustained-release tablet according to claim 6, characterized in that: The waxy skeleton material accounts for 10%-15% of the total mass of the potassium citrate sustained-release tablet, and the lubricant accounts for 0.4%-1% of the total mass of the potassium citrate sustained-release tablet.

9. A method for preparing the potassium citrate sustained-release tablets according to any one of claims 1 to 8, characterized in that: Potassium citrate, polyvinyl alcohol, sodium alginate and a waxy skeleton material are mixed, granulated by a twin-screw hot melt extruder, and then compressed by a tablet press to obtain the potassium citrate sustained-release tablet.

10. The method for preparing the potassium citrate sustained-release tablets according to claim 9, wherein: The preparation method specifically comprises the following steps: The potassium citrate is crushed by a crusher or a screening granulator; Add the processed potassium citrate, polyvinyl alcohol, sodium alginate and waxy skeleton material into a mixer for premixing; The premixed particles are fed into a twin-screw hot melt extrusion granulator through a feeder for hot melt extrusion granulation; The hot melt extruded particles are further granulated using an oscillating granulator or a screening granulator; Add the granulated particles and lubricant into a mixer and mix them to obtain mixed particles; The mixed granules are compressed into tablets using a fully automatic high-speed tablet press to obtain the potassium citrate sustained-release tablets.

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