A kind of potassium chloride sustained-release micropill and its preparation method and application

Abstract

The present invention relates to the field of drug sustained-release and controlled-release preparations, and in particular to a potassium chloride sustained-release micro-pill and a preparation method and application thereof, wherein the potassium chloride sustained-release micro-pill comprises a potassium chloride pellet and a sustained-release coating layer coated on the outside of the potassium chloride pellet; wherein the potassium chloride pellet comprises an irregularly shaped potassium chloride crystal mother core located at the center and potassium chloride powder attached to the surface of the potassium chloride crystal mother core by a binder; the roundness of the potassium chloride sustained-release micro-pill is greater than 85%, and it is released according to the first-order rate law during the release process. The present application replaces the sugar pill as the mother core with potassium chloride crystals, and can avoid the addition of excipients such as sucrose, starch, and dextrin while effectively increasing the content of potassium chloride, so that the potassium chloride sustained-release micro-pill can be suitable for people with metabolic disorders, and the preparation process of the potassium chloride sustained-release micro-pill is shortened.

Description

Technical Field

[0001] The invention relates to the field of drug sustained-release and controlled-release preparations, and in particular to potassium chloride sustained-release micropills and a preparation method and application thereof. Background Art

[0002] Potassium is one of the important inorganic cations in the human body. Potassium can maintain the excitability of cells, the osmotic pressure inside and outside cells, and the acid-base balance. It can also regulate cell metabolism and is an indispensable element for the body. Potassium supplementation is mainly for hypokalemia. If the body lacks potassium, it is easy to cause hypokalemia, resulting in symptoms such as numbness of the limbs, general fatigue, or decreased appetite. If not treated in time, it will also cause breathing difficulties, chest tightness and shortness of breath, and even arrhythmia, which will cause great harm to the body. In this case, potassium supplementation treatment is needed in a timely manner.

[0003] Currently, the main treatment for hypokalemia is potassium supplementation through infusion. However, if the infusion speed is too fast or the concentration is too high during the potassium supplementation process, it will irritate the blood vessels, causing severe pain, and in severe cases, phlebitis. In order to reduce the above adverse reactions, it is usually necessary to control the infusion speed and concentration, which leads to the problem that the potassium supplementation time is usually longer.

[0004] Therefore, there are some solutions in the prior art for treating hypokalemia using potassium chloride sustained-release granules (potassium chloride sustained-release tablets and sustained-release capsules). These solutions can effectively avoid the negative effects of potassium supplementation during infusion by slowly releasing potassium chloride in the digestive system during use.

[0005] Regarding potassium chloride sustained-release granules, the following patents are currently available:

[0006] CN104873473A discloses a potassium chloride sustained-release tablet and a preparation method thereof, wherein the preparation is directly compressed into tablets by gastric-soluble sustained-release pellets, enteric-soluble sustained-release pellets and other pharmaceutically acceptable excipients, wherein the gastric-soluble sustained-release pellets are composed of potassium chloride, mesoporous carbon, acrylic resin IV and surfactant, and the enteric-soluble sustained-release pellets are composed of potassium chloride, mesoporous carbon, acrylic resin I-III and surfactant. However, the process in the patent requires the use of a relatively large variety of excipients, and the process is to prepare sustained-release pellets and then compress them into tablets, so the entire process is relatively complicated, the process is long, and it is labor-consuming and time-consuming.

[0007] CN103006696B discloses a method for preparing a potassium chloride sustained-release tablet, wherein the granulation ingredients of the potassium chloride sustained-release tablet are: potassium chloride, hydroxypropyl methylcellulose E (E5), lactose, hydroxypropyl methylcellulose (E15) and microcrystalline cellulose; the film coating ingredients are: acrylic resin (RS100), acrylic resin (RL100), fine talcum powder, triethyl citrate (TEC), 95% ethanol; the sugar coating ingredients are: sucrose, gelatin, talcum powder and purified water. In the preparation process, potassium chloride and auxiliary materials are crushed, mixed, wet granulated, dried, granulated, tableted and coated in sequence to finally prepare potassium chloride sustained-release tablets. The tablet involves 15 categories, and the sustained-release tablet may have a burst release. For the elderly, especially those with slow intestinal peristalsis, it may stick to the intestinal wall and cause damage.

[0008] CN102961363A discloses a potassium chloride sustained-release capsule, the content of which is a sustained-release micro-pill, which is composed of 70-97% potassium chloride as an auxiliary material, 0-10% as a molding material, 2-20% as a sustained-release material, 0.5-5% as a plasticizer, and 0-10% as an anti-adherent agent in weight percentage. The process in this patent adopts an extrusion spheronization method, and the yield of a single pellet is low. After drying and sieving, it needs to be squeezed again, which prolongs the time of the process and requires repeated extrusion to become a finished product, which does not meet the GMP requirements. In addition, the process of CN102961363A also uses ethanol as a solvent, so there are potential safety hazards, and anti-riot facilities are required. For serious air pollution, environmental protection measures are required.

[0009] Therefore, although potassium chloride sustained-release granules can avoid some problems caused by potassium supplementation by infusion, they also introduce defects such as uneven drug dispersion leading to excessive local drug concentration and excessive retention time of drug granules in the upper gastrointestinal tract.

[0010] On this basis, the authorization announcement number is CN 107823189 B. This patent uses sugar pills as masterbatch and adds potassium chloride to make potassium chloride pellets, which are then coated to make sustained-release pellets. The sugar pills are composed of sucrose, starch, and dextrin and are made through the processes of crushing-mixing-granulation drying-screening and the like.

[0011] Compared with common granules, potassium chloride sustained-release pellets have three major advantages. On the one hand, the uniform dispersion of drugs in small-dose units can reduce the irritation to the gastric mucosa caused by excessive local drug concentration; on the other hand, the concentrated active ingredients can also make the blood drug concentration quickly reach the therapeutic concentration to improve the drug absorption rate and maintain the drug release rate, thereby improving bioavailability; on the third hand, the pellets can make the drug empty from the stomach as quickly as possible to avoid being affected by the patient's diet, and also reduce the effect of gastric emptying rate on the retention time of pellets in the upper gastrointestinal tract, thereby reducing the intra-individual and inter-individual differences in blood drug concentration and ensuring uniform absorption.

[0012] However, the potassium chloride sustained-release micropills in the patent use sugar pills with a high sucrose content as the mother core, but sucrose is not good for obese and diabetic patients. Therefore, this type of potassium chloride sustained-release micropills cannot be used for obese and diabetic patients. In addition, the potassium chloride sustained-release micropills use too many types of auxiliary materials in the preparation process and the process route is long, so the preparation process is often time-consuming and labor-intensive. Summary of the invention

[0013] The present invention aims to overcome the defects of potassium chloride sustained-release micropills in the prior art, such as low potassium chloride content, many types of auxiliary materials, long process route and limited user population, and provides a potassium chloride sustained-release micropill and a preparation method and application thereof to overcome the above-mentioned shortcomings.

[0014] To solve the above shortcomings, the present invention is implemented through the following technical solutions:

[0015] In a first aspect, the present invention first provides a potassium chloride sustained-release pellet.

[0016] It comprises potassium chloride pellets and a sustained-release coating layer coated on the outside of the potassium chloride pellets; wherein,

[0017] The potassium chloride pellets include an irregularly shaped potassium chloride crystal mother core located at the center and potassium chloride powder attached to the surface of the potassium chloride crystal mother core by a binder;

[0018] The potassium chloride sustained-release micropellets have a roundness >85%, and are released according to a first-order rate rule during the release process.

[0019] Compared with the potassium chloride sustained-release microcapsules with sucrose pellets as the mother core, the potassium chloride sustained-release microcapsules in the present application use potassium chloride crystals as the mother core of the sustained-release microcapsules, thereby avoiding the addition of auxiliary materials such as sucrose, starch, and dextrin. At the same time, the potassium chloride sustained-release microcapsules can be suitable for people with metabolic disorders (such as obese people and diabetics), thereby expanding the application population and the scope of application.

[0020] Secondly, the present application uses potassium chloride crystals instead of sugar pills as the mother core, which can also effectively increase the potassium chloride content, and can increase the potassium chloride content in the potassium chloride sustained-release pellets from 88.5% to 92.5%, thereby being suitable for the preparation of potassium chloride compound preparations and facilitating the tableting of micropills.

[0021] At the same time, since the addition of sugar pills is avoided, the production process required for making sugar pills in the sugar pill production process can be eliminated, thereby shortening the process of potassium chloride sustained-release pellets.

[0022] Finally, the applicant unexpectedly discovered during the experiment that the shape of the mother core inside the sustained-release microcapsules has an important influence on the morphology of the final sustained-release microcapsules and the release pattern of the sustained-release microcapsules.

[0023] Generally speaking, the closer the shape of the mother core is to a sphere, the more evenly the powder will adhere to its surface, making the final sustained-release microcapsules closer to a sphere, which is manifested in a higher roundness. The higher roundness and smoother surface enable the sustained-release microcapsules to follow the first-order rate release during the drug release process, which is more in line with the law of pharmacokinetic.

[0024] The more irregular the shape of the mother core is, the worse the roundness of the sustained-release microcapsules will be. There will often be edges and bumps on the surface, which will lead to uneven distribution of the drug powder inside. As a result, the drug release rate will not follow the law of first-order rate release during the drug release process, resulting in premature release or sudden release, which is unacceptable for sustained-release drugs.

[0025] However, although the potassium chloride crystal mother core at the center of the potassium chloride sustained-release micropellets in the present application is an irregular shape approximating a rectangular parallelepiped or a cube, the potassium chloride sustained-release micropellets in the present application can still ensure the actual effect of roundness>85%, and the potassium chloride release rate can still follow the law of first-order rate release, which obviously subverts the traditional cognition and achieves unexpected technical effects.

[0026] Therefore, in summary, compared with the potassium chloride sustained-release tablets and potassium chloride sustained-release pellets containing a sugar core in the prior art, the present application can not only achieve a more stable drug release effect and reduce the drug's irritation to the gastrointestinal tract, but also reduce the addition of sucrose and other excipients, thereby being suitable for people with metabolic disorders, expanding its scope of application, simplifying its process route, and reducing the difficulty of preparation.

[0027] Preferably, the cross-section of the potassium chloride crystal mother nucleus is a rounded rectangle, and the ratio of the length of its arc side to the adjacent straight side is ≥0.3.

[0028] Conventional potassium chloride crystals are usually square or rectangular crystals under microscope observation, and have water chestnuts or right angles at the edges. The presence of these edges and corners will cause the adhesive to be difficult to spread during the preparation of potassium chloride pellets, resulting in the inability of potassium chloride powder to evenly adhere to the surface of potassium chloride crystals, resulting in the inability to obtain sustained-release pellets with higher roundness. Therefore, in order to improve the uniform combination between the potassium chloride crystal mother core and the potassium chloride powder in the present application, the potassium chloride crystal mother core is first chamfered to a certain extent, so that its edges and corners are transformed from the original sharp edges and corners to arc-shaped edges with radians, thereby greatly improving the uniformity of the combination with the powder, and finally making the roundness of the potassium chloride sustained-release pellets meet the established requirements.

[0029] Preferably, the potassium chloride powder comprises potassium chloride powder and a powdered diluent.

[0030] The potassium chloride powder layer coated on the outside of the pill core of the potassium chloride sustained-release pellets in the prior art usually only contains potassium chloride powder and a binder, and the binder needs to be prepared into a solution before use. In addition to potassium chloride powder and a binder, a certain amount of powdered diluent is added to the potassium chloride powder layer in the present application, so that the potassium chloride powder layer can be bonded to the surface of the potassium chloride crystal mother core.

[0031] The reason is that the prior art is different from the present application in two aspects: (1) The types of pellet cores used in the prior art and the present application are different. The sucrose pellet core used in the prior art has a certain degree of adhesiveness and surface roughness, so the potassium chloride powder can be directly bonded to the sucrose pellet core through a binder. However, the potassium chloride crystal mother core used in the present application has a lower surface roughness and does not have adhesiveness. Therefore, it is difficult for pure potassium chloride powder to be directly bonded to the potassium chloride crystal mother core through a binder. Even if the content of the binder is forcibly increased, the roundness and surface roughness of the obtained potassium chloride pellets will inevitably deteriorate. (2) The sucrose pellet core used in the prior art is spherical, so the potassium chloride powder can be evenly distributed on the surface of the sucrose pellet core. However, since the structure of the potassium chloride crystal mother core of the present application is irregular, it is impossible to make the obtained potassium chloride pellets have a higher roundness by simply using potassium chloride powder and a binder.

[0032] In the present application, although the potassium chloride crystal nucleus and potassium chloride powder inside the potassium chloride pellet are the same component, the compatibility between the potassium chloride crystal nucleus and the potassium chloride powder is not excellent, resulting in an uneven surface structure of the potassium chloride pellets obtained after bonding with an adhesive, resulting in a low roundness of the potassium chloride pellets. However, the inventors of the present application have found that when a certain amount of diluent is added to the potassium chloride pellets, the compatibility of the potassium chloride crystal nucleus and the potassium chloride powder can be effectively improved, thereby effectively improving the roundness of the potassium chloride sustained-release pellets, so that it can be released according to the first-order rate law during the release of potassium chloride.

[0033] Preferably, the diluent includes any one of low-substituted hydroxypropyl methylcellulose and micro-powder silica gel, or a combination of two thereof.

[0034] After checking the diluents, the applicant found that the type of diluent has an important influence on the roundness of potassium chloride pellets. Compared with other diluents, in the present application, when the diluent is selected from low-substituted hydroxypropyl methylcellulose and micro-powder silica gel, it can achieve better results.

[0035] Preferably, the mass ratio of the potassium chloride powder to the diluent is 85-99:15-1.

[0036] Preferably, the binder is a combination of one or more of water, ethanol solution, low-substituted hydroxypropyl methylcellulose solution, and colloidal silicon dioxide aqueous solution.

[0037] Preferably, the potassium chloride content in the potassium chloride sustained-release pellets is 88.5%-92.5%.

[0038] Preferably, the diameter of the potassium chloride pellets is 0.5-1.4 mm.

[0039] Preferably, the sustained-release coating layer is composed of an isolation layer, a sustained-release layer and a color coating layer in sequence.

[0040] Preferably, the mass of the sustained-release coating layer is 3%-4.8% of the mass of the potassium chloride pellets.

[0041] In a second aspect, the present application also provides a method for preparing the potassium chloride sustained-release pellets as described above, comprising the following steps:

[0042] (S.1) sieving potassium chloride crystals to obtain potassium chloride crystal mother nuclei;

[0043] (S.2) adding potassium chloride crystal core, binder and potassium chloride powder into a centrifugal granulator in sequence, thereby forming a potassium chloride powder layer on the surface of the potassium chloride crystal core, thereby obtaining potassium chloride pellets with a roundness of more than 85%;

[0044] (S.3) coating the surface of the potassium chloride pellets to form a sustained-release coating layer on the surface of the potassium chloride pellets to obtain the potassium chloride sustained-release micropellets.

[0045] Preferably, the step (S.2) further includes placing the potassium chloride crystal mother core in a centrifugal granulator for chamfering.

[0046] The potassium chloride sustained-release micro-pellets in the present application first undergo a screening step for potassium chloride crystals during the preparation process. Since the potassium chloride crystals after screening have many edges and corners on their surface, they are not suitable for preparing potassium chloride pellets. Therefore, the present application performs a chamfering step after the potassium chloride crystals are screened, so that the edges and corners of the potassium chloride crystals are transformed from the original sharp edges and corners to arc-shaped edges with a radian, thereby greatly improving the uniformity of the combination with the powder, and finally making the roundness of the potassium chloride sustained-release micro-pellets meet the established requirements.

[0047] Preferably, during the chamfering process in (S.2), the rotation speed of the centrifugal granulator is 35-55 rpm, and the chamfering time is 5-17 minutes.

[0048] In this application, the applicant found through experiments that the rotation speed of the centrifugal granulator has an impact on the angle of potassium chloride crystals. When the rotation speed of the centrifugal granulator is 35-55 rpm and the chamfering time is 5-17 minutes, the potassium chloride crystals can reach the required range.

[0049] Preferably, the blast air volume of the centrifugal granulator is controlled at 5-10HZ, and the air source pressure is controlled at 0.03-0.6MPa.

[0050] Preferably, the (S.3) further comprises the step of mixing potassium chloride powder and a diluent to form potassium chloride powder.

[0051] Preferably, the spraying speed of the binder and potassium chloride powder in (S.3) is controlled at 0-200 r / min.

[0052] Preferably, the coating step in (S.4) comprises the steps of sequentially forming an isolation layer, a sustained-release layer and a color coating layer on the surface of the potassium chloride pellets.

[0053] In a third aspect, the present invention also provides the use of the potassium chloride sustained-release pellets as described above in the preparation of hypokalemia drugs or potassium chloride sustained-release tablets.

[0054] Therefore, the present invention has the following beneficial effects:

[0055] (1) This application uses potassium chloride crystals to replace sugar pellets as the mother core, which can effectively increase the content of potassium chloride and avoid the addition of auxiliary materials such as sucrose, starch, and dextrin, so that potassium chloride sustained-release micropellets can be suitable for people with metabolic disorders (such as obese people and diabetics), thereby expanding the application range and the scope of application;

[0056] (2) The production process required for making sugar pills in the sugar pill production process was eliminated, thereby shortening the preparation process of potassium chloride sustained-release pellets;

[0057] (3) After using irregular potassium chloride crystals, they can still maintain good roundness, avoiding the uneven distribution of internal drug powder, so that the potassium chloride release rate can still follow the law of first-order rate release. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 This is a schematic diagram of the structure of the potassium chloride sustained-release pellets prepared in this application.

[0059] Figure 2 This is a magnified microscope photo of potassium chloride raw material.

[0060] Figure 3 This is a microscope magnified photo of potassium chloride raw material and after chamfering for 5 minutes at 50 rpm in a coating granulator.

[0061] Figure 4 This is a microscope magnified photo of potassium chloride raw material and after chamfering for 11 minutes at 50 rpm in a coating granulator.

[0062] Figure 5 This is a microscope magnified photo of potassium chloride raw material and after chamfering in a coating granulator at 50 rpm for 15 minutes.

[0063] Figure 6 is a microscope photograph of potassium chloride pellet 10.

[0064] Figure 7 The comparative release curves of the prepared potassium chloride sustained-release micropellets No. 4 and No. 5.

[0065] Among them: 1. Potassium chloride crystals, 2. Potassium chloride powder layer, 3. Isolation layer, 4. Sustained release layer, 5. Color coating layer. DETAILED DESCRIPTION

[0066] The present invention is further described below in conjunction with specific embodiments. Those of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.

[0067] Example 1

[0068] like Figure 1 As shown, the present application provides a potassium chloride sustained-release micropill, whose structure includes potassium chloride crystals 1, a potassium chloride powder layer 2, an isolation layer 3, a sustained-release layer 4 and a color coating layer 5 from the inside to the outside.

[0069] The preparation method comprises the following steps:

[0070]

Preparation of Potassium Chloride Crystal Core

[0071] When potassium chloride crystals are observed under a microscope, they are square or rectangular crystals with right angles, while sugar pills are spherical. Generally speaking, the spherical mother nucleus is easy to spread when preparing potassium chloride pellets, and the powder bonding is relatively uniform. Therefore, the present application first screens potassium chloride crystals, and then removes the edges and corners of the potassium chloride crystals into a radian type through chamfering treatment of a centrifugal granulator.

[0072] Specifically, different rotation speeds of 30 rpm, 35 rpm, 40 rpm, 45 rpm, and 50 rpm were designed for the potassium chloride crystals in the coating granulator for 5 minutes. The right-angle metamorphosis of the potassium chloride crystals in the centrifugal granulator was observed under a microscope, and the amount of potassium chloride crystals falling in the centrifugal granulator was weighed and compared. The specific results are shown in Table 1 below.

[0073] Table 1: The amount of powder lost after chamfering of potassium chloride crystals at the same time at different speeds of centrifugal granulator

[0074] Material Name Weight (g) Coating granulator (rpm) Time (minutes) Powder loss (g) Crystal edge morphology Ratio of arc side to adjacent straight side Potassium chloride crystals1 500 30 5 0 Sharp edges - Potassium chloride crystals2 500 35 5 2 Sharp edges - Potassium chloride crystals 3 500 40 5 3 Sharp edges - Potassium chloride crystals 4 500 45 5 5 Sharp edges - Potassium chloride crystals 5 500 50 5 7 Most of them have sharp edges, and a small part is rounded. ＜0.3 Potassium chloride crystals 6 500 55 5 8 Most of them have sharp edges, and a small part is rounded. ＜0.3

[0075] The experimental results show that the friction force is small when the centrifugal granulator rotates at a low speed, and the potassium chloride crystals will not loosen. As the speed of the centrifugal granulator increases, the edges and corners of the potassium chloride crystals begin to wear, thus forming chamfers. When the speed of the centrifugal granulator is 50 rpm, the friction force is large, and the chamfering of the edges and corners of the potassium chloride crystals is aggravated, resulting in an increase in the amount of powder falling off. When the speed of the centrifugal granulator is 55 rpm, the amount of powder falling off tends to decrease. Therefore, 50 rpm is the optimal speed value for the centrifugal granulator.

[0076] Then, we took 50 rpm as the control point, and when the speed of the centrifugal granulator was , the chamfering time was set to 7 minutes, 9 minutes, 11 minutes, 13 minutes, 15 minutes, 17 minutes, etc. The specific results of the investigation are shown in Table 2 below.

[0077] Table 2 The speed of the centrifugal granulator is 50 rpm. The amount of powder falling off after chamfering potassium chloride crystals at different times of 7, 9, 11, 13, 15, and 17 minutes

[0078] Material Name Weight (g) Coating granulator (rpm) Time (minutes) Powder loss (g) Crystal edge morphology Ratio of arc side to adjacent straight side Potassium chloride crystals7 500 50 7 9 There are still a few edges and corners, most of them are rounded ＜0.3 Potassium chloride crystals8 500 50 9 12 All corners are rounded ＞0.3 Potassium chloride crystals 9 500 50 11 15 All corners are rounded ＞0.4 Potassium chloride crystals 10 500 50 13 20 All corners are rounded ＞0.4 Potassium chloride crystals 11 500 50 15 25 All corners are rounded ＞0.5 Potassium chloride crystals 12 500 50 17 25 All corners are rounded ＞0.5

[0079] The above experiments show that: With the increase of chamfering time of centrifugal granulation, the powder loss of potassium chloride crystals gradually increases, and the edge wear effect becomes more obvious. When the centrifugal granulator is at 50 rpm, the increase in powder loss when the polishing time is 17 minutes compared with 15 minutes is not obvious. Therefore, the potassium chloride crystal is set at 50 rpm and 15 minutes in the centrifugal granulator as the optimal chamfering parameter for potassium chloride crystals.

[0080] The potassium chloride raw material and the potassium chloride crystals obtained by polishing at 50 rpm for 5 minutes (potassium chloride crystal 5), 11 minutes (potassium chloride crystal 9), and 15 minutes (potassium chloride crystal 11) in a coating granulator were observed under a microscope. The magnified photos thereof under the microscope are as follows: Figure 2 , Figure 3 , Figure 4 as well as Figure 5 shown.

[0081] Preparation of potassium chloride pellets

[0082] Potassium chloride powder and a powdered diluent are prepared into potassium chloride powder, and then the potassium chloride powder is attached to the surface of a potassium chloride crystal mother core by a binder to form a potassium chloride powder layer, thereby obtaining potassium chloride pellets.

[0083] Wherein: the diluent is selected from low-substituted hydroxypropyl methylcellulose (D-HPMC-E5) and micro powder silica gel.

[0084] For comparison, ethyl cellulose, microcrystalline cellulose and polyvinyl pyrrolidone were also selected as comparative diluents to compare the roundness of potassium chloride pellets.

[0085] The binder is selected from purified water, ethanol aqueous solution, low-substituted hydroxypropyl methylcellulose aqueous solution, and colloidal silicon dioxide aqueous solution.

[0086] The mother core is selected from chamfered potassium chloride crystals 8, potassium chloride crystals 9, potassium chloride crystals 10, potassium chloride crystals 11, potassium chloride crystals 5 with imperfect chamfering, and potassium chloride crystal raw materials that have not been chamfered.

[0087] The specific steps are as follows:

[0088] 1. Grinding: Grind potassium chloride through a 100-mesh sieve to obtain potassium chloride powder;

[0089] 2. Mixing: Mix potassium chloride powder and diluent in proportion to obtain potassium chloride powder;

[0090] 3. Add potassium chloride crystals to the centrifugal granulator, start the centrifugal granulator host, open the blast, control the host turntable speed at 20HZ, and the blast air volume at 5-10HZ, the air source pressure at 0.03-0.6MPa, control the speed and chamfering time, and obtain the target potassium chloride crystal mother nucleus. Then control the speed of the peristaltic pump during spraying at 100 r / min, add the binder and potassium chloride powder at the same time, and stop supplying powder and spraying liquid when the pellets grow to the target specifications. The host polishes at a speed of 45 rpm for about 1 minute, and then discharges the material;

[0091] 4. Drying: Place the potassium chloride pellets prepared above in a boiling dryer for drying. Turn on the heating switch, set the air inlet temperature to 105℃±5℃, record the start time of heating, and the drying time is 30-50 minutes.

[0092] 5. The potassium chloride pellets were obtained by sieving, and the corresponding production size and roundness of the potassium chloride pellets were examined.

[0093] Among them, the roundness test method is as follows:

[0094] 1. Spread the potassium chloride pellets evenly on a watch glass;

[0095] 2. Use a microscope (magnification 10×4 or 10×5 or 10×10) for visual observation, and take a small potassium chloride pellet with intact edges within the field of view for observation;

[0096] 3. Measure the shortest diameter and the longest diameter of the potassium chloride pellets, and calculate the roundness of the potassium chloride pellets;

[0097] The roundness calculation formula is as follows: roundness = (shortest diameter of potassium chloride pellets / longest diameter of potassium chloride pellets) × 100%.

[0098] The roundness evaluation criteria are as follows:

[0099] When the roundness is less than 80%, the rating is poor;

[0100] When 80%≤roundness<85%, the rating is poor;

[0101] When 85%≤roundness<88%, the rating is qualified;

[0102] When 88%≤roundness<90%, the rating is good;

[0103] When the roundness is ≥90%, the rating is excellent.

[0104] The specific parameter settings and comparisons are shown in Tables 3, 4, 5, 6 and 7 below:

[0105] Table 3 Experimental diluent D-HPMC-E5, formula of different types of adhesives

[0106] Potassium chloride pellet number Mother nucleus Potassium chloride powder Theoretical percentage of potassium chloride powder Thinner Adhesives Corresponding production size (mm) Corresponding size roundness 1 Potassium chloride crystals 11 Main drug: diluent 95：5 D-HPMC-E5 Aqueous solution 0.5-0.6 qualified 2 Potassium chloride crystals 11 Main drug: diluent 95：5 D-HPMC-E5 50% alcohol solution 0.5-0.6 qualified 3 Potassium chloride crystals 11 Main drug: diluent 95：5 D-HPMC-E5 1%D-HPMC-E5 0.5-0.6 qualified 4 Potassium chloride crystals 11 Main drug: diluent 95：5 D-HPMC-E5 3%D-HPMC-E5 0.8-1.0 qualified 5 Potassium chloride crystals 11 Main drug: diluent 95：5 D-HPMC-E5 2% Colloidal Silica 0.8-1.0 better 6 Potassium chloride crystals 11 Main drug: diluent 95：5 D-HPMC-E5 5% Colloidal Silica 0.8-1.1 excellent

[0107] Table 4 Experimental diluent is micro powder silica gel, formula of different types of adhesives

[0108] Potassium chloride pellet number Mother nucleus Potassium chloride powder Theoretical percentage of potassium chloride powder Thinner Adhesives Corresponding production size (mm) Corresponding size roundness 7 Potassium chloride crystals 11 Main drug: diluent 95：5 Micro powder silica gel Aqueous solution 0.5-0.6 qualified 8 Potassium chloride crystals 11 Main drug: diluent 95：5 Micro powder silica gel 50% alcohol solution 0.5-0.6 qualified 9 Potassium chloride crystals 11 Main drug: diluent 95：5 Micro powder silica gel 2% Colloidal Silica 0.5-0.6 qualified 10 Potassium chloride crystals 11 Main drug: diluent 95：5 Micro powder silica gel 5% Colloidal Silica 0.8-1.0 excellent 11 Potassium chloride crystals 11 Main drug: diluent 95：5 Micro powder silica gel 1%D-HPMC-E5 0.8-1.0 better 12 Potassium chloride crystals 11 Main drug: diluent 95：5 Micro powder silica gel 3%D-HPMC-E5 0.8-1.1 better

[0109] Table 5. Formula of the same adhesive using comparative diluents

[0110] Potassium chloride pellet number Mother nucleus Potassium chloride powder Theoretical percentage of potassium chloride powder Thinner Adhesives Corresponding production size (mm) Corresponding size roundness 13 Potassium chloride crystals 11 Main drug: diluent 95：5 Ethyl cellulose 5% Colloidal Silica 0.6-0.7 Difference 14 Potassium chloride crystals 11 Main drug: diluent 95：5 Microcrystalline Cellulose 5% Colloidal Silica 0.8-0.9 Poor 15 Potassium chloride crystals 11 Main drug: diluent 95：5 Polyvinylpyrrolidone 5% Colloidal Silica 0.6-1.4 Difference

[0111] Table 6 Formula of the same adhesive using different potassium chloride crystals

[0112] Potassium chloride pellet number Mother nucleus Potassium chloride powder Theoretical percentage of potassium chloride powder Thinner Adhesives Corresponding production size (mm) Corresponding size roundness 16 Potassium chloride crystals8 Main drug: diluent 95：5 Micro powder silica gel 5% Colloidal Silica 0.8-1.0 qualified 17 Potassium chloride crystals 9 Main drug: diluent 95：5 Micro powder silica gel 5% Colloidal Silica 0.8-1.0 better 18 Potassium chloride crystals 10 Main drug: diluent 95：5 Micro powder silica gel 5% Colloidal Silica 0.8-1.0 better 19 Potassium chloride crystals 5 Main drug: diluent 95：5 Micro powder silica gel 5% Colloidal Silica 0.8-1.0 Difference 20 Potassium chloride crystal raw material Main drug: diluent 95：5 Micro powder silica gel 5% Colloidal Silica 0.8-1.0 Difference

[0113] Table 7 Formula of the same potassium chloride crystal and binder with different diluent addition amounts

[0114] Potassium chloride pellet number Mother nucleus Potassium chloride powder Theoretical percentage of potassium chloride powder Thinner Adhesives Corresponding production size (mm) Corresponding size roundness 21 Potassium chloride crystals 11 Main drug: diluent 99：1 D-HPMC-E5 5% Colloidal Silica 0.8-1.1 qualified 22 Potassium chloride crystals 11 Main drug: diluent 85：15 D-HPMC-E5 5% Colloidal Silica 0.8-1.1 excellent

[0115] From the data in Table 3 and Table 4, it can be seen that different binders are related to the production size of the potassium chloride pellets finally prepared. For example, when water is selected as the binder, the pellet growth rate is slow, so its size can only reach 0.5-0.6 mm, while the size can be greatly improved after using colloidal silica and D-HPMC-E5 as binders. However, no matter which binder is used, the roundness can still be maintained at a high level after using the diluent in this application.

[0116] From the data in Table 5, it can be seen that the type of diluent has a relatively important influence on the roundness of potassium chloride pellets. When the diluent is replaced from low-substituted hydroxypropyl methylcellulose (D-HPMC-E5) and micro-powdered silica gel to ethyl cellulose, microcrystalline cellulose, and polyvinyl pyrrolidone, the roundness decreases significantly.

[0117] In addition, from the data in Table 6, it can be seen that whether the potassium chloride crystals are fully chamfered also affects the roundness of the final potassium chloride pellets. When the potassium chloride crystals are not chamfered or the chamfers are insufficient, the roundness of the potassium chloride pellets obtained is poor, and only after sufficient chamfering, the roundness can be greatly improved. Among them, the photo of potassium chloride pellet 10 with excellent roundness is shown in the figure. Figure 6 shown.

[0118] From the data in Table 7, it can be seen that the potassium chloride pellets in the present application can have a minimum usage ratio of diluent to potassium chloride powder of 1:99, and can still achieve relatively excellent roundness performance.

[0119]

Potassium chloride pellet coating

[0120] After potassium chloride crystals and potassium chloride powder are prepared into potassium chloride pellets, we continue to coat the surface of the potassium chloride pellets to obtain a sustained-release coating layer, which is composed of an isolation layer, a sustained-release layer and a color coating layer from the inside to the outside.

[0121] Specifically, their respective molding steps are as follows:

[0122] Production of isolation layer:

[0123] Place potassium chloride pellets in the fluidized bed: turn on the blower, air volume 430m 3 / h to make the potassium chloride pellets flow, heat the material temperature to 60 degrees, pass the isolation layer solution (2% hydroxypropyl methylcellulose purified aqueous solution) through a peristaltic pump with a speed of 60 (rpm), atomize through a spray gun with an air pressure of 0.02, so that the isolation layer solution is evenly distributed on the surface of the potassium chloride pellets, dry for 30 minutes, and obtain isolation layer potassium chloride pellets.

[0124] Preparation of sustained-release layer:

[0125] The isolation layer of potassium chloride pellets is placed in the fluidized bed: the blower is turned on, and the air volume is 430m 3 / h to make the potassium chloride pellets flow, heat the material temperature to 60 degrees, pass the isolation layer (coating material is 30% polymethyl methacrylate resin latex, 30% purified water; plasticizer: 20% triethyl citrate; anti-sticking agent: 20% talcum powder) solution through a peristaltic pump with a peristaltic pump speed of 50 (rpm), and atomize it through a spray gun with a spray gun air pressure of 0.02, so that the isolation layer solution is evenly distributed on the surface of the potassium chloride pellets, dry for 30 minutes, and cool the coated pellets, sieve them, and test the release degree to meet the requirements, which is the potassium chloride sustained-release pellets.

[0126] Production of color coating layer:

[0127] Potassium chloride sustained-release pellets are placed in the fluidized bed: the blower is turned on, with an air volume of 400m3 / h to make the potassium chloride sustained-release pellets flow, heat the material temperature to 60 degrees, pass the colored solution (10% pigment solution, adhesive: 1% hydroxypropyl methylcellulose) through a peristaltic pump with a peristaltic pump speed of 40 (rpm), and atomize it through a spray gun with a spray gun air pressure of 0.02 to make the colored solution evenly distributed on the surface of the potassium chloride pellets, increase the weight by 1%, and dry for 30 minutes. After cooling, the colored potassium chloride sustained-release pellets are sieved, and the release degree that meets the requirements is detected, which is the colored potassium chloride sustained-release pellets.

[0128] The in vitro release experiment was carried out according to the dissolution and release test method (General Rule 0931 Method 2) of the 2020 edition of the Chinese Pharmacopoeia, and the content was determined by titration to calculate the cumulative release percentage. The selection of the specific type of potassium chloride pellets, the weight gain of the coating layer, the roundness, and the release at different times are shown in Table 8 below.

[0129] Table 8 Properties of different potassium chloride sustained-release pellets prepared

[0130] Potassium chloride sustained-release pellets No. Potassium chloride pellets Weight gain of isolation layer Sustained release layer weight gain Color coat weight gain Total weight gain Roundness 1h release 4h release 8h release Is the release in accordance with the first-order rate law? 1 Potassium chloride pellets 5 1% 1% 1% 3% excellent 18.25 58.11 97.13 yes 2 Potassium chloride pellets 5 1% 2.5% 1% 4.5% excellent 14.92 65.04 85.41 yes 3 Potassium chloride pellets 5 1% 2.8% 1% 4.8% excellent 8.86 49.22 78.6 yes 4 Potassium chloride pellets 10 1% 2.5% 1% 4.5% excellent 13.11 45.15 62.36 yes 5 Potassium chloride pellets 13 1% 2.5% 1% 4.5% Difference 30.29 65.72 78.28 no 6 Potassium chloride pellets 19 1% 2.5% 1% 4.5% Difference 48.16 79.15 96.89 no Potassium chloride tablets available - - - - - - 61.13 77.74 94.01 no

[0131] From the data in Table 8 above, it can be seen that the potassium chloride sustained-release micropellets (No. 1-4) prepared by the present invention have an average release of 11.89% in 1 hour, a release of 57.13% in 4 hours, and a release of 82.00% of the potassium chloride sustained-release micropellets in 8 hours, indicating that the potassium chloride sustained-release micropellets prepared by the present invention can be steadily and slowly released within 8 hours.

[0132] It can be seen from the potassium chloride sustained-release micropellets No. 1-3 that the potassium chloride sustained-release micropellets in the present application can control the release rate of the potassium chloride pellets by controlling the weight gain of the coating layer, thereby meeting the release rate requirements of various regions for different types of potassium chloride sustained-release micropellets.

[0133] Comparison of the potassium chloride sustained-release micropellets prepared in No. 2, No. 4, No. 5 and No. 6 shows that, under the premise of the same weight gain, the potassium chloride sustained-release micropellets prepared in No. 5 and No. 6 have lower roundness, resulting in a faster release rate in the first hour, indicating that there is a burst release during the release process, which is obviously not conducive to safe release and long-term sustained release. Comparison of the release curves of the potassium chloride sustained-release micropellets prepared in No. 4 and No. 5 Figure 7 shown.

[0134] Compared with commercially available potassium chloride tablets, which are released quickly within 1-8 hours, there is a burst release phenomenon, and the release is basically completed within 8 hours, so the sustained release effect is not particularly obvious.

[0135] Therefore, the potassium chloride sustained-release micropellets prepared in the present application effectively avoid the phenomenon of sudden release of the dose, thereby avoiding damage to the gastric mucosa. Therefore, they have the advantages of being able to accurately control the time and frequency of administration, high safety, and good adaptability.

[0136] The specific embodiments described herein are merely examples of the spirit of the present invention. A person skilled in the art of the present invention may make various modifications or additions to the specific embodiments described or replace them in a similar manner, but this will not deviate from the spirit of the present invention or exceed the scope defined by the appended claims.

Claims

1. A potassium chloride sustained-release pellet, characterized in that: It comprises potassium chloride pellets and a sustained-release coating layer coated on the outside of the potassium chloride pellets; wherein, The potassium chloride pellets include an irregularly shaped potassium chloride crystal mother core located at the center and a potassium chloride powder layer attached to the surface of the potassium chloride crystal mother core by a binder, wherein the potassium chloride powder layer includes potassium chloride powder and a powdery diluent, wherein the diluent is selected from any one of low-substituted hydroxypropyl methylcellulose and micro-powder silica gel or a combination of two thereof; The potassium chloride pellets and potassium chloride sustained-release pellets have a roundness greater than 85%, and the potassium chloride sustained-release pellets release potassium chloride according to a first-order rate rule during the release process; The potassium chloride crystal mother core is chamfered so that the cross section of the potassium chloride crystal mother core is a rounded rectangle, and the ratio of the length of the arc side to the adjacent straight side is greater than 0.

5.

2. The potassium chloride sustained-release pellet according to claim 1, characterized in that: The mass ratio of the potassium chloride powder to the diluent is 85-99:15-1.

3. The potassium chloride sustained-release pellet according to claim 1, characterized in that: The binder is a combination of one or more of water, ethanol solution, low-substituted hydroxypropyl methylcellulose solution, and colloidal silicon dioxide aqueous solution.

4. The potassium chloride sustained-release pellet according to claim 1, characterized in that: The potassium chloride content in the potassium chloride sustained-release micropellets is 88.5%-92.5%.

5. The potassium chloride sustained-release pellet according to claim 1, characterized in that: The diameter of the potassium chloride pellets is 0.5-1.4 mm.

6. The potassium chloride sustained-release pellet according to claim 1, characterized in that: The sustained-release coating layer is composed of an isolation layer, a sustained-release layer and a color coating layer in sequence.

7. A potassium chloride sustained-release pellet according to claim 1 or 6, characterized in that: The mass of the sustained-release coating layer is 3%-4.8% of the mass of the potassium chloride pellets.

8. A method for preparing the potassium chloride sustained-release pellets as claimed in any one of claims 1 to 7, characterized in that: The following steps are involved: (S.1) sieving potassium chloride crystals to obtain potassium chloride crystal mother nuclei; (S.2) placing the potassium chloride crystal core in a centrifugal granulator for chamfering, and then sequentially adding a binder and potassium chloride powder into the centrifugal granulator to form a potassium chloride powder layer on the surface of the potassium chloride crystal core, thereby obtaining potassium chloride pellets with a roundness of more than 85%; (S.3) coating the surface of the potassium chloride pellets to form a sustained-release coating layer on the surface of the potassium chloride pellets to obtain the potassium chloride sustained-release micropellets.

9. The method according to claim 8, characterized in that During the chamfering process in (S.2), the rotation speed of the centrifugal granulator is 35-55 rpm, and the chamfering time is 5-17 minutes.

10. The method according to claim 9, characterized in that The blast air volume of the centrifugal granulator is controlled at 5-10HZ, and the air source pressure is controlled at 0.03-0.6MPa.

11. The method according to claim 8, characterized in that The (S.2) also includes the step of mixing potassium chloride powder and a diluent to form potassium chloride powder.

12. The method according to claim 8 or 11, characterized in that: The coating step in (S.3) comprises the steps of sequentially forming an isolation layer, a sustained-release layer and a color coating layer on the surface of the potassium chloride pellets.

13. Use of the potassium chloride sustained-release pellets as claimed in any one of claims 1 to 7 in the preparation of a hypokalemia drug or a potassium chloride sustained-release tablet.

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