Potassium chloride composite skeleton sustained release tablet and preparation method thereof

Abstract

The invention provides a potassium chloride composite skeleton sustained release tablet which comprises the following substances in parts by weight: 100 parts of potassium chloride and 5-15 parts of auxiliary materials, the auxiliary materials comprise 3.5-10 parts of polymer auxiliary materials and 1.5-5 parts of wax auxiliary materials, and optionally added plasticizers, organic reagents and flow aids; the invention also provides a preparation method of the potassium chloride composite skeleton sustained-release tablet, which comprises the following steps: uniformly wrapping the polymer and the waxy auxiliary material on the surface of potassium chloride particles through a melt kneading technology, and carrying out tabletting and heat treatment processes to obtain the potassium chloride composite skeleton sustained-release tablet. The potassium chloride sustained-release tablet obtained by the invention has the drug loading capacity of 85-95%, has the advantages of small tablet weight and small dosage of auxiliary materials, and meanwhile, the drug can be stably and slowly released without a local burst release phenomenon. In addition, the invention has the advantages of simple preparation process, low production cost and stable quality, and is suitable for industrial and large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical manufacturing, and in particular relates to a potassium chloride composite skeleton sustained-release tablet and a preparation method thereof. Background Art

[0002] Potassium chloride is a commonly used electrolyte balance regulator in clinical practice. It has a definite clinical efficacy and is widely used in various clinical departments. Indications: 1. Treatment of hypokalemia caused by various reasons, such as insufficient food intake, vomiting, severe diarrhea, the use of potassium-excreting diuretics, hypokalemic familial periodic paralysis, long-term use of glucocorticoids and supplementation of hypertonic glucose, etc. 2. Prevention of hypokalemia When patients have potassium loss, especially if hypokalemia is harmful to patients (such as patients with digitalization), preventive potassium salt supplementation is required, such as eating very little, severe or chronic diarrhea, long-term use of adrenocortical hormones, potassium-losing nephropathy, and Bartter's syndrome, etc. 3. Frequent, multifocal premature beats or rapid arrhythmias caused by digitalis poisoning.

[0003] However, oral administration of potassium chloride may cause gastrointestinal irritation symptoms, such as nausea, vomiting, throat discomfort, chest pain (esophageal irritation), flatulence, abdominal pain, abdominal discomfort, diarrhea, and even peptic ulcer, bleeding, perforation, and obstruction. It is more likely to occur when fasting, taking large doses, or in patients with existing gastrointestinal diseases. Hyperkalemia is prone to occur when overdosed or with existing renal impairment. It manifests as increased serum potassium concentration (6.5-8.0mEq / L), weakness, fatigue, numbness of the hands, feet, lips, and mouth, unexplained anxiety, confusion, dyspnea, slow heart rate, arrhythmia, conduction block, and even cardiac arrest.

[0004] Therefore, in order to prevent and treat hypokalemia and avoid potassium chloride dumping in the gastrointestinal tract, sustained-release preparations of potassium chloride are developed so that potassium chloride can be released in a controlled manner in the gastrointestinal tract, avoiding excessive local concentrations of potassium ions and reducing and avoiding adverse reactions.

[0005] The disclosed preparation methods and literatures of potassium chloride sustained-release preparations usually include the following two categories and four subcategories of preparation methods:

[0006] 1. Single unit type sustained release

[0007] a) Matrix sustained release

[0008] The drug release mechanism of skeleton-type potassium chloride sustained-release tablets is mainly diffusion through the pores of the skeleton, resulting in a lower risk of dose dumping.

[0009] CN110251472A discloses a method for producing potassium chloride sustained-release tablets using a hot-melt sustained-release process: potassium chloride and acrylic resin (RS) are uniformly mixed, a plasticizer (citrate, sebacate, phthalate) and a wetting agent (95% ethanol) are added for wet granulation, drying, granulation, tableting, to obtain potassium chloride sustained-release tablets, and high-temperature molding at a temperature of 125 to 140°C for 30 to 90 minutes to obtain potassium chloride sustained-release tablets; the prescription and process of this invention are simple and easy to mass produce, but in the high-temperature molding stage, it is not possible to ensure that the acrylic resin can be completely wrapped on the surface of the potassium chloride particles, there is a risk of dose dumping, and the drug loading of the potassium chloride sustained-release tablets prepared by this process is low, between 50% and 80%, and the tablet size is large.

[0010] CN 105769905 B discloses a potassium chloride sustained-release tablet and a preparation method thereof: potassium chloride is uniformly mixed with ethyl cellulose and / or a solid lipid material (glyceryl monostearate, stearic acid), a hydroxypropyl methylcellulose aqueous solution is added for wet granulation, fluidized bed drying, granulation, and tableting by adding a filler and a lubricant to obtain a potassium chloride sustained-release tablet. The wetting agent used in the process is purified water, which increases the possibility of dissolution of the potassium chloride raw material during the preparation process, and the tablet prepared by the present invention has a small drug loading, with a maximum drug loading of 50%. For tablets of the same specification, the tablet size prepared by the process is large, the amount of auxiliary materials used is large, and the production cost is increased.

[0011] CN109125280 A and CN111228231 B disclose a potassium chloride sustained-release preparation and a preparation method thereof: potassium chloride raw material and hydrogenated cottonseed oil are uniformly mixed, granulated in a hot melt extruder, a flow aid (silicon dioxide) and a lubricant (magnesium stearate) are added, mixed, and tableted to obtain potassium chloride sustained-release tablets. The invention discloses a simple prescription and an easy preparation method, but the hot melt extrusion equipment required for this process is expensive and the maintenance cost is very high. In addition, the wax auxiliary material hydrogenated cottonseed oil may be thermally decomposed by high temperature, and the color changes, affecting the appearance of the preparation. The maximum drug loading of the potassium chloride sustained-release tablet prepared by this method is 78.4%.

[0012] CN106176804A discloses a method for preparing potassium chloride sustained-release tablets using an ebullient bed: well-mixed potassium chloride fine powder and cetostearyl alcohol are placed in an ebullient bed, heated to 55-65°C, maintained for 5min, cooled, magnesium stearate is added and mixed, and tabletted to obtain potassium chloride sustained-release tablets. This invention has a simple prescription and an easy preparation method. However, only cetostearyl alcohol is used as a skeleton sustained-release material. Whether there is a risk of dose dumping in the dissolution curve of the preparation needs further testing and clarification. In addition, cetostearyl alcohol (melting point 49-56°C) of about 20.0% in the tablet may be melted and deformed by high temperature, causing the tablet thermal stability to decrease and the dissolution curve to change.

[0013] Bao Yusheng et al. reported a method for preparing potassium chloride wax skeleton sustained-release tablets: potassium chloride and hydrogenated vegetable oil were crushed and sieved, and granules were prepared using a hot-melt twin-screw extruder. The cooled material was mixed evenly with magnesium stearate, and tablets were pressed to obtain potassium chloride sustained-release tablets. This preparation method is easy to implement and has a simple prescription, but it also uses expensive hot-melt extrusion equipment. In addition, the single use of hydrogenated vegetable oil wax material also poses certain challenges to the thermal stability of the preparation, and there is also a defect of low tablet drug loading (maximum drug loading 78.9%).

[0014] Wu Jiankun reported a method for preparing potassium chloride-ethyl cellulose skeleton sustained-release tablets: placing potassium chloride APIs that have passed 60 mesh in a fluidized bed, coating with EC-N10 ethanol solution to prepare potassium chloride-EC sustained-release pellets, adding hydrogenated vegetable oil to mix, and tableting to obtain potassium chloride sustained-release tablets. The potassium chloride sustained-release tablets prepared by this method have a large drug loading (93.75%), a simple prescription, and a simple preparation method. However, whether the preparation prepared by this method is bioequivalent to the potassium chloride sustained-release tablets that have been marketed needs further verification.

[0015] b) Membrane controlled sustained release

[0016] The drug release mechanism of membrane-controlled sustained-release potassium chloride sustained-release tablets is to achieve the sustained-release effect by coating ordinary tablet cores with sustained-release materials. This preparation process has high requirements for the coating process, and trace coating film defects will inevitably appear during the coating process, resulting in sudden drug release.

[0017] CN103006696B discloses a method for preparing a potassium chloride sustained-release tablet: potassium chloride, hydroxypropyl methylcellulose, microcrystalline cellulose and lactose are crushed and mixed, passed through an 80-mesh sieve, and wet granulated with a hydroxypropyl methylcellulose aqueous solution, dried, granulated, and tableted to obtain a potassium chloride tablet core. A film coating is applied using a sustained-release coating solution, which is mainly composed of an acrylic resin (RS100 and RL100), an anti-adhesive (talcum powder), a plasticizer (TEC) and a solvent (95% ethanol) to obtain a potassium chloride sustained-release film-coated tablet. Further, the potassium chloride sustained-release film-coated tablet is subjected to a sugar coating process, and finally, after polishing and packaging, a potassium chloride sustained-release tablet is obtained. The potassium chloride sustained-release tablet obtained by the patent of the present invention has many preparation processes, complicated process parameters, and limited production efficiency. The sugar coating process requires a large amount of time and resources in industrial production, and its sugar coating poses certain challenges to the stability of the tablet. In addition, the drug loading of the tablet is low (70.0%).

[0018] CN106466302 A discloses an oral potassium chloride sustained-release tablet and a preparation method thereof: potassium chloride is wet-granulated by an ethanol solution of polyvinyl pyrrolidone, dried, added with a filler (microcrystalline cellulose) and a lubricant (magnesium stearate) to mix, tableted, to obtain a potassium chloride tablet core, and further coated with a sustained-release coating. The sustained-release coating solution is mainly composed of an ethanol aqueous solution of acrylic resin (RL), ethyl cellulose (EC-N50), polyethylene glycol and talcum powder, and potassium chloride sustained-release tablets are obtained by coating. The preparation process has high requirements for the tablet core coating process. Trace coating film defects of the product will inevitably appear during the coating process, which is easy to cause dose dumping and produce side effects on the gastrointestinal tract. In addition, organic solvents are required in both the tablet core and the coating process, and corresponding protective and environmental protection measures need to be taken in the large-scale production stage.

[0019] US5505962 discloses a method for preparing potassium chloride sustained-release tablets: potassium chloride raw materials are wet granulated with 11.1% povidone ethanol solution, the wet granules are dried at 40-50°C for 10 hours, magnesium stearate is added and mixed, tableted, potassium chloride tablet cores are obtained, and further coated with sustained-release coating. The sustained-release coating liquid is mainly composed of ethyl cellulose, polyvinyl pyrrolidone and propylene glycol ethanol solution, and potassium chloride sustained-release tablets are obtained after coating. The potassium chloride sustained-release tablets prepared by this process need to be wrapped with a thicker sustained-release coating film to achieve the expected sustained-release effect, but there is still a risk of dose dumping caused by the coating defects of the aforementioned membrane controlled-release products.

[0020] Bao Yongchu et al. reported a method for preparing potassium chloride sustained-release tablets by acrylic resin aqueous coating process: potassium chloride raw materials are mixed with microcrystalline cellulose, wet granulated, dried, added with magnesium stearate and talcum powder, and pressed into tablets to obtain potassium chloride tablet cores, which are further coated with sustained-release coating. The sustained-release coating solution is mainly composed of an aqueous solution of RS 30D, RL 30D, TEC and talcum powder. After acrylic resin coating, a 5% HPMC (6cps) aqueous solution is used for outer coating to avoid sticking during tablet storage. After coating, the tablets are placed in an oven for constant temperature heat treatment for 12 hours to obtain potassium chloride sustained-release tablets. This method can adjust the coating membrane permeability and the drug release rate of the preparation by adjusting the ratio of RS30D and RL 30D. However, the moisture resistance of the tablets and whether they are bioequivalent to the marketed preparations need further study.

[0021] Chen Lizhen et al. reported a method for preparing membrane-controlled potassium chloride sustained-release tablets: potassium chloride API (below 100 mesh) was mixed with povidone K30, and purified water was added for wet granulation. After drying, magnesium stearate was added and mixed, and tablets were pressed to obtain potassium chloride tablet cores. The sustained-release coating was further coated, and the sustained-release coating liquid was composed of an ethanol solution of RS100, RL 100, TEC and talcum powder. Potassium chloride sustained-release tablets were obtained after coating. This preparation method belongs to membrane-controlled sustained-release, and the process is simple and easy, but ethanol is required in the prescription, and protective and environmental protection measures need to be taken in industrial production. In addition, this method still has the risk of dose dumping caused by the coating defects of the aforementioned membrane-controlled release products.

[0022] c) Synergy between matrix controlled release and membrane controlled release

[0023] CN110354092 A discloses a method for preparing a potassium chloride sustained-release tablet with synergistic skeleton sustained-release and film sustained-release: after wet granulation of potassium chloride and polymethacrylate ammonium emulsion, magnesium stearate is added to the dry granules for tableting to obtain a potassium chloride skeleton sustained-release tablet core; the skeleton sustained-release tablet core is coated with polymethacrylate ammonium controlled-release coating (water, acetone, isopropanol, RL 100, RS100 are mixed, N, N-diethylpropargylamine and magnesium stearate are added in sequence and stirred to obtain polymethacrylate ammonium controlled-release liquid), and a potassium chloride sustained-release tablet with synergistic skeleton sustained-release and film sustained-release is obtained. This preparation method controls the diffusion rate of the drug by the combined application of coating film diffusion and skeleton diffusion, thereby achieving a slow-release effect, and the risk of dose dumping is low. However, the preparation process of this patent is complicated, and acetone and isopropanol organic reagents are also used in the prescription. In large-scale production, corresponding protection and environmental protection measures must be strictly taken. In addition, the preparation process also involves a cumbersome sugar coating process, and the production cost is further increased.

[0024] CN86107734A discloses a method for preparing a potassium chloride sustained-release preparation: ethyl cellulose and waxy auxiliary materials (stearic acid and / or medium-chain triglycerides) are dissolved in a 10% ethanol solution, wet granulated with potassium chloride raw material, dried, and added with magnesium stearate to obtain potassium chloride tablets. Further, potassium chloride tablets are coated with a sustained-release coating (ethyl cellulose, hydroxypropyl methylcellulose, dibutyl sebacate, stearic acid and magnesium stearate in dichloromethane ethanol solution) to obtain potassium chloride sustained-release tablets. Harmful and irritating dichloromethane is used in this process prescription, which has certain safety hazards in industrial production, and corresponding environmental protection measures need to be taken.

[0025] US4871546 discloses a method for preparing a potassium chloride sustained-release tablet with membrane-controlled sustained-release and skeleton-controlled sustained-release: potassium chloride, corn starch and stearic acid are passed through a 20-mesh sieve, mixed, and wet granulated with a polyvinyl pyrrolidone aqueous solution, dried, tableted, and the tablet core is coated with a sustained-release coating (a dichloromethane alcohol solution of polymethyl methacrylate, PEG4000, polyvinyl acetate and diethyl phthalate) to obtain a potassium chloride sustained-release tablet. However, it can be seen from the tablet dissolution curve that the front section releases faster, and there is a risk of dose burst release. The tablet dissolution rate can reach 55.0% at 1 hour.

[0026] Xu Yingjuan et al. reported a method for preparing potassium chloride sustained-release tablets: potassium chloride and Eudragit RS PO were mixed, passed through a 40-mesh sieve, and Eudragit NE30D was added for wet granulation. After drying, magnesium stearate was added and mixed, and tablets were pressed. The sustained-release coating was further applied, and the sustained-release coating liquid was mainly composed of Eudragit (RS100 and RL 100), polyethylene glycol 6000, talcum powder, acetone, and 1,2-propylene glycol to obtain potassium chloride sustained-release tablets. This process uses a large amount of excipients and a large number of excipient types, the tablet drug loading is low, the production cost is increased, and organic solvents such as acetone and propylene glycol are also involved. There are certain safety hazards in large-scale production, and corresponding environmental protection measures need to be taken.

[0027] 2. Multi-unit sustained release

[0028] Membrane controlled release pellets: Potassium chloride is prepared by mesoporous carbon, dry granulation or coating granulation technology to obtain drug-loaded pellet cores, and then coated with hydrophobic substances (acrylic resins I-III, IV, ethyl cellulose) and / or wax excipients (liquid paraffin), polymethyl methacrylate resin latex to prepare sustained-release pellets (e.g. CN104873473A, CN102961363A, CN107823189A), and the preparations are potassium chloride sustained-release pellets, potassium chloride sustained-release capsules or potassium chloride sustained-release tablets. This type of process has very strict requirements on pellet coating equipment and parameter control technology, and the production process is relatively complex and the cost is high. In addition, membrane controlled-release pellet technology also has the disadvantage of small tablet drug loading.

[0029] US5422122 A discloses a method for preparing a potassium chloride sustained-release tablet: potassium chloride, ethyl cellulose, a water-soluble polymer (polyvinyl alcohol, polyvinyl pyrrolidone or hydroxypropyl methylcellulose) and cyclohexane are heated, stirred and mixed until the polymer is dissolved, the cooled mixed liquid is placed in a rotary evaporator, cyclohexane is evaporated and removed, and a fluidized bed is further used for drying and sieving, and the surface of the obtained potassium chloride particles is coated with a layer of ethyl cellulose polymer. The potassium chloride-ethyl cellulose particles are further coated with an aqueous solution of hydroxypropyl methylcellulose to obtain potassium chloride particles coated with two layers of polymers, microcrystalline cellulose and cross-linked polyvinylpyrrolidone are added and mixed, and tablets are pressed to obtain a multi-unit released potassium chloride sustained-release tablet. This process requires two coating steps, the process is relatively cumbersome, and the parameter control requirements are relatively strict. The most important thing is that a cyclohexane organic solvent with a pungent odor will be used in the process, and protection, environmental protection and explosion-proof treatments are required in large-scale production, and the production cost is further increased.

[0030] US4572833 discloses a method for preparing a multi-unit potassium chloride sustained-release tablet: paraffin and isopropanol are mixed, stirred at 70°C, and ethyl cellulose, silicon dioxide and tributyl acetyl citrate are added at the same time to obtain a mixed and homogeneous coating solution; potassium chloride particles are coated with a fluidized bed, and the coating solution is maintained at 70°C. The surface of the obtained potassium chloride particles is coated with a paraffin sustained-release coating, and potassium chloride sustained-release tablets, sustained-release capsules or sustained-release granules can be prepared according to demand. This type of process only has a one-step coating process, but the coating solution has high temperature requirements and still requires the use of organic solvents.

[0031] US4863743 discloses a method for preparing a multi-unit potassium chloride sustained-release tablet: ethyl cellulose and polyethylene glycol 4500 are dissolved in an organic solvent (chloroform: methanol = 4:1) to obtain a coating solution, and the coating solution is used to coat potassium chloride crystals (30-50 mesh); the coated potassium chloride particles (93%), microcrystalline cellulose 101 (6%) and cross-linked polyvinylpyrrolidone (1%) are mixed and tableted to obtain potassium chloride sustained-release tablets. This process requires the use of a large amount of chloroform solvent, and corresponding environmental protection and personnel protection measures need to be taken in the industrial production stage.

[0032] The KLOR-CON M series of potassium chloride sustained-release tablets developed and produced by UPSHER-SMITH Company have a preparation method disclosed in patents US6780437 B2 and US7056534 B2: using a methanol solution of ethyl cellulose as a coating agent, potassium chloride crystals (20-60 mesh) are coated in a fluidized bed, and potassium chloride sustained-release granules are obtained after drying. Finally, fillers, disintegrants and glidants are added, and potassium chloride sustained-release tablets are obtained by tableting. This type of technology mainly determines its sustained-release effect by controlling the thickness of the ethyl cellulose layer on the surface of the potassium chloride crystals.

[0033] Shanghai Haihong Industrial (Group) Chaohu Zhongchen Pharmaceutical Co., Ltd. has publicly disclosed a method for using NE 30D to prepare potassium chloride sustained-release tablets: add water and talcum powder to Eudragit NE30D and stir evenly to obtain a coating solution; take potassium chloride crystals and place them in a multi-functional granulating and pilling coating machine for bottom spray coating to obtain potassium chloride sustained-release granules, add microcrystalline cellulose, sodium carboxymethyl starch, micropowder silica gel and magnesium stearate, mix, and press to obtain potassium chloride sustained-release tablets.

[0034] The preparation method of the multi-unit potassium chloride sustained-release tablets described above is to coat potassium chloride crystals with sustained-release coating, add disintegrants, mix, and compress the tablets. After the tablets enter the gastrointestinal tract, they disintegrate in water, and the particles disperse to form a suspension. The release rate is controlled by a single microcapsule. This technology can avoid the sudden release caused by uneven coating of the coated tablets or rupture of the coating film during packaging and transportation. The multi-unit sustained-release particles are evenly dispersed in the gastrointestinal tract and will not cause gastric irritation. However, this technology requires the use of organic solvents, explosion-proof facilities must be used in large-scale production, and organic solvent residue detection must be added during finished product inspection. Most importantly, the tablets are huge in size, the drug loading is small, and patients have difficulty swallowing.

[0035] From the current public technical situation, potassium chloride sustained-release preparations often have the following problems and difficulties:

[0036] 1. The process of potassium chloride sustained-release preparation is complicated: Potassium chloride API is highly water-soluble, and it is difficult to control the release of potassium chloride using simple and low-cost technology. If potassium chloride is to be released evenly and slowly, expensive equipment, materials and complicated processes are required;

[0037] 2. Large tablet size and small drug loading: Existing potassium chloride sustained-release preparation technology and marketed preparations have the defects of small tablet drug loading and large tablet size, which increases production costs and makes it difficult for patients to swallow. The following lists the information of potassium chloride sustained-release tablets and reference preparations that have been marketed at home and abroad.

[0038] From the table, we can see that the drug loading of potassium chloride sustained-release tablets is relatively small (except K-Tab), ranging from 66% to 77%, and the tablet size is relatively large.

[0039] Although K-Tab has a significant drug loading capacity (94.1%), it also has certain defects: ①. K-Tab is released quickly in the early stage, which poses a risk of gastrointestinal irritation; ②. It is not bioequivalent to the mainstream products currently on the international and domestic market; ③. K-Tab uses PVAC materials in its prescription, which has no registered pharmaceutical excipients in China and is difficult to obtain.

[0040] 3. The stability of potassium chloride sustained-release preparations needs to be improved: the waxy materials in the prescription of potassium chloride sustained-release preparations are easily affected by high temperatures, which increases the difficulty of the preparations during storage and transportation. In addition, the coating of some potassium chloride preparations will also be affected by high temperature and high humidity, resulting in reduced stability of the preparations and changes in efficacy.

[0041] In summary, the market is currently looking forward to the emergence of potassium chloride sustained-release preparations with simple production process, large drug loading, small tablet size, significant stability, and equivalent sustained-release effect.

[0042] Summary of the invention

[0043] In view of the current potassium chloride sustained-release preparation production process is complicated, and the drug loading is small, the company through a large number of experimental studies, unexpectedly and pleasantly discovered a new skeleton sustained-release technology. The present invention uses a kneading machine with extremely high cost performance, potassium chloride crystals, polymer auxiliary materials and wax auxiliary materials are melt-mixed to obtain potassium chloride sustained-release particles, and the tablets are pressed to obtain skeleton controlled-release potassium chloride sustained-release tablets. The production process is simple and easy to industrialize. The technology overcomes the defect of the existing potassium chloride sustained-release preparation with a small drug loading, has the advantages of less auxiliary material usage, large drug loading (85% to 95%), and low production cost. At the same time, the present invention also provides a product prepared by the technology, with significant sustained-release function, no drug burst release phenomenon, and significant preparation stability, which is not affected by bad weather such as high temperature and high humidity. In addition, after the potassium chloride sustained-release tablet is completely dissolved, the auxiliary material skeleton remains intact like a sponge, has strong anti-pinching performance, and will not be squeezed or deformed or broken by food in the gastrointestinal tract.

[0044] The technical solution of the present invention is a method for preparing a potassium chloride composite skeleton sustained-release tablet, comprising the following components in parts by weight:

[0045]

[0046] The preparation steps of the potassium chloride composite skeleton sustained-release tablets of the present invention are as follows:

[0047] S1 weighing: weigh the corresponding amount of potassium chloride API crystals and excipients;

[0048] S2: mixing, taking the potassium chloride crystals from step S1, the polymer auxiliary material, the wax auxiliary material and the optional plasticizer, placing them in a kneader, and mixing them uniformly at room temperature;

[0049] S3: Heating: the kneading machine is heated to 45-65°C, and an organic solvent may be added, and the mixture is melt-kneaded under a sealed cover, and the temperature is continuously raised to 70-100°C to melt the polymer and the wax auxiliary material. If an organic solvent is added, hot kneading and devolatilization must be utilized in this step.

[0050] S4 cools down, and after the material in S3 is cooled, it is sieved to obtain particles with uniform diameter and good fluidity;

[0051] S5 total mixing, after S4 material screening, a flow aid can be optionally added to improve the fluidity of the material;

[0052] S6 tableting, taking the material of S5 and tableting it in a tablet press to obtain potassium chloride sustained-release tablet cores;

[0053] S7 heat treatment, take S6 tablets and heat treat them in an oven at 60-90°C for 2-24 hours, and after cooling, obtain potassium chloride sustained-release tablets.

[0054] Preferably, the polymer auxiliary material is selected from at least one of quaternary ammonium methacrylate copolymer and ethyl cellulose (EC); further preferably, the polymer auxiliary material is a quaternary ammonium methacrylate copolymer.

[0055] Preferably, the quaternary ammonium methacrylate copolymer is a commercially available pharmaceutically suitable copolymer of methyl methacrylate-ethyl acrylate-trimethylammonium ethyl methacrylate chloride, such as the one produced by Yingde Maofeng Pharmaceutical Co., Ltd. RL 100, RL PO, RS100, RS PO or Evonik Rohm of Germany RL 100, RL PO, RS100, RSPO, or other equivalent copolymers may be used, such as ammonio methacrylate I or ammonio methacrylate II named in the Chinese Pharmacopoeia, quaternary ammonium methacrylate copolymers (Ammonio Methacrylate Copolymer) named in the European Pharmacopoeia and the United States Pharmacopoeia, more preferably ammonio methacrylate I and II (RL PO, RS PO) in powder form, and more preferably ammonio methacrylate II (RS PO) with strong sustained-release function.

[0056] Preferably, ethyl cellulose has a viscosity of 7 to 100 mPa.s, as measured by a 5 wt% solution thereof in ethanol-toluene (1:4, g / g) at 25°C using an Ubbelohde viscometer according to the pharmacopoeia standards of various countries. Preferred commercially available ethyl cellulose includes ethyl cellulose produced by DuPont Polymers, Aqualon from Ashland TM Ethyl cellulose, and ethyl cellulose produced by Taian Ruitai Cellulose Co., Ltd.

[0057] Preferably, the wax auxiliary material is solid at room temperature and is selected from at least one of C12-C26 higher fatty acids, C12-C26 higher fatty alcohols, C12-C26 higher fatty acid glycerides, hydrogenated vegetable oils, animal and plant waxes, polyethylene waxes, and mineral waxes.

[0058] Wax excipients with stronger hydrophobicity are further preferred, including lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, erucic acid, 12-hydroxystearic acid and its calcium salt and magnesium salt (such as calcium stearate, magnesium stearate); lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, arachidic alcohol, behenyl alcohol; lauric acid glyceryl, myristic acid glyceryl, palmitic acid glyceryl, monostearic acid glyceryl, mono- and distearic acid glyceryl, stearic acid palmitic acid glyceryl, arachidic acid glyceryl, behenic acid glyceryl, mixed fatty acid glycerides; hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated castor oil, hydrogenated rapeseed oil, hydrogenated palm oil, hydrogenated coconut oil; lanolin, beeswax, spermaceti, shellac wax, insect white wax, carnauba wax, rice bran wax, sugarcane wax, candelilla wax; polyethylene wax; paraffin wax, microcrystalline wax.

[0059] Preferably, a plasticizer may be added to soften the polymer auxiliary material and lower its glass transition temperature (Tg), so that the polymer auxiliary material and the wax auxiliary material can be melted in a shorter time and at a lower temperature, thereby saving energy and time.

[0060] Preferably, the plasticizer is selected from tri-n-butyl citrate (TBC), triethyl citrate (TEC), acetyl tributyl citrate (ATBC), polyethylene glycol (PEG), dibutyl sebacate (DBS), diethyl sebacate (DES) and castor oil. Preferably, the amount of the plasticizer is 0 to 30% of the polymer excipient dry weight. More preferably, the amount of the plasticizer is 0 to 20% of the polymer excipient dry weight. Most preferably, no plasticizer is added.

[0061] Preferably, the order and method of adding the plasticizer are as follows: for solid plasticizers such as polyethylene glycol, they can be pre-mixed with the API, polymer excipients and wax excipients at low temperature; for liquid plasticizers such as TBC, TEC, DBS, castor oil, etc., after the API, polymer excipients and wax excipients are evenly mixed, the liquid plasticizer is mixed with the organic solvent, added to the material, and melt-kneaded.

[0062] Preferably, the organic solvent comprises or consists of the following ICH Class 3 solvents: ethanol, isopropanol, acetone, ethyl acetate. It is further preferred that isopropanol, which has better compatibility with wax and is inexpensive, be used as the organic solvent.

[0063] Preferably, the amount of organic solvent used is 0-15% of the total dry weight of the material. More preferably, the amount of organic solvent used is 0-11% of the total dry weight of the material. Most preferably, no organic solvent is added.

[0064] Preferably, the API, polymer excipient, wax excipient and plasticizer are mixed uniformly under low temperature conditions, and the temperature in the kneader is set to continuously rise from room temperature to 50°C. Within this temperature range, the wax excipient will be pre-melted and applied to the surface of the potassium chloride crystals.

[0065] Preferably, when the kneader temperature is within 45 to 65 ° C, an organic solvent is added, and the organic solvent melts the polymer auxiliary material and the wax auxiliary material, reduces the Tg of the auxiliary material, enhances the fluidity of the auxiliary material, and is more efficiently and evenly coated on the surface of the potassium chloride crystal. After the surface of the potassium chloride crystal is evenly coated with the auxiliary material, the kneader temperature is increased to 70 to 90 ° C. As the organic solvent evaporates and the temperature rises, the Tg of the auxiliary material is reached, and the auxiliary material is transformed into a viscoelastic state and a viscous flow state, and the materials in the kneader gather in large lumps. Take the material in the kneader and place it under a microscope for observation. The surface of the potassium chloride particles is coated with a uniform film coating, and it is frosted, which is significantly different from the uncoated potassium chloride crystals.

[0066] Preferably, after potassium chloride, polymer auxiliary material and wax auxiliary material are uniformly mixed at low temperature, no organic solvent may be added, and the kneader temperature is continuously increased to 80-100° C. Within this temperature range, which is higher than the Tg of the polymer auxiliary material mixture, the material is transformed from a glassy state to a viscoelastic state and a viscous flow state, and the whole material is aggregated into a mass, which is effectively and evenly wrapped on the surface of the potassium chloride crystal.

[0067] Preferably, under high temperature conditions, the polymer excipients and the wax excipients melt above Tg, transform from a glassy state to a viscous flow state, and are evenly distributed and smeared on the surface of potassium chloride crystals. Due to the hydrophobicity of the wax excipients and the ductility of the polymer excipients, the pungent salty taste of potassium chloride can be effectively masked, ensuring that there will be no local sudden release of the potassium chloride drug when it enters the gastrointestinal tract.

[0068] Preferably, the addition of an organic solvent can make the polymer excipient and the wax excipient quickly and efficiently become a viscous flow state, and efficiently distribute and wrap the surface of the potassium chloride particles to form a dense sustained-release film. In addition, during the heating stage, compared with not adding an organic solvent, the process of adding an organic solvent only requires a lower temperature (70-90° C.), low energy consumption, and low production cost.

[0069] Preferably, when the polymer excipient and the wax excipient are evenly and tightly wrapped on the surface of the potassium chloride crystal, as the material is cooled, the potassium chloride coated particles are gradually separated and dispersed into small agglomerates and granules. The small agglomerates are sized and sieved to obtain small particles with uniform diameters. The sieved particles are observed under a microscope. The excipients are firmly, tightly and evenly wrapped on the surface of the potassium chloride crystal and do not fall off due to scratching or collision by external force, thereby ensuring its sustained release effect and preventing sudden release.

[0070] Preferably, the sieved material has good fluidity, and a glidant such as magnesium stearate, silicon dioxide, talc, etc. may be optionally added.

[0071] Silicon dioxide having a good flow-aiding effect and an antistatic function is further preferred.

[0072] Preferably, the tablets are placed in an oven at 60 to 90°C for heat treatment for 2 to 24 hours. After the potassium chloride sustained-release tablet core is heat-treated, the surface of the tablet core tends to be translucent and smooth, and the hardness of the tablet core is significantly increased; during the heat treatment process, the polymer excipients and wax excipients in the potassium chloride sustained-release tablet core change from a solid state to a molten flow state at high temperature, which can fill the gaps inside the tablet core and form a dense potassium chloride skeleton sustained-release tablet after cooling. The heat treatment process can improve the thermal stability of potassium chloride sustained-release tablets and extend their shelf life.

[0073] Preferably, the properties and Tg of the materials in the formulation are different, and the temperature and time of the heat treatment are also different.

[0074] Preferably, the subsequent application of potassium chloride composite skeleton sustained-release tablets can be directly coated with an aqueous moisture-proof film coating agent, and commercially available moisture-proof coating premixes, self-prepared or other aqueous moisture-proof coating agents can be selected.

[0075] Preferably, commercially available coating agents such as OPADRY produced by Colorcon TM AMB coating premix (composed of polyvinyl alcohol, polyethylene glycol, etc.).

[0076] Preferably, the coating agent is homemade: according to the German Hans-Ulrich Petereit editor-in-chief " (Polymethacrylate) Application Technical Guide --- The preparation method is guided by the book "Application Guidelines", and the aqueous dispersion coating is made by high-speed shearing of methacrylate amine alkyl copolymer, stearic acid, and sodium lauryl sulfate in water (magnesium stearate or talc can be added as an anti-sticking agent). Preparation method example: first add purified water, then add sodium lauryl sulfate, and dissolve it at the lowest speed of the high-speed shear disperser, then add stearic acid and E PO, and disperse at 3000-4000 r / min. After no visible solids, magnesium stearate or talc is added as an anti-sticking agent in portions, and dispersed at 6000 r / min. It takes about 30 minutes to form a uniform aqueous dispersion. It is preferred to use a methacrylic acid-ethyl acrylate copolymer aqueous dispersion with polyethylene glycol plasticization for film coating.

[0077] Preferably, pigments or colorants may be added to the coating solution to further improve the appearance of the tablet. Preferably, pigments or colorants that do not cause destabilization, coagulation, signs of unevenness, or similar undesirable effects of the coating solution when added directly to the coating solution (such as by stirring) in a conventional amount of 5 to 40% by weight based on the weight of the coating film-forming copolymer are used. Such as various aluminum lake pigments and iron oxide pigments. Aluminum lake pigments such as: Sunset Yellow (E110, FD&C Yellow 6), Indigo Carmine (E132, FD&C Blue 2), Tartrazine (E102, FD&C Yellow 5), Cochineal Red 4R (E125, FD&C Cochineal Red A), Quinoline Yellow (E104, FD&C Yellow 10), Erythrosine (E127, FD&C Red 3), Azorubine (E122, FD&C Carmoisine), Amaranth (E123, FD&C Red 2), Acid Brilliant Green (E142, FD&C GreenS), etc. Iron oxide pigments such as: Red iron oxide, Yellow iron oxide, Purple iron oxide, Black iron oxide, Brown iron oxide, etc.

[0078] The preparation methods and coating process parameters of the above-mentioned aqueous moisture-proof coating agents all adopt the methods and process parameters recommended and disclosed by the suppliers.

[0079] The potassium chloride composite skeleton sustained-release tablets prepared by the technical solution disclosed in this patent have the following significant advantages compared with the existing technical solutions and products:

[0080] The invention has outstanding novelty: compared with the current preparation method of potassium chloride sustained-release preparation, the invention has novel technology, applies the kneading machine in the food field to the pharmaceutical field, adopts the hot-melt kneading technology to hot-melt knead and wrap a very small amount of polymer auxiliary materials and wax auxiliary materials on the surface of potassium chloride crystals, utilizes the hydrophobicity of the wax auxiliary materials and the ductility of the polymer auxiliary materials to form a firm and dense sustained-release film on the surface of the potassium chloride crystals, and obtains potassium chloride sustained-release tablets through tableting, which can be stably sustained-released within 8 hours. After complete dissolution, the tablet skeleton is complete and remains intact like a sponge, and the skeleton is not easy to break when squeezed by hand, further ensuring that there is no local sudden release of the drug.

[0081] 1. The present invention has significant innovation: compared with the potassium chloride sustained-release tablets currently available at home and abroad, the hot-melt kneading technology disclosed in this patent solves the pain point of the current potassium chloride sustained-release preparation with a small drug loading, and has the advantages of less auxiliary materials and a large drug loading (85% to 95%); in addition, this patent creates a new heat treatment process. During the heat treatment process, the polymer auxiliary materials and wax auxiliary materials in the potassium chloride sustained-release tablet core change from a solid state to a molten flow state at high temperature, which can fill the internal gaps of the tablet core and form a dense potassium chloride skeleton sustained-release tablet after cooling. The heat treatment process can improve the thermal stability of the preparation and extend its shelf life; finally, the present invention also overcomes the defects of the previous cumbersome production process of potassium chloride sustained-release tablets. The preparation process of the present invention is simple: it only involves simple and common process steps such as weighing, kneading, granulation, total mixing, tableting, heat treatment, and coating.

[0082] 3. The present invention has practical practicability: the present invention uses a kneading machine with extremely high cost performance, which is cheap and easy to obtain, easy to mass produce, and involves fewer variable parameters in the preparation process; in addition, the preparation prescription of the present invention only involves polymer excipients and wax excipients, and plasticizers, organic solvents and glidants can be selected. The total amount of excipients used is small, and the production cost is low. Most importantly, the present invention also provides a flexible and comprehensive preparation method, and potassium chloride sustained-release tablets with different sustained-release effects can be obtained by adjusting the ratio of polymer excipients and wax excipients. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The dissolution curves of the Klor-Con 8mEq reference preparation of Example 2, Example 13 and Comparative Example 1 are shown;

[0084] Figure 2 The dissolution curves of Example 11 and Comparative Example 3 K-Tab 20mEq reference preparation;

[0085] Figure 3 The dissolution curves of Examples 1, 6, 7, 8, 10 and Comparative Example 1 Klor-Con 8mEq reference preparation are shown;

[0086] Figure 4 The dissolution curves of Examples 3, 4, 5, 9 and Comparative Example 1 Klor-Con 8mEq reference preparation are shown;

[0087] Figure 5 Dissolution profiles of two tablet strengths (500 mg and 600 mg) prepared for Example 10;

[0088] Figure 6 This is the dissolution curve diagram of Example 12 before and after heat treatment. DETAILED DESCRIPTION

[0089] The specific embodiments of the present invention are further described below in conjunction with the accompanying drawings. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0090] To ensure the accuracy of data comparison, the dissolution method and detection method of potassium chloride sustained-release tablets in the following examples and comparative examples are the same, and the dissolution conditions are: slurry method; temperature: 37±0.5°C; rotation speed: 50rpm; dissolution medium: 900ml of water; double-row sampling, 10ml per row each time, after sampling, equal volume of the same medium is replenished; sampling time points: 0.5, 1, 2, 4, 6, 8h. Detection conditions: potentiometric titration, titrant: 0.01mol / L AgNO3 solution.

[0091] The raw and auxiliary materials used in the present invention are as follows:

[0092] Potassium chloride produced by Tianjin Haiguang Pharmaceutical Co., Ltd.;

[0093] Potassium chloride produced by Jiangsu Qinfen Pharmaceutical Co., Ltd.;

[0094] Potassium chloride produced by Hebei Huachen Pharmaceutical Group Co., Ltd.;

[0095] Polymethacrylate ammonium ester II (RS PO) produced by Yingde Maofeng Pharmaceutical Co., Ltd.;

[0096] Ethyl cellulose produced by Taian Ruitai Cellulose Co., Ltd.;

[0097] Hexadecanol produced by Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd.;

[0098] Octadecanol produced by Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd.;

[0099] Cetostearyl alcohol produced by Hunan Furong Pharmaceutical Co., Ltd.;

[0100] Stearic acid produced by Huzhou Zhanwang Pharmaceutical Co., Ltd.;

[0101] Glyceryl behenate produced by Guangzhou Tianrun Pharmaceutical Co., Ltd.;

[0102] Paraffin wax produced by Hunan Erkang Pharmaceutical Co., Ltd.;

[0103] Polyethylene glycol PEG 6000 produced by Nanjing Well Pharmaceutical Co., Ltd.;

[0104] Tributyl citrate TBC produced by Qihua Chemical Co., Ltd.;

[0105] Silicon dioxide produced by Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0106] Comparative Example 1 The reference preparation Klor-Con 8mEq produced by Upsher-Smith Laboratories, LLC of the United States has the following public prescription information: hydrogenated vegetable oil, magnesium stearate, polyethylene glycol, polyvinyl alcohol, silicon dioxide, talc and titanium dioxide. The dissolution rate of the reference preparation Klor-Con 8mEq was determined by the same dissolution method as in Example 1.

[0107] Comparative Example 2: Reference preparation Klor-Con 10 mEq produced by Upsher-Smith Laboratories, LLC, USA.

[0108] Comparative Example 3: The reference preparation K-Tab 20mEq produced by Abbvie, USA, has the following public prescription information: castor oil, cellulose, colloidal silicon dioxide, magnesium stearate, paraffin, polyvinyl acetate, titanium dioxide, vanillin and vitamin E. The dissolution rate of the reference preparation K-Tab 20mEq was determined by the same dissolution method as in Example 3.

[0109] Example 1

[0110] Example 1 The prescription information of potassium chloride composite skeleton sustained-release tablets is shown in the following table:

[0111] Prescription composition Excipients Number of copies Test amount (g) API Potassium chloride 100 750.0 Polymer excipients Polymethacrylate Ⅱ(RS PO) 5.33 40.0 Wax accessories Cetostearyl alcohol 2.67 20.0 Plasticizers Tributyl Citrate(TBC) 0.53 4.0 Organic solvents Ethanol 12.44 93.3 Glidants Silicon dioxide 0.16 1.2

[0112] The preparation method of potassium chloride composite skeleton sustained-release tablets in this embodiment 1 is as follows:

[0113] Potassium chloride, cetostearyl alcohol and RS PO are placed in a W-shaped kneader with a jacket, and mixed evenly at room temperature. TBC is weighed and mixed in ethanol, and then added to the kneader for melting and mixing. When the temperature rises to 55±5°C, the temperature is increased to volatilize the ethanol. When the temperature rises to 70±5°C, the heating is stopped and the temperature is cooled. The whole particles are sieved, silicon dioxide is added for total mixing, and tablets are pressed using a single-punch tablet press. The tablet weight is 653.0 mg (specification 8 mEq) and the drug loading is 92.0%. The potassium chloride sustained-release tablet core is placed in a 60±5°C oven for heat treatment for 2 hours, and the surface of the tablet is smooth and translucent.

[0114] Example 2

[0115] In the prescription of potassium chloride composite skeleton sustained-release tablets, PEG 6000 is used as a plasticizer, and no glidant is added. The prescription information of Example 2 is shown in the following table:

[0116] Prescription composition Excipients Number of copies Test amount (g) API Potassium chloride 100 750 Polymer excipients Polymethacrylate Ⅱ(RS PO) 7.33 55.0 Wax accessories Cetostearyl alcohol 3.67 27.5 Plasticizers Polyethylene glycol 6000 (PEG 6000) 0.73 5.5 Organic solvents Isopropyl alcohol 10.31 77.3

[0117] The preparation method of the potassium chloride composite skeleton sustained-release tablets of this embodiment 2 is as follows:

[0118] Potassium chloride, cetostearyl alcohol, RS PO and PEG 6000 are placed in a W-shaped kneader with a jacket, mixed evenly at room temperature, and isopropanol is added for melting and mixing; when the temperature rises to 55±5°C, the temperature is increased to volatilize the isopropanol; when the temperature rises to 70±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; a single-punch tablet press is used for tableting, with a tablet weight of 670.0 mg (specification 8mEq) and a drug loading of 89.5%; the potassium chloride sustained-release tablet core is placed in a 70±5°C oven for heat treatment for 4 hours, and the tablet surface is smooth and translucent.

[0119] Compared with Example 1, no glidant is added to the prescription of Example 2, and isopropanol is used as the organic solvent. After the material is sieved and granulated, the fluidity is good, and the tableting process is smooth, and the weight difference of the tablets is 3.0%. The dissolution experiment shows that the potassium chloride sustained-release tablets prepared in Example 2 release the drug uniformly within 8 hours, and its dissolution curve is similar to the reference preparation of Comparative Example 1 Klor-Con 8mEq, and the tablet skeleton after release is complete, sponge-like, and is not easily broken by hand. Example 2 can confirm the feasibility of the technology of the present invention without adding a glidant in the prescription.

[0120] Example 3

[0121] PEG 6000 is used as a plasticizer in the potassium chloride composite skeleton sustained-release tablets, and no organic solvent or glidant is added to the prescription. The prescription information of Example 3 is shown in the following table:

[0122] Prescription composition Excipients Number of copies Test amount (g) API Potassium chloride 100 750 Polymer excipients Polymethacrylate Ⅱ(RS PO) 6.00 45.0 Wax accessories Cetostearyl alcohol 3.00 22.5 Plasticizers Polyethylene glycol 6000 (PEG 6000) 0.60 4.5

[0123] The preparation method of the potassium chloride composite skeleton sustained-release tablets of this embodiment 3 is as follows:

[0124] Potassium chloride, cetostearyl alcohol, RS PO and PEG 6000 are placed in a W-shaped kneader with a jacket and mixed evenly at room temperature; the temperature is increased, and when the temperature rises to 90±5°C, the heating is stopped and the temperature is cooled; the whole granules are sieved; a single-punch tablet press is used for tableting, with a tablet weight of 658.0 mg (specification 8mEq) and a drug loading of 91.2%; the potassium chloride sustained-release tablet core is placed in an oven at 80±5°C for heat treatment for 16 hours, and the tablet hardness is significantly increased, and the tablet surface is smooth and translucent.

[0125] Compared with Example 2, PEG is used as a plasticizer in the prescription of Example 3, and no organic solvent is used in the prescription. When the material is kneaded, it can be melt-mixed normally, and the surface of the potassium chloride crystal is still wrapped with a layer of film coating under a microscope. The dissolution experiment shows that the potassium chloride sustained-release tablets prepared in Example 3 can release the drug evenly and slowly within 8 hours without a sudden release phenomenon, and the tablet skeleton after release is complete, sponge-like, and is not easily broken by hand. It can be confirmed by Example 3 that the technology of the present invention does not use an organic solvent in the preparation process, and potassium chloride sustained-release tablets with good sustained-release effect can still be obtained without adding a flow aid in the prescription. However, without adding an organic solvent, melt mixing requires a higher temperature and a longer time to reach the Tg of the material to ensure that the material is melt-mixed evenly, and the temperature and time of the heat treatment are higher and longer, and the energy consumption is high and the time is long without adding an organic solvent.

[0126] Example 4

[0127] No plasticizer, organic solvent or glidant is added to the prescription of potassium chloride composite skeleton sustained-release tablets. The prescription information of Example 4 is shown in the following table:

[0128] Prescription composition Excipients Number of copies Test amount (g) API Potassium chloride 100 750.0 Polymer excipients Polymethacrylate Ⅱ(RS PO) 6.00 45.0 Wax accessories Cetostearyl alcohol 3.60 27.0

[0129] The preparation method of the potassium chloride composite skeleton sustained-release tablets of this embodiment 4 is as follows:

[0130] Potassium chloride, cetostearyl alcohol and RS PO are placed in a W-shaped kneader with a jacket and mixed evenly at room temperature; the temperature is increased, and when the temperature rises to 90±5°C, the heating is stopped and the temperature is cooled; the whole granules are sieved; a single-punch tablet press is used for tableting, with a tablet weight of 658.0 mg (specification 8mEq) and a drug loading of 91.2%; the potassium chloride sustained-release tablet core is placed in a 75±5°C oven for heat treatment for 14 hours, and the tablet hardness is significantly increased, and the tablet surface is smooth and translucent.

[0131] Compared with Examples 2 and 3, only polymer excipients and wax excipients are added to the prescription of Example 4, and no plasticizer, organic solvent and flow aid are used. The materials can be smoothly carried out in melt mixing, sieving granulation, tableting and heat treatment processes, and the dissolution experiment shows that the potassium chloride sustained-release tablets prepared in Example 4 can release the drug uniformly and slowly within 8 hours without burst release, and the tablet skeleton after release is complete, sponge-like, and is not easily broken by hand. Example 4 can confirm that the technology of the present invention can also obtain potassium chloride sustained-release tablets with good sustained-release effect when only polymer excipients and wax excipients are used in the sustained-release prescription, and the drug loading of this embodiment can reach 91%, the prescription is simple, the preparation process is simple, the production cost is low, and it is easy to scale production.

[0132] Example 5

[0133] Octadecanol is used as a wax excipient in the prescription of potassium chloride composite skeleton sustained-release tablets, and no plasticizer or glidant is added to the prescription. The prescription information of Example 5 is shown in the following table:

[0134] Prescription composition Excipients Number of copies Test amount (g) API Potassium chloride 100 750.0 Polymer excipients Polymethacrylate Ⅱ(RS PO) 5.63 42.2 Wax accessories Octadecanol 3.37 25.3 Organic solvents Ethyl acetate 9.88 74.1

[0135] The preparation method of the potassium chloride composite skeleton sustained-release tablets of this embodiment 5 is as follows:

[0136] Potassium chloride, octadecyl alcohol and RS PO are placed in a W-shaped kneader with a jacket, mixed evenly at room temperature, and ethyl acetate is added for melting and mixing; when the temperature rises to 55±5°C, the temperature is increased to volatilize the ethyl acetate; when the temperature rises to 85±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; a single-punch tablet press is used for tableting, with a tablet weight of 654.0 mg (specification 8mEq) and a drug loading of 91.7%; the potassium chloride sustained-release tablet core is placed in an oven at 80±5°C for heat treatment for 12 hours, and the surface of the tablet is smooth and translucent.

[0137] Compared with Example 4, the prescription of Example 5 uses octadecyl alcohol as a wax auxiliary material, and ethyl acetate is used as an organic solvent, and the material can be smoothly carried out in melt mixing, sieving granulation, tableting and heat treatment processes. The dissolution experiment shows that the potassium chloride sustained-release tablets prepared in Example 5 can release the drug evenly and slowly within 8 hours without a sudden release phenomenon, and the tablet skeleton after release is complete, sponge-like, and is not easily broken by hand. It can be confirmed by Example 5 that when the technology of the present invention uses octadecyl alcohol as a wax auxiliary material, a potassium chloride sustained-release tablet with a good sustained-release effect can also be prepared.

[0138] Example 6

[0139] The potassium chloride composite skeleton sustained-release tablets use stearic acid as a wax excipient and ethyl cellulose as a polymer excipient, and no organic solvent or plasticizer is added to the prescription. The prescription information of Example 6 is shown in the following table:

[0140] Prescription composition Excipients Number of copies Test amount (g) API Potassium chloride 100 750.0 Polymer excipients Ethyl cellulose 4.69 35.2 Wax accessories Stearic acid 2.81 21.1 Glidants Silicon dioxide 0.16 1.2

[0141] The preparation method of the potassium chloride composite skeleton sustained-release tablets of this embodiment 6 is as follows:

[0142] Potassium chloride, stearic acid and EC are placed in a W-shaped kneader with a jacket and mixed evenly at room temperature; the temperature is increased, and when the temperature rises to 95±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; silicon dioxide is added for total mixing, and the material has good fluidity and an angle of repose of <30°; a single-punch tablet press is used for tableting, with a tablet weight of 645.0 mg (specification 8mEq) and a drug loading of 93.0%; the potassium chloride sustained-release tablet core is placed in an oven at 85±5°C for heat treatment for 20 hours, and the tablet surface is smooth and translucent, and the hardness is significantly increased.

[0143] Compared with Examples 4 and 5, in the prescription of Example 6, stearic acid is used as a wax auxiliary material and ethyl cellulose is used as a polymer auxiliary material, and no plasticizer and organic reagent are added. The materials can be smoothly carried out in melt mixing, sieving granulation, tableting and heat treatment processes, and the drug loading of the potassium chloride sustained-release tablets of this Example 6 is as high as 93.0%. The dissolution experiment shows that the potassium chloride sustained-release tablets prepared in Example 6 can release the drug uniformly and slowly within 8 hours without a sudden release phenomenon, and the drug release is less than 60% at 8 hours. It can be confirmed by Example 6 that when the technology of the present invention uses stearic acid as a wax auxiliary material and ethyl cellulose as a polymer auxiliary material, a potassium chloride sustained-release tablet with a good sustained-release effect can also be prepared.

[0144] Example 7

[0145] In the prescription of potassium chloride composite skeleton sustained-release tablets, behenic acid glyceryl is used as a wax excipient, and no organic solvent is added to the prescription. The prescription information of Example 7 is shown in the following table:

[0146] Prescription composition Excipients Number of copies Test amount (g) API Potassium chloride 100 750.0 Polymer excipients Polymethacrylate Ⅱ(RS PO) 5.33 40.0 Wax accessories Glyceryl Behenate 2.67 20.0 Plasticizers Tributyl Citrate(TBC) 0.53 4.0 Glidants Silicon dioxide 0.16 1.2

[0147] The preparation method of the potassium chloride composite skeleton sustained-release tablets of this embodiment 7 is as follows:

[0148] Potassium chloride, glyceryl behenate, RS PO and TBC are placed in a W-shaped kneader with a jacket and mixed evenly at room temperature; the temperature is increased, and when the temperature rises to 90±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; silicon dioxide is added for total mixing, and the material has good fluidity and an angle of repose of <30°; a single-punch tablet press is used for tableting, with a tablet weight of 653.0 mg (specification 8 mEq) and a drug loading of 91.9%; the potassium chloride sustained-release tablet core is placed in an oven at 85±5°C for heat treatment for 16 hours, and the surface of the tablet is smooth and translucent.

[0149] Example 8

[0150] In the prescription of potassium chloride composite skeleton sustained-release tablets, two waxes, glyceryl behenate and cetyl alcohol, are used together as wax excipients, and no organic solvent is added to the prescription. The prescription information of Example 8 is shown in the following table:

[0151]

[0152]

[0153] The preparation method of the potassium chloride composite skeleton sustained-release tablets in this embodiment 8 is as follows:

[0154] Potassium chloride, glyceryl behenate, hexadecanol, RS PO and PEG 6000 are placed in a jacketed W-shaped kneader and mixed evenly at room temperature; the temperature is increased, and when the temperature rises to 95±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; silicon dioxide is added for total mixing, and the material has good fluidity and an angle of repose of <30°; a single-punch tablet press is used for tableting, with a tablet weight of 663.0 mg (specification 8 mEq) and a drug loading of 90.5%; the potassium chloride sustained-release tablet core is placed in an oven at 85±5°C for heat treatment for 20 hours, and the surface of the tablet is smooth and translucent, and the hardness is significantly increased.

[0155] In the prescription of Example 8, two waxes, glyceryl behenate and hexadecyl alcohol, are used together as wax excipients, and the ratio of the two waxes is 1:1. PEG 6000 is used as a plasticizer in the prescription, and the materials can be smoothly carried out in melt mixing, sieving granulation, tableting and heat treatment processes. The dissolution experiment shows that the potassium chloride sustained-release tablets prepared in Example 8 can release the drug steadily and slowly within 8 hours without burst release. Example 8 can confirm the feasibility of using two wax excipients together in the technology of the present invention. Compared with Example 7, Example 8 can also effectively improve the dissolution of the tablets, so that the tablet skeleton after dissolution is complete and not easy to break.

[0156] Example 9

[0157] The potassium chloride composite skeleton sustained-release tablets use paraffin wax and cetostearyl alcohol as wax excipients. No organic solvent or plasticizer is added to the prescription. The tablet specification is 500 mg. The prescription information of Example 9 is shown in the following table:

[0158]

[0159] The preparation method of the potassium chloride composite skeleton sustained-release tablets in this embodiment 9 is as follows:

[0160] Potassium chloride, cetostearyl alcohol, paraffin and RS PO are placed in a W-shaped kneader with a jacket and mixed evenly at room temperature; the temperature is increased, and when the temperature rises to 80±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; silicon dioxide is added for total mixing, and the material has good fluidity and an angle of repose of less than 30°; a single-punch tablet press is used for tableting, with a tablet weight of 539.0 mg (specification 500 mg) and a drug loading of 92.8%; the potassium chloride sustained-release tablet core is placed in a 75±5°C oven for heat treatment for 10 hours, and the surface of the tablet is smooth and translucent.

[0161] In the prescription of Example 9, paraffin and cetostearyl alcohol are used as wax excipients, and the materials can be smoothly processed in melt mixing, sieving granulation, tableting and heat treatment processes. The dissolution experiment shows that the potassium chloride sustained-release tablets prepared in Example 9 can release the drug steadily and slowly within 8 hours without burst release. Example 9 can confirm that the technology of the present invention uses two wax excipients together, and changes the tablet specification to 500 mg, and still obtains potassium chloride sustained-release tablets with good sustained-release function.

[0162] Example 10

[0163] In the prescription of potassium chloride composite skeleton sustained-release tablets, paraffin wax and cetostearyl alcohol are used as wax excipients. No organic solvent and plasticizer are added to the prescription. The prescription information of Example 10 is shown in the following table:

[0164]

[0165] The preparation method of the potassium chloride composite skeleton sustained-release tablets in this embodiment 10 is as follows:

[0166] Potassium chloride, cetostearyl alcohol, paraffin and RS PO were placed in a W-shaped kneader with a jacket and mixed evenly at room temperature; the temperature was raised, and when the kneader temperature rose to 80±5°C, the heating was stopped and the temperature was cooled; the whole particles were sieved; silicon dioxide was added for total mixing, and the material had good fluidity and a repose angle of <30°; two specifications of tablets were prepared using a single punch tablet press, namely, tablet weight 645.0 mg (specification 8mEq) and tablet weight 538.0 mg (specification 500 mg), and the drug loading was 93.0%. The potassium chloride sustained-release tablet core was placed in an oven at 80±5°C for heat treatment for 12 hours, and the tablet surface was smooth and bright, and the hardness was significantly increased.

[0167] In the prescription of Example 10, paraffin and cetostearyl alcohol are used as wax excipients, the proportion of paraffin accounts for 1 / 5 of the total wax, and two tablets of different specifications are prepared. The dissolution data show that the potassium chloride sustained-release tablets prepared in Example 10 can release the drug steadily and slowly within 8 hours without burst release, and the dissolution curves of the two tablets are similar.

[0168] Embodiment 11

[0169] In the prescription of potassium chloride composite skeleton sustained-release tablets, paraffin wax and cetostearyl alcohol are used as wax excipients to prepare 1500 mg tablets. The prescription information of Example 11 is shown in the following table:

[0170]

[0171] The preparation method of the potassium chloride composite skeleton sustained-release tablets in this embodiment 11 is as follows:

[0172] Potassium chloride, cetostearyl alcohol, paraffin and RS PO are placed in a W-shaped kneader with a jacket, mixed evenly at room temperature, and acetone is added for melting and mixing. When the temperature rises to 55±5°C, the temperature is increased to volatilize the acetone; when the temperature rises to 85±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; silicon dioxide is added for total mixing, the material has good fluidity, and the angle of repose is less than 30°; a single-punch tablet press is used for tableting, the tablet weight is 1584 mg (specification 20mEq), and the drug loading is 94.7%; the potassium chloride sustained-release tablet core is placed in an oven at 80±5°C for heat treatment for 24 hours, and the tablet surface is smooth and translucent.

[0173] In the prescription of embodiment 11, paraffin and cetostearyl alcohol are used as wax auxiliary materials together, and the ratio of paraffin accounts for 1 / 6 of total wax, and the material can be smoothly carried out in melt mixing, sieving whole grain, tableting and heat treatment process. Shown by dissolution data, the 1500mg tablet prepared by the present embodiment can steadily and slowly release medicine within 8h, without sudden release phenomenon, and after the tablet is dissolved, the skeleton is complete, like sponge. It can be confirmed by embodiments 9, 10 and 11 that the technology of the present invention can obtain potassium chloride sustained-release tablets with good sustained-release effect in various specifications.

[0174] From the dissolution curve, it can be seen that compared with Comparative Example 3, Example 11 can improve the defects of K-Tab that the early release is fast and easy to cause gastrointestinal irritation, and Example 11 has a similar drug loading amount as K-Tab, up to 94.0%. Most importantly, the technology of the present invention can imitate potassium chloride sustained-release tablets similar to K-Tab without using PVAC, using a kneader and different wax ratios.

[0175] Example 12

[0176] Comparing the dissolution curves of potassium chloride sustained-release tablets before and after heat treatment, the prescription information of Example 12 is shown in the following table:

[0177]

[0178] The preparation method of potassium chloride composite skeleton sustained-release tablets in this embodiment 12 is as follows:

[0179] Potassium chloride, cetostearyl alcohol, paraffin and RS PO are placed in a W-shaped kneader with a jacket and mixed evenly at room temperature; the temperature is increased, and when the temperature rises to 90±5°C, the heating is stopped and the temperature is cooled; the whole particles are sieved; silicon dioxide is added for total mixing, and the material has good fluidity and an angle of repose of less than 30°; a single-punch tablet press is used for tableting, with a tablet weight of 648 mg (specification 8 mEq) and a drug loading of 92.6%; the potassium chloride sustained-release tablet core is placed in a 75±5°C oven for heat treatment for 14 hours, and the potassium chloride sustained-release tablets that have been heat treated for 14 hours and those that have not been heat treated are taken for dissolution testing.

[0180] From the dissolution curve, it can be seen that the unheat-treated potassium chloride core has a faster release in the early stage, and the release can reach 84% in 2 hours, which will cause gastrointestinal irritation and other adverse reactions. The potassium chloride sustained-release core that has been heat-healed at 75°C for 14 hours has a sustained-release effect equivalent to the reference preparation Klor-Con 8mEq. Therefore, the heat treatment process is crucial to the release of potassium chloride. During the heat treatment process, the polymer excipients and wax excipients in the potassium chloride sustained-release core change from a solid state to a molten flow state at high temperature, which can fill the gaps inside the core and form a dense potassium chloride skeleton sustained-release tablet after cooling, which can significantly improve the stability of the preparation.

[0181] Example 13

[0182] In the prescription of potassium chloride composite skeleton sustained-release tablets, hydrogenated castor oil and cetostearyl alcohol are used as wax excipients, and no organic solvent and plasticizer are added to the prescription. The prescription information of Example 13 is shown in the following table:

[0183]

[0184] Potassium chloride, cetostearyl alcohol, hydrogenated castor oil and RS PO were placed in a jacketed W-shaped kneader and mixed evenly at room temperature; the temperature was raised, and when the kneader temperature rose to 90±5°C, the heating was stopped and the temperature was cooled; the whole particles were sieved; silicon dioxide was added for total mixing, and the material had good fluidity and a repose angle of <30°; a single-punch tablet press was used for tableting, and the tablet weight was 647.0 mg (specification 8 mEq) and the drug loading was 92.7%. The potassium chloride sustained-release tablet core was placed in an oven at 85±5°C for heat treatment for 4 hours, and the tablet surface was smooth and bright, and the hardness was significantly increased.

[0185] In the prescription of Example 13, two waxes, hydrogenated castor oil and cetostearyl alcohol, are used as wax excipients, and the proportion of hydrogenated castor oil accounts for 1 / 4 of the total wax. The dissolution data show that the potassium chloride sustained-release tablet prepared in Example 13 can release the drug steadily and slowly within 8 hours without a sudden release phenomenon, and the tablet skeleton after release is intact, sponge-like, and is not easily broken by hand. In addition, the dissolution curve of Example 13 is similar to that of the reference preparation of Klor-Con 8mEq in Comparative Example 1.

[0186] The prescription information and drug loading information of the potassium chloride sustained-release tablets in the above examples are summarized as follows:

[0187]

[0188]

[0189] Embodiment 14

[0190] Example 14 is based on Example 4, with the exception that the fraction of polymer auxiliary material is 3.5, the fraction of wax auxiliary material is 1.5, and the rest remain unchanged.

[0191] Embodiment 15

[0192] Example 15 is based on Example 4, with the exception that the number of polymer auxiliary materials is 10, the number of wax auxiliary materials is 5, and the rest remain unchanged.

[0193] Example 16

[0194] Example 16 is based on Example 4, with the exception that the number of polymer auxiliary materials is modified to 7, the number of wax auxiliary materials is modified to 4, and the rest remain unchanged.

[0195] The present invention discloses a new method and technology for preparing potassium chloride sustained-release tablets. The dissolution curves with different sustained-release effects can be obtained by adjusting the ratio of polymer excipients and wax excipients. The method has extremely strong flexibility, and potassium chloride sustained-release tablets with different specifications of the same prescription obtain similar dissolution curves. Most importantly, under the condition of obtaining the same sustained-release effect, the drug loading of the sustained-release tablet of the present invention is higher, which can reach 85% to 95%, and the tablet size is smaller, which is easy for patients to swallow. The stability of the sustained-release preparation is enhanced by a heat treatment process, and its shelf life is extended. Finally, the preparation technology of potassium chloride sustained-release tablets disclosed in this patent has low production cost, simple production process, and is easy to mass produce.

[0196] The embodiments of the present invention are described in detail above with reference to the accompanying drawings, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions and variations of these embodiments are made without departing from the principles and spirit of the present invention, and still fall within the scope of protection of the present invention.

Claims

1. A potassium chloride composite skeleton sustained-release tablet, characterized in that: It includes the following components by weight:

2. The potassium chloride composite skeleton sustained-release tablet according to claim 1, characterized in that: The polymer auxiliary material is selected from one or both of quaternary ammonium methacrylate copolymer and ethyl cellulose.

3. The potassium chloride composite skeleton sustained-release tablet according to claim 1, characterized in that: The wax auxiliary material is selected from at least one of C12-C26 higher fatty acids, C12-C26 higher fatty alcohols, C12-C26 higher fatty acid glycerides, hydrogenated vegetable oils, animal and plant waxes, polyethylene waxes and mineral waxes.

4. The potassium chloride composite skeleton sustained-release tablet according to claim 1, characterized in that: The plasticizer is selected from at least one of tri-n-butyl citrate, triethyl citrate, acetyl tributyl citrate, polyethylene glycol, dibutyl sebacate, diethyl sebacate and castor oil.

5. The potassium chloride composite skeleton sustained-release tablet according to claim 1, characterized in that: The organic solvent is selected from at least one of ethanol, isopropanol, acetone and ethyl acetate.

6. The method for preparing the potassium chloride composite skeleton sustained-release tablet according to any one of claims 1 to 5, characterized in that: Potassium chloride, polymer auxiliary materials, wax auxiliary materials and optionally added plasticizers are mixed uniformly with organic reagents in a kneader at low temperature in advance, and then the temperature is raised to 70-100° C. to melt the polymer and wax auxiliary materials and uniformly coat the surfaces of potassium chloride crystals. Potassium chloride sustained-release tablet cores with sustained-release function are obtained through devolatilization, cooling, sieving and tableting.

7. The method for preparing the potassium chloride composite skeleton sustained-release tablet according to claim 6, characterized in that: After sieving, a glidant is added to the material to improve the fluidity of the material. The glidant can be selected from at least one of silicon dioxide, magnesium stearate and talc.

8. The method for preparing the potassium chloride composite skeleton sustained-release tablet according to claim 6, characterized in that: The potassium chloride sustained-release tablet core prepared by tableting is heat-treated at 60-90° C. for 2-24 hours.

9. The method for preparing the potassium chloride composite skeleton sustained-release tablet according to claim 6, characterized in that: The drug loading of the tablets is between 85% and 95%.

Images