A solid preparation for dialysis and a method for preparing the same

Abstract

The application discloses a solid preparation for dialysis and a preparation method thereof. The solid preparation comprises sodium chloride, potassium chloride, calcium chloride, magnesium chloride and a pH regulator. The sodium chloride is located in an inner layer of the preparation, the potassium chloride, the calcium chloride and the magnesium chloride are located in a middle layer of the preparation, and the pH regulator is located in an outer layer of the preparation. The pH regulator comprises glucose acid and sodium citrate. The three-layer design of the preparation not only solves the deliquescence problems of the calcium chloride and the magnesium chloride, but also solves the stability problem of the preparation. In addition, the porous sodium chloride with uniform granularity and porosity is used in the inner layer, so that the solid preparation with uniform granularity can be formed.

Description

Technical Field

[0001] This invention belongs to the field of hemodialysis technology, specifically relating to a solid preparation for dialysis and its preparation method. Background Technology

[0002] Hemodialysis uses diffusion, ultrafiltration, and convection principles to remove harmful substances and excess water from the blood. It is one of the most commonly used renal replacement therapies and is mainly suitable for end-stage renal disease, acute kidney injury, drug or toxin poisoning, and severe water, electrolyte, and acid-base imbalances.

[0003] Hemodialysis preparations can be divided into acid concentrates (A concentrate) and bicarbonate concentrates (B concentrate). A concentrate is an acidic mixture containing salts, which is used to prepare dialysate for clinical dialysis treatment by mixing it with dialysis water in a specified ratio. Considering transportation costs, storage, and container disposal, it is now generally produced as a solid dosage form, i.e., prepared as dialysis A powder and dialysis B powder.

[0004] Dialysis A powder is generally composed of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and a pH adjuster, and its formulation can be adjusted as needed. Current preparation processes typically involve directly mixing the various raw materials and then packaging them. However, due to the varying properties of the raw materials (such as particle size differences, and the high hygroscopicity of calcium chloride and magnesium chloride), this not only results in uneven particle size and a high content of fine powder in the formulation, but also makes the formulation highly unstable during long-term storage and transportation, affecting its quality and efficacy, and reducing its shelf life.

[0005] CN201811367192.4 A solid dosage form for hemodialysis and its preparation method are disclosed. Sodium chloride and potassium chloride are used as masterbatches. Other components are prepared into solutions and then adhered to the surface of the masterbatches for wet granulation. This improves the dispersion effect of the raw materials. However, calcium chloride and magnesium chloride, which are highly hygroscopic, are still on the surface of the preparation. This cannot solve the problem of moisture absorption of the preparation and also brings other problems: (1) When the pH adjuster is an organic acid salt (such as sodium citrate or sodium malate), it is easy to complex with calcium chloride and magnesium chloride to form an insoluble substance after mixing. This leads to instability of the solution during granulation and even more instability during storage and transportation after granulation, which affects the quality of the solid dosage form. (2) The adhesion of other component solutions to the surface of sodium chloride and potassium chloride is unstable. The surface layer is easy to fall off, increasing the content of fine powder and causing instability of the preparation components. (3) The particle size of the product is not uniform and the test is not up to standard.

[0006] In summary, the urgent problem to be solved is how to provide a solid dosage form for dialysis and its preparation method that can not only solve the problem of the influence of calcium chloride and magnesium chloride deliquescence on the dosage form, but also form a stable solid dosage form and improve the particle uniformity of the dosage form. Summary of the Invention

[0007] The purpose of this invention is to provide a solid preparation for dialysis and its preparation method. Through a three-layer design consisting of an inner layer (sodium chloride), a middle layer (potassium chloride, calcium chloride, magnesium chloride), and an outermost layer (pH adjuster), the deliquescence problem of calcium chloride and magnesium chloride is solved, as well as the stability problem of the preparation. Furthermore, the inner layer uses porous sodium chloride with uniform particle size and pore size, which can form a solid preparation with uniform particle size.

[0008] The objective of this invention is achieved as follows:

[0009] A solid dosage form for dialysis includes sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and a pH adjuster, with a conventional formulation of its main components. The sodium chloride is located in the inner layer of the dosage form, the potassium chloride, calcium chloride, and magnesium chloride are located in the middle layer, and the pH adjuster is located in the outer layer. The pH adjuster includes gluconic acid and sodium citrate.

[0010] Furthermore, the mass ratio of gluconic acid to sodium citrate is 1:(0.1-0.4).

[0011] The present invention also provides a method for preparing the above-mentioned solid dosage form for dialysis, specifically including the following steps:

[0012] (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in water to form liquid one, spray the solution one onto the surface of sodium chloride for wet granulation, and obtain the first particle;

[0013] (2) Add water to the pH adjuster to make liquid II, spray liquid II onto the surface of the first particle, and then dry it to obtain the solid preparation for dialysis.

[0014] The present invention also provides sodium chloride for use in solid preparations for dialysis, wherein the sodium chloride is porous sodium chloride, and the method for preparing the porous sodium chloride includes the following steps:

[0015] S1. Mix sodium chloride powder with additives evenly, and then dry press (25-40 tons of pressure) to form the product. The additives include bicarbonate and water in a mass ratio of 1:(10-20).

[0016] S2. Heat the molded body at 60-70℃ for 1-5 hours, then place it in a rotary evaporator (80-90℃) to evaporate and remove volatile small molecules, then wash with ethanol and dry.

[0017] S3. Dry the material obtained in step S2 at 110-130℃ for 20-40 minutes, then sinter it at 810-850℃ for 1-3 hours, and then cool it to room temperature to obtain porous sodium chloride.

[0018] Furthermore, the bicarbonate is triethylammonium bicarbonate, and the amount of additive added is 4-13% of the mass of sodium chloride powder.

[0019] This invention also provides another method for preparing a solid dosage form for dialysis, wherein the outer layer of the solid dosage form further includes coated sodium chloride flake crystals and sodium hexametaphosphate, the coated sodium chloride flake crystals being formed by spraying molten higher fatty acid acid onto the surface of the sodium chloride flake crystals, and the method for preparing the solid dosage form for dialysis includes the following steps:

[0020] (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in water to form liquid one, spray the solution one onto the surface of sodium chloride for wet granulation, and obtain the first particle;

[0021] (2) At room temperature, the pH adjuster and sodium hexametaphosphate are dissolved in water, and then coated sodium chloride flake crystals are added to obtain liquid two. Liquid two is sprayed onto the surface of the first particle and then dried. Then, the coating layer on the surface of the sodium chloride flake crystals is removed by ultrasonic washing with acetone and then dried to obtain the solid preparation for dialysis.

[0022] Furthermore, the higher fatty acid is 3-methyl-15-phenylpentadecanoic acid.

[0023] Furthermore, the mass of the coated sodium chloride flake crystals and sodium hexametaphosphate is 6-14% and 5-8% of the mass of gluconic acid, respectively, and the mass ratio of the higher fatty acid to the sodium chloride flake crystals is (0.05-0.08):1.

[0024] Furthermore, in step (1), the amount of water used in liquid one is 1-2 times the total mass of potassium chloride, calcium chloride, and magnesium chloride, and in step (2), the amount of water used in liquid two is 1-3 times the mass of the pH adjuster.

[0025] Preparation of sodium chloride flaky crystals:

[0026] Dissolve excess sodium chloride in deionized water and stir at room temperature for 9-12 hours. Filter to obtain the mother liquor (i.e., a saturated aqueous solution of sodium chloride at room temperature). Add glycine (3-6% of the saturated solution) to the saturated solution. Then place the resulting solution in an open container and evaporate it in a 40°C forced-air drying oven for 4-6 hours. Filter and dry to obtain sodium chloride flaky crystals with a length of 100-300 μm and a thickness of 10-20 μm.

[0027] The present invention also provides the application of a solid dosage form for dialysis in the preparation of a hemodialysis drug, wherein the drug is prepared by combining the above-mentioned solid dosage form for dialysis as agent A with agent B containing sodium bicarbonate.

[0028] The beneficial effects of this invention are:

[0029] 1. The inner layer of the solid dialysis preparation of the present invention is sodium chloride (masterbatch), the middle layer is potassium chloride, calcium chloride and magnesium chloride, and the outer layer is a pH adjuster. This not only solves the deliquescence problem of calcium chloride and magnesium chloride, but also solves the problem of stable coexistence of organic acid salt pH adjusters with calcium chloride and magnesium chloride.

[0030] 2. In this invention, porous sodium chloride is selected. Its porous structure can be tightly adsorbed with the middle layer, promoting the stable bonding between the inner and middle layers. The outer layer contains gluconic acid and citric acid. After the two form a large number of hydrogen bonds in an aqueous solution in a certain proportion, they can easily form an adhesion layer on the surface of the middle layer. Therefore, the three-layer structure of the solid dialysis preparation prepared by this invention is tightly bonded, and can form a stable system without falling off.

[0031] 3. In order to obtain a solid preparation for dialysis with uniform particle size, this invention is the first to start by improving the uniform particle size of sodium chloride masterbatch. Using bicarbonate as a pore-forming agent, it is possible to prepare porous sodium chloride with high porosity, uniform pore size and good uniformity. Furthermore, the porous sodium chloride sintered at high temperature can effectively remove impurities and microorganisms (such as endotoxins), resulting in high product purity.

[0032] 4. Because porous sodium chloride is easily broken due to the instability of the pores, the particle size of the porous sodium chloride actually involved in the formulation production process varies greatly, which increases the fine powder content of the solid formulation. The bicarbonate of the present invention is further selected as triethylammonium bicarbonate, which decomposes rapidly under heating conditions to produce carbon dioxide to create pores. It not only plays a role in pore creation, but also has the effect of stabilizing pores and tightening shrinkage.

[0033] The decomposition products of triethylammonium bicarbonate contain tertiary amines, which have an anti-adhesion effect. They can prevent the inner walls of pores from sticking together during the pore formation process and promote the stability of the pore structure. In addition, the tertiary amines in the pores can absorb water vapor from sodium chloride materials, causing the area around the pores to shrink and form compact pores.

[0034] The stable and compact pores also enhance the stability and strength of porous sodium chloride, enabling the particle size stability of porous sodium chloride to be maintained during the formulation production process.

[0035] 5. Since the inner layer of the solid preparation, sodium chloride masterbatch, has a highly absorbent porous structure, and the middle layer contains highly deliquescent calcium chloride and magnesium chloride, the present invention needs to further enhance the protective effect of the outer layer on the internal materials. Accordingly, the present invention also adds coated sodium chloride flake crystals to the outer layer. Pure sodium chloride is very stable to moisture in the air, and the sodium chloride flake crystals dispersed in the outer layer form multiple barrier layers, which significantly enhances the stability of the preparation.

[0036] 6. In order to prevent sodium chloride flake crystals from dissolving in water and affecting their crystal form during solid dosage form preparation, the present invention also coats the sodium chloride flake crystals with higher fatty acids, which can isolate the sodium chloride flake crystals from water and maintain the flake crystal morphology of sodium chloride. Finally, the higher fatty acids are washed with acetone to remove them, which will not affect the composition of the solid dosage form.

[0037] Furthermore, the advanced fatty acid used in this invention is 3-methyl-15-phenylpentadecanoic acid, which, after coating the surface of sodium chloride flake crystals, can improve the strength of the crystals and prevent the brittle sodium chloride flake crystals from breaking during formulation preparation. In addition, after the molten 3-methyl-15-phenylpentadecanoic acid is coated on the surface of sodium chloride flake crystals and cooled, its shrinkage is small, avoiding damage to the crystals.

[0038] 7. The outer layer of the solid formulation of the present invention also contains sodium hexametaphosphate, which not only plays a binding and dispersing role in the outer layer material, but also adheres to the surface of the coated sodium chloride flake crystals, which can fill the pores left after the coating layer is removed and ensure the integrity of the outer layer structure. Implementation

[0039] The present invention will be further described below with reference to embodiments. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0040] Example 1

[0041] The main formulation of the solid dialysis preparation in this embodiment is as follows:

[0042]

[0043] In this embodiment, sodium chloride is located in the inner layer of the formulation, potassium chloride, calcium chloride, and magnesium chloride are located in the middle layer of the formulation, and the pH adjuster is located in the outer layer of the formulation. The pH adjuster includes gluconic acid and sodium citrate in a mass ratio of 1:0.1.

[0044] Preparation method of solid dosage forms for dialysis:

[0045] (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in an equal amount of water to form liquid one. Filter the solution one (0.1-1μm) and spray it onto the surface of sodium chloride for conventional wet granulation to obtain the first particle.

[0046] (2) Add 1 part water to the pH adjuster to make liquid two, spray liquid two onto the surface of the first particle, and then dry to obtain the solid preparation for dialysis.

[0047] Example 2

[0048] Based on Example 1, the sodium chloride in this example is porous sodium chloride, and its preparation method includes the following steps:

[0049] S1. Mix sodium chloride powder and additives evenly, and then dry press (25 tons pressure) to form the product. The amount of additive added is 4% of the mass of sodium chloride powder, which includes triethylammonium bicarbonate and water in a mass ratio of 1:10.

[0050] S2. Heat the molded body at 60℃ for 5 hours, then place it in a rotary evaporator (80℃) to evaporate and remove volatile small molecules, then wash with ethanol and dry.

[0051] S3. The material obtained in step S2 is dried at 110℃ for 40 min, then sintered at 810℃ for 3 h, and then cooled to room temperature to obtain uniform porous sodium chloride with a particle size of 50-100 μm.

[0052] The rest is the same as in Example 1.

[0053] Example 3

[0054] Based on Example 2, the outer layer of the solid dialysis preparation in this example further includes coated sodium chloride flake crystals and sodium hexametaphosphate. The coated sodium chloride flake crystals are formed by spraying molten 3-methyl-15-phenylpentadecanoic acid onto the surface of the sodium chloride flake crystals. The mass of the coated sodium chloride flake crystals and sodium hexametaphosphate is 6% and 5% of the mass of gluconic acid, respectively, and the mass ratio of the higher fatty acid to the sodium chloride flake crystals is 0.05:1.

[0055] Preparation of sodium chloride flaky crystals:

[0056] Excess sodium chloride was dissolved in deionized water and stirred at room temperature for 9 hours. The solution was then filtered to obtain the mother liquor (i.e., a saturated aqueous solution of sodium chloride at room temperature). Glycine (3% of the saturated solution) was added to the saturated solution. The resulting solution was then placed in an open container and evaporated in a 40°C forced-air drying oven for 4 hours. After filtration and drying, sodium chloride flaky crystals were obtained. The length of the crystals was 100-300 μm and the thickness was 10-20 μm.

[0057] The method for preparing the solid dosage form for dialysis includes the following steps:

[0058] (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in an equal amount of water to form liquid one. Spray solution one onto the surface of sodium chloride for wet granulation to obtain the first particle.

[0059] (2) At room temperature, the pH adjuster and sodium hexametaphosphate are dissolved in water (the amount of water is 1 times the mass of the pH adjuster), and then coated sodium chloride flake crystals are added to obtain liquid two. Liquid two is sprayed onto the surface of the first particle and then dried. Then, the coating layer on the surface of the sodium chloride flake crystals is removed by ultrasonic washing with acetone and then dried to obtain the solid preparation for dialysis.

[0060] The rest is the same as in Example 2.

[0061] Example 4

[0062] The main formulation of the solid dialysis preparation in this embodiment is as follows:

[0063]

[0064] In this embodiment, the inner layer of the formulation is sodium chloride, the middle layer is composed of potassium chloride, calcium chloride, and magnesium chloride, and the outer layer comprises a pH adjuster, coated sodium chloride flake crystals, and sodium hexametaphosphate. The pH adjuster comprises gluconic acid and sodium citrate in a mass ratio of 1:0.2. The mass of the coated sodium chloride flake crystals and sodium hexametaphosphate is 10% and 6% of the mass of gluconic acid, respectively. The coated sodium chloride flake crystals are formed by spraying molten 3-methyl-15-phenylpentadecanoic acid onto the surface of the sodium chloride flake crystals, with a mass ratio of 3-methyl-15-phenylpentadecanoic acid to sodium chloride flake crystals of 0.07:1.

[0065] The sodium chloride is porous sodium chloride, and its preparation method includes the following steps:

[0066] S1. Mix sodium chloride powder and additives evenly, and then dry press (32 tons pressure) to form the mixture. The amount of additive added is 8% of the mass of sodium chloride powder, which includes triethylammonium bicarbonate and water in a mass ratio of 1:15.

[0067] S2. Heat the molded body at 65°C for 3 hours, then place it in a rotary evaporator (85°C) to evaporate and remove volatile small molecules, then wash with ethanol and dry.

[0068] S3. The material obtained in step S2 is dried at 120℃ for 30 min, then sintered at 830℃ for 2 h, and then cooled to room temperature to obtain uniform porous sodium chloride with a particle size of 50-100 μm.

[0069] Preparation of sodium chloride flaky crystals:

[0070] Excess sodium chloride was dissolved in deionized water and stirred at room temperature for 10 hours. The solution was then filtered to obtain a mother liquor (i.e., a saturated aqueous solution of sodium chloride at room temperature). Glycine (4.5% of the saturated solution) was added to the saturated solution. The resulting solution was then placed in an open container and evaporated in a 40°C forced-air drying oven for 5 hours. After filtration and drying, sodium chloride flake crystals were obtained. The length of the crystals was 100-300 μm and the thickness was 10-20 μm.

[0071] Preparation of solid dosage forms for dialysis:

[0072] (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in 1.5 times the amount of water to form liquid one. Spray solution one onto the surface of sodium chloride for wet granulation to obtain the first particle.

[0073] (2) At room temperature, the pH adjuster and sodium hexametaphosphate are dissolved in water (the amount of water is twice the mass of the pH adjuster), and then coated sodium chloride flake crystals are added to obtain liquid two. Liquid two is sprayed onto the surface of the first particle and then dried. Then, the coating layer on the surface of the sodium chloride flake crystals is removed by ultrasonic washing with acetone and then dried to obtain the solid preparation for dialysis.

[0074] The rest is the same as in Example 3.

[0075] Example 5

[0076] The main formulation of the solid dialysis preparation in this embodiment is as follows:

[0077]

[0078] In this embodiment, the inner layer of the formulation is sodium chloride, the middle layer is composed of potassium chloride, calcium chloride, and magnesium chloride, and the outer layer comprises a pH adjuster, coated sodium chloride flake crystals, and sodium hexametaphosphate. The pH adjuster comprises gluconic acid and sodium citrate in a mass ratio of 1:0.4. The masses of the coated sodium chloride flake crystals and sodium hexametaphosphate are 14% and 8% of the mass of gluconic acid, respectively. The coated sodium chloride flake crystals are formed by spraying molten 3-methyl-15-phenylpentadecanoic acid onto the surface of sodium chloride flake crystals, with a mass ratio of 3-methyl-15-phenylpentadecanoic acid to sodium chloride flake crystals of 0.08:1.

[0079] The sodium chloride is porous sodium chloride, and its preparation method includes the following steps:

[0080] S1. Mix sodium chloride powder and additives evenly, and then dry press (40 tons pressure) to form the mixture. The amount of additive added is 13% of the mass of sodium chloride powder, which includes triethylammonium bicarbonate and water in a mass ratio of 1:20.

[0081] S2. Heat the molded body at 70°C for 1 hour, then place it in a rotary evaporator (90°C) to evaporate and remove volatile small molecules, then wash with ethanol and dry.

[0082] S3. The material obtained in step S2 is dried at 130℃ for 20 min, then sintered at 850℃ for 1 h, and then cooled to room temperature to obtain uniform porous sodium chloride with a particle size of 50-100 μm.

[0083] Preparation of sodium chloride flaky crystals:

[0084] Excess sodium chloride was dissolved in deionized water and stirred at room temperature for 12 hours. The solution was then filtered to obtain a mother liquor (i.e., a saturated aqueous solution of sodium chloride at room temperature). Glycine (6% of the saturated solution) was added to the saturated solution. The resulting solution was then placed in an open container and evaporated in a 40°C forced-air drying oven for 6 hours. After filtration and drying, sodium chloride flake crystals were obtained. The length of the crystals was 100-300 μm and the thickness was 10-20 μm.

[0085] Preparation of solid dosage forms for dialysis:

[0086] (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in twice the amount of water to form liquid one. Spray solution one onto the surface of sodium chloride for wet granulation to obtain the first particle.

[0087] (2) At room temperature, the pH adjuster and sodium hexametaphosphate are dissolved in water (the amount of water is 3 times the mass of the pH adjuster), and then coated sodium chloride flake crystals are added to obtain liquid two. Liquid two is sprayed onto the surface of the first particle and then dried. Then, the coating layer on the surface of the sodium chloride flake crystals is removed by ultrasonic washing with acetone and then dried to obtain the solid preparation for dialysis.

[0088] The rest is the same as in Example 3.

[0089] Comparative Example 1

[0090] The difference between this comparative example and Example 1 is that the solid preparation for dialysis consists of only two layers: an inner layer of sodium chloride and an outer layer of potassium chloride, calcium chloride, magnesium chloride, and a pH adjuster.

[0091] Comparative Example 2

[0092] The difference between this comparative example and Example 1 is that the inner layer of the solid dialysis preparation is sodium chloride and potassium chloride.

[0093] Comparative Example 3

[0094] The difference between this comparative example and Example 1 is that, in the solid dialysis preparation, sodium chloride is located in the inner layer of the preparation, the pH adjuster is located in the middle layer of the preparation, and potassium chloride, calcium chloride, and magnesium chloride are located in the outer layer of the preparation.

[0095] Comparative Example 4

[0096] The difference between this comparative example and Example 1 is that the pH adjuster in the solid dialysis preparation is gluconic acid.

[0097] Comparative Example 5

[0098] The difference between this comparative example and Example 1 is that the pH adjuster in the solid dialysis preparation is sodium citrate.

[0099] Comparative Example 6

[0100] The difference between this comparative example and Example 1 is that the pH adjuster in the solid dialysis preparation is citric acid.

[0101] Comparative Example 7

[0102] The difference between this comparative example and Example 1 is that the mass ratio of gluconic acid to sodium citrate in the solid dialysis preparation is 1:0.05.

[0103] Comparative Example 8

[0104] The difference between this comparative example and Example 1 is that the mass ratio of gluconic acid to sodium citrate in the solid dialysis preparation is 1:0.5.

[0105] Comparative Example 9

[0106] The difference between this comparative example and Example 2 is that, in the preparation step of the porous sodium chloride, the bicarbonate in the additive is replaced with polyvinyl alcohol.

[0107] Comparative Example 10

[0108] The difference between this comparative example and Example 2 is that, in the preparation step of the porous sodium chloride, the bicarbonate in the additive is sodium bicarbonate.

[0109] Comparative Example 11

[0110] The difference between this comparative example and Example 2 is that, in the preparation step of the porous sodium chloride, the bicarbonate in the additive is ammonium bicarbonate.

[0111] Comparative Example 12

[0112] The difference between this comparative example and Example 2 is that, in the preparation step of the porous sodium chloride, the amount of additive added is 3% of the mass of the sodium chloride powder.

[0113] Comparative Example 13

[0114] The difference between this comparative example and Example 2 is that, in the preparation step of the porous sodium chloride, the amount of additive added is 14% of the mass of the sodium chloride powder.

[0115] Comparative Example 14

[0116] The difference between this comparative example and Example 3 is that the outer layer of the solid dialysis preparation does not contain sodium hexametaphosphate.

[0117] Comparative Example 15

[0118] The difference between this comparative example and Example 3 is that the outer layer of the solid dialysis preparation does not contain coated sodium chloride flake crystals.

[0119] Comparative Example 16

[0120] The difference between this comparative example and Example 3 is that the sodium chloride flakes in the coated sodium chloride flake crystals are replaced with conventional sodium chloride powder.

[0121] Comparative Example 17

[0122] The difference between this comparative example and Example 3 is that the coated sodium chloride flake crystals are directly replaced with sodium chloride flake crystals, that is, no coating is performed.

[0123] Comparative Example 18

[0124] The difference between this comparative example and Example 3 is that the 3-methyl-15-phenylpentadecanoic acid coating on the surface of the sodium chloride flake crystals is replaced with stearic acid.

[0125] I. Basic parameters of the solid dialysis preparation obtained by this invention

[0126] Following the relevant methods in the pharmaceutical industry standard "Concentrates for Hemodialysis and Related Uses" (YY 0598-2015), the solid preparations obtained in Examples 1-5 of this invention were dissolved and subjected to relevant tests. The results are shown in Table 1 below.

[0127] Table 1

[0128]

[0129] As can be seen from Table 1, the solid dialysis preparations obtained in Examples 1-5 of the present invention meet all the requirements of industry standards and are of excellent quality.

[0130] II. Particle uniformity of the solid dialysis preparation obtained by the present invention

[0131] The particle size distribution of the solid formulations prepared in Examples 1-5 and Comparative Examples 1-18 of this invention was tested, and the results are shown in Table 2 below.

[0132] Table 2

[0133]

[0134] As can be seen from Table 2, the solid dialysis preparations obtained in Examples 1-5 of the present invention have a fine powder content of less than 1.25%, especially in Examples 3-5 where the fine powder content is less than 0.10%, and the particle size distribution of the preparations is between 10-24 mesh, with good particle uniformity.

[0135] Building upon Example 1, Example 2 used porous sodium chloride with uniform particle size as the inner layer. This not only improved the uniformity of the inner layer but also ensured a tighter bond between the inner and intermediate layers, ultimately enhancing the particle uniformity of the formulation. Building upon Example 2, Example 3 further incorporated coated sodium chloride flaky crystals and sodium hexametaphosphate into the outer layer of the formulation for protection. This addressed the issues of high water absorption in the porous masterbatch of the inner layer and high deliquescence in the intermediate layer, further improving and stabilizing the particle uniformity of the formulation.

[0136] Compared with Example 1, Comparative Examples 1-8 changed the design of the inner, middle, and outer layers of the solid dialysis formulation and the type of pH adjuster, respectively; compared with Example 2, Comparative Examples 9-13 changed the type and amount of porous sodium chloride additive, respectively; compared with Example 3, Comparative Examples 14-18 changed the outer layer components, respectively; the particle uniformity of the final formulations all decreased to varying degrees.

[0137] III. Stability of the solid dialysis preparation obtained by this invention

[0138] In accordance with the relevant methods of "Concentrates for Hemodialysis and Related Uses" (YY 0598-2015), the initial solute concentration and the solute concentration after one year of storage of the solid dialysis preparations prepared in Examples 1, 3-5 and Comparative Examples 1-8, 14-18 of this invention were tested. The results are shown in Tables 3 and 4 below.

[0139] Table 3 Initial solute concentration (%)

[0140]

[0141]

[0142] Table 4. Solute concentration (%) after 1 year of storage

[0143]

[0144]

[0145] The stability of solute concentration is related to the structural stability and homogeneity of the formulation itself, as well as the coexistence stability between its components. As shown in Table 3 above, the initial solute concentrations of the solid dialysis preparations obtained by this invention all meet industry requirements. Comparison of Table 3 and Table 4 above shows that the solid dialysis preparations obtained in Examples 3-5 of this invention exhibit good component stability, with no significant change in solute concentration after one year of storage.

[0146] Based on Example 1, Example 3 used porous sodium chloride with uniform particle size as the inner layer, and also added coated sodium chloride flake crystals and sodium hexametaphosphate to the outer layer of the formulation for protection. Therefore, the stability of Example 3 is higher than that of Example 1.

[0147] Compared with Example 1, Comparative Examples 1-8 changed the design of the inner, middle, and outer layers of the solid dosage form for dialysis, as well as the type of pH adjuster; compared with Example 3, Comparative Examples 14-18 changed the components added to the outer layer; the stability of the final formulations decreased to varying degrees.

[0148] It should be noted that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A solid preparation for dialysis, comprising sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and a pH adjuster, characterized in that: The sodium chloride is located in the inner layer of the formulation, the potassium chloride, calcium chloride, and magnesium chloride are located in the middle layer of the formulation, and the pH adjuster is located in the outer layer of the formulation. The pH adjuster is composed of gluconic acid and sodium citrate. The mass ratio of gluconic acid to sodium citrate is 1:(0.1-0.4).

2. A method for preparing a solid dialysis preparation according to claim 1, characterized in that: Specifically, the following steps are included: (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in water to form liquid one, spray liquid one onto the surface of sodium chloride for wet granulation to obtain the first particle; (2) Add water to the pH adjuster to make liquid II, spray liquid II onto the surface of the first particle, and then dry it to obtain the solid preparation for dialysis.

3. The method for preparing solid dialysis preparations according to claim 2, characterized in that: In step (1), the amount of water used in liquid one is 1-2 times the total mass of potassium chloride, calcium chloride, and magnesium chloride. In step (2), the amount of water used in liquid two is 1-3 times the mass of the pH adjuster.

4. A method for preparing a solid dialysis preparation according to claim 1, characterized in that: The outer layer of the solid dialysis preparation further includes coated sodium chloride flake crystals and sodium hexametaphosphate. The coated sodium chloride flake crystals are made by spraying molten higher fatty acid acids onto the surface of the sodium chloride flake crystals. The preparation method of the solid dialysis preparation includes the following steps: (1) Dissolve potassium chloride, calcium chloride and magnesium chloride in water to form liquid one, spray liquid one onto the surface of sodium chloride for wet granulation to obtain the first particle; (2) At room temperature, the pH adjuster and sodium hexametaphosphate are dissolved in water, and then coated sodium chloride flake crystals are added to obtain liquid two. Liquid two is sprayed onto the surface of the first particle and then dried. Then, the coating layer on the surface of the sodium chloride flake crystals is removed by ultrasonic washing with acetone and then dried to obtain the solid preparation for dialysis.

5. The method for preparing solid dialysis preparations according to claim 4, characterized in that: The higher fatty acid is 3-methyl-15-phenylpentadecanoic acid.

6. The method for preparing solid dialysis preparations according to claim 4, characterized in that: The mass of the coated sodium chloride flake crystals and sodium hexametaphosphate is 6-14% and 5-8% of the mass of gluconic acid, respectively, and the mass ratio of the higher fatty acids to the sodium chloride flake crystals is (0.05-0.08):

1.

7. The application of a solid dosage form for dialysis in the preparation of hemodialysis drugs, characterized in that: The drug is prepared as agent A, using the solid dialysis formulation of claim 1, and combined with agent B, which contains sodium bicarbonate.

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