KR20090067809A - Solid preparation for dialysis and preparation method thereof - Google Patents

Abstract

The present invention relates to a process for the preparation of a solid preparation for dialysis, and to a solid preparation for dialysis, which is prepared by the preparation method and which comprises a) an electrolyte and b) a pH adjusting agent, and which may further comprise c) glucose. The solid preparation for dialysis of the present invention, unlike conventional dialysis solvent powder or granules, has a high dissolution rate and low hygroscopicity so that the dialysis solution can be prepared quickly and easily. There is an advantage that can be provided.

Description

A solid formulation for dialysis and a method for processing thereof

The present invention relates to a process for the preparation of a solid preparation for dialysis, and to a solid preparation for dialysis, which is prepared by the preparation method and which comprises a) an electrolyte and b) a pH adjusting agent, and which may further comprise c) glucose.

Dialysis therapy is aimed at removing wastes in the blood of renal failure patients and controlling electrolytes.The dialysis solution used here is prepared by diluting a solution containing various electrolytes and pH adjusting agents and sodium bicarbonate in water for injection. do.

Formulations containing the various types of electrolytes described above typically contain at least two or more electrolytes from among electrolytes such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, and produce a powder having a uniform content of each component. Since it is difficult to prepare in a liquid phase (Liquid Phase), but in consideration of the ease of storage, it is preferable to be prepared in a solid (Solid Phase) formulation in the form of a powder.

Accordingly, Japanese Patent Application Laid-Open No. 1994-335528 and Japanese Patent Application Laid-Open No. 1990-311418 include mixing, compressing, grinding and assembling the electrolyte components of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate in a dry granulation apparatus. Later, a method of producing granules by pulverization is disclosed, and Japanese Patent Laid-Open No. 2004-121822 discloses a method of granulating by spraying a solution of glucose or calcium chloride dissolved in a pulverized electrolyte component. However, there is a disadvantage in that foreign matter may be mixed due to wear of the device during compression and grinding, and components such as calcium chloride and magnesium chloride have deliquequescence and are difficult to be uniformly mixed, thereby obtaining granules having a uniform content. It is difficult to achieve uniformity of the content of the pulverized electrolyte only through a mixing process in a separate special mixing facility that can mix the pulverized product after pulverization, and thus there is a problem that the overall manufacturing process becomes long and complicated. In addition, the conventional solid preparations prepared as described above have a high hygroscopicity and exhibit a phenomenon that the dissolution rate is remarkably lowered by forming solids due to aggregation or aggregation during long-term storage.

Further, Japanese Laid-Open Patent Publication No. 1999-343230, Japanese Laid-Open Patent Publication No. 2000-26280, Japanese Laid-Open Patent Publication No. 2001-149468, Japanese Laid-Open Patent Publication No. 2001-327597 and the like have a fluidized bed assembly in which sodium chloride particles are coated with another electrolyte. A method for producing a solid formulation by the method is disclosed, and Japanese Patent Application Laid-Open No. 1994-178802 and Japanese Patent Application Laid-Open No. 1994-4562 disclose a method for producing a solid formulation having a bilayer structure having nuclear particles, and registered in Korea. No. 398299 discloses a solid dialysis agent comprising sodium chloride and calcium chloride as nucleus layers, two electrolyte layers and a pH adjuster, and three layers of glucose. However, since the solid dialysis agent is delayed in dissolving sodium chloride particles, which serve as seeds during dissolution, do not dissolve simultaneously with other coated components and remain completely dissolved, the dissolution rate increases. Therefore, there is a problem in that the dissolution of the nuclear particles is slow if not sufficiently stirred during the preparation of the dialysate solution, and it is difficult to visually identify the electrolyte insoluble particles in water, thereby providing a patient with a dialysate solution in which the electrolyte is not completely dissolved. In addition, in the case of a fluidized bed granulation method of coating another electrolyte solution, there is a problem that low density and low strength granules are easily generated, and in the method of preparing a solid preparation having a two-layer structure, between electrolytes during heating and mixing during the manufacturing process Because of the sticky nature, it is difficult to uniformly distribute each component, so that content irregularities easily occur, and thus, a large facility is required to prevent this, and thus, there is a disadvantage that a specialized and large-scale facility is required. .

In addition, WO81 / 00515 discloses a powder dialysis preparation using a spray drying method, which is intended to improve the distribution of electrolyte components uniformly, and does not solve the problem of low fluidity or low solubility of the spray dried material.

As described above, the solid preparation for dialysis prepared by the conventional manufacturing method has problems such as content unevenness, high hygroscopicity, low flowability and / or dissolution rate.

Accordingly, the present inventors have studied to solve the above problems, and as a result of spray drying the electrolyte solution to prepare a spray dried product, a high content uniformity, high fluidity, low flow through the process of granulating by spraying a binder on the spray dried material Granules having a mass deviation and low hygroscopicity and a particularly good dissolution rate were prepared, and solid granules for dialysis were prepared by spraying a pH modifier such as acetic acid on the granules.

Thus, the present inventors confirmed that the solid preparation for dialysis prepared by the above production method solved the above-mentioned problems and completed the present invention.

That is, an object of the present invention is to provide a solid preparation for dialysis and a method for producing the same, which have improved dissolution rate, uniformity of content distribution of each component, and production efficiency.

In order to achieve the above object, the present invention after preparing an aqueous electrolyte solution, the first step of preparing a spray dried thereof; A second step of preparing granules by spraying a binder solution on the spray dried material of the first step; And a third step of drying and granulating the granules prepared in the second step and spraying the pH adjuster.

In the manufacturing method of the present invention, prior to performing the second step may further comprise the step of mixing the glucose powder in the spray drying of the first step. In this case, the binder solution in the second step is sprayed onto the mixture of the spray dried product and the glucose prepared in the first step.

In the production method of the present invention, the spray dried product is the electrolyte solution inlet temperature (In-Let temp.): 100 ~ 300 ℃, Outlet temperature (Out-Let temp.): 100 ~ 200 ℃, air injection rate 600 ~ It is characterized in that it is prepared by spray drying under conditions of 1000 l / h.

The electrolyte component of the present invention is characterized in that it is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate and mixtures thereof.

The binder solution of the present invention is characterized by using water or aqueous glucose solution, preferably 0-50% aqueous glucose solution.

Addition amount of the binder solution of the present invention is characterized in that 3 to 10% by weight, preferably 5 to 7% by weight relative to the total weight of the spray dried product or the mixture of the spray dried product and the glucose powder.

PH adjuster of the present invention is characterized in that it is added in an amount of 1.0 to 4.0% by weight based on the total weight of the granules. The pH adjuster is characterized in that at least one selected from the group consisting of acetic acid, oxalic acid, succinic acid, citric acid, tartaric acid, an organic acid including maleic acid and an inorganic acid containing hydrochloric acid.

In addition, the present invention is prepared by the above production method, and after the 15 g of the solid preparation for dialysis in a flow cell (Matersizer X, Malvern, UK) using a particle size analyzer (Matersizer X, Malvern, UK), the particles of the preparation is dissolved A solid preparation for dialysis is provided, wherein the time for starting the preparation particles to completely dissolve and disappear is 110 seconds or less.

The present invention also provides a solid preparation for dialysis, which is prepared by the above production method and which comprises a) an electrolyte component and b) a pH adjuster.

Solid preparation for dialysis of the present invention is characterized in that it may further comprise c) glucose in addition to the above components.

Hereinafter, the present invention will be described in detail.

The present invention after preparing an aqueous electrolyte solution, the first step of preparing a spray dried material thereof; A second step of preparing granules by spraying a binder solution on the spray dried material of the first step; And a third step of drying and granulating the granules prepared in the second step and injecting and mixing the pH adjusting agent.

Here, the electrolyte solution in the first step is an electrolyte component selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate and mixtures thereof in water or purified water and 30 to 50 ℃ preferably 40 ℃ It is prepared by heating. At this time, the total weight of the electrolyte component is used 2 to 4% by weight based on the total weight of water or purified water.

In addition, the spray dried material is left in the electrolyte solution prepared as described above for 10 to 15 hours, preferably about 12 hours, the input temperature (In-Let temp.): 100 ~ 300 ℃, the discharge temperature (Out-Let temp.): It is prepared by spray drying under conditions of 100 to 200 ° C. and an air injection rate of 600 to 1,000 l / h.

In the production method of the present invention, the electrolyte components are sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate relative to their total mixed weight, respectively 78.22 ~ 93.86: 1.26 ~ 3.65: 1.24 ~ 3.60: 0.86 ~ 2.49: 2.77 ~ 12.04 It is preferable to mix and use by the weight% compounding quantity.

The spray dried product prepared in the first step preferably has a powder particle diameter of 20 to 75 μm in order to increase the dissolution rate and fluidity of the solid dialysis solvent finally prepared according to the present invention.

Meanwhile, after preparing the spray dried product as described above, glucose in powder form may be added, thereby preventing degeneration of glucose, which is weak in heat, from the drying process. At this time, the glucose is preferably mixed so as to be 0 to 20% by weight based on the total weight of the spray dried product and the glucose mixture.

In this case, the second step according to the invention consists of a wet granulation step of spraying a binder solution onto the mixture of spray dried and glucose and drying the resultant to granulate. On the other hand, when glucose is not mixed in the spray dry matter in the first step, the second step is performed only on the spray dry matter.

The binder solution is sprayed through an air atomizer-type nozzle equipped with a fine spray nozzle, where the atomized binder solution enables uniform mixing of the electrolyte spray dried product and the glucose mixture. As such, by spraying the binder solution through the nozzle, it is possible to form high quality granules in a smaller amount than when the nozzle is not used, thereby reducing the drying time.

The addition amount of the binder solution of the present invention is characterized in that 3 to 10% by weight, preferably 5 to 7% by weight relative to the total weight of the spray dried product or the mixture of the spray dried product and the glucose powder.

In the preparation of the dialysis preparation of the present invention, when the aqueous glucose solution is used as the binder solution, the binding force is increased, the ratio of the fine granules is lowered, the flowability of the granules is improved, and the solubility is positive. In this case, the concentration of the aqueous glucose solution used as the binder solution is 0 to 50%, preferably 35 to 45% of the aqueous glucose solution when the preparation of the present invention contains glucose or 0% when the glucose solution is not included. It is characterized by that. This is because, when the concentration of the aqueous glucose solution exceeds 50%, the dissolution time of the glucose takes a long time, and there is a possibility that the dissolved aqueous glucose solution is precipitated during production.

The drying temperature of the granules prepared in the second step is about 30 ~ 60 ℃ is appropriate, when drying at high temperature for a long time discoloration of glucose or 5-hydroxymethylflural (5-HMF) which is a decomposition product of glucose This is because there is a possibility that is generated.

The pH adjuster is at least one selected from the group consisting of acetic acid, oxalic acid, succinic acid, citric acid, tartaric acid, organic acid containing maleic acid, and hydrochloric acid, preferably acetic acid, more preferably It is characterized by glacial acetic acid having a purity of 99% or more. Like the binder solution, the pH adjuster is sprayed using a nozzle equipped with an orifice that can be finely sprayed to complete the preparation within a short time, without causing a pH change due to volatilization of the pH adjuster. To be distributed.

At this time, the pH adjuster is 1.0 with respect to the total weight of the granules in order to produce a pH range of pH 4.0 ~ 5.5, which is an appropriate acidic pH range targeted by the dialysis solid preparation of the present invention without affecting the stability of glucose It may be sprayed to a content of ˜4.0% by weight. When the solid preparation of the present invention prepared in the appropriate pH range of pH 4.0 to 5.5 is mixed with the weakly basic sodium bicarbonate, the acid and bicarbonate react to produce CO ₂ , and the pH of the final dialysate is 7.0 without precipitation of carbonate. It is in the range of ~ 7.4.

In the preparation according to the present invention, 15 g of the preparation is introduced into a flow cell using a particle size analyzer (Mastersizer X, Malvern, UK), and the time for the particles to dissolve completely disappears from the time when the particles start dissolving. 110 seconds or less. The characteristics of such a preparation is to obtain a spray dried product having a particle size of 20 μm to 75 μm in the first step of preparing the spray dried product of the present invention, and to prepare granules by spraying a binder solution on the spray dried material of the first step. By spraying and mixing the pH adjuster into the granules, it is achievable by allowing granules of 20 to 100 mesh (about 850 μm to 150 μm) to be obtained at least 75% of the total formulation. When the particle diameter is less than 200 mesh (about 75 μm), particles tend to aggregate, so that a decrease in solubility may occur, adversely affect the fluidity, and handling problems such as scattering may occur. If the particle diameter exceeds 18 mesh (about 1,000 mu m), the dissolution rate is particularly slow, which is not preferable.

The hygroscopicity of the preparations according to the invention is about 0.01-7.0%, more preferably about 0.1-5.0% after being left for 18 hours at 25 ° C. and 60% relative humidity conditions.

The formulation according to the present invention has an angle of repose of 40 ° or less and a density of 0.6-1.0 g / ml is suitable, more preferably an angle of repose of 40 ° or less and a density of 0.7-0.85 g / ml. This yields a spray dried product having a powder particle size of about 20 μm to 75 μm in the first step of preparing the spray dried product of the present invention, and after the preparation of granules by spraying a binder solution on the object including the spray dried product of the first step , By spraying a pH adjuster to the granules can be achieved through the process of mixing. When the angle of repose is 40 ° or less, the fluidity is improved, which prevents the introduction of a large amount of undesired formulations at a time when taking out the formulation, and can be smoothly added to a weight control device commonly used for powder packaging. It is advantageous.

In the dialysis preparation of the present invention prepared by the above method, the composition of the electrolyte component, the pH adjuster and the glucose is preferably blended as shown in Table 1 below.

ingredient amount Na ⁺ 120 to 145 mEq / L K ⁺ 1 to 4 mEq / L Ca ^{2 +} 1 to 4 mEq / L Mg ^{2 +} 0.5 to 2 mEq / L Cl ^- 90 to 140 mEq / L CH3COO ^- 2 to 14 mEq / L glucose 0 to 2.5 g / L

In the present invention, as well as improving the fluidity, as well as to ensure the uniformity of the electrolyte components as well as the additional components, and particularly has a good dissolution rate, has been disclosed a solid preparation for dialysis and a method for producing the same.

The solid preparation for dialysis prepared by the preparation method of the present invention is a dialysis solvent obtained by granulating the sprayed dry matter, and thus the content uniformity, dissolution rate, and fluidity of the electrolyte components are excellent, and thus, the dialysis liquid may be restored to a uniform liquid phase. . In addition, the hygroscopicity is very low, so it does not react sensitively by relative humidity, so it does not form a solid or agglomerate due to agglomeration during manufacture and storage, so the problem of low dissolution rate is very low. maintain.

Hereinafter, although an Example and a test example are given and this invention is demonstrated more concretely, these are for illustrating this invention, and the scope of the present invention is not limited by these.

Example  One

255.24 g of sodium chloride (Dominion, New Zealand), 6.264 g of potassium chloride (Merck, Germany) 34.242 g of sodium acetate (Verdugt, Spain), 9.264 g of calcium chloride (Merck, Germany) and 4.272 g of magnesium chloride (Merck, Germany) in 886.62 g of water Melted. The solution was poured into a spray dryer (B-191, BUchi, Switzerland) and spray dried under the conditions of [Table 2] to obtain 200 g of a spray dried product. 200 g of the spray dried product and 28.846 g of glucose (Dextrose anhydrous, Samyang Genex) were added to a granulator (FM-VG-01, POWREX, JAPAN) and mixed for 8 minutes under conditions of chopper 2000 rpm and blade 150 rpm. Granules were produced by spraying 15 g of distilled water, a binder solution, using a nozzle air atomizer with a single pore orifice (0.8 mm in diameter) while mixing. The resulting granules were dried in a drying oven at 50 ° C. for 6 hours and then sized using 20 mesh sieves. The granulated granules were placed in a granulator, and operated at chopper 2000 rpm and blade 150 rpm, and 4.58 g of acetic acid was mixed using the nozzle sprayer to prepare a solid formulation. The above process is shown in Table 3 below.

Condition value Inlet temperature 200 ℃ Outlet temperature 110 ℃ ~ 130 ℃ Air injection speed 800 l / h Injection volume 1.2 g / min

1. Preparation of Electrolyte Solution Sodium chloride 255.24 g 886.62 g of distilled water warmed to 40 ℃ dissolved the electrolyte on the left and left for 12 hours Potassium chloride 6.264 g Calcium Chloride 9.264g Magnesium chloride 4.272g Sodium acetate 34.242 g 2. Preparation of spray dried product (appliance: B-191, BUchi , Switzerland ) Inlet temperature 200 ℃ Preparation of spray dried product under the condition of 1. Outlet temperature 110 ℃ ~ 130 ℃ Air injection speed 800l / h Injection volume 1.2g / min 3. Mixing (equipment: FM - VG -01, POWREX , JAPAN ) Spray Dried 200g Spray dried product and glucose are put in the device and blade: 150rpm, chopper: 2000rpm Glucose 28.846 g 15 g of distilled water 4. Drying (equipment: Dry Oven OF -22, JEIO Tech , Korea ) 6 hours drying at 50 ℃ 5. Formulation Established with 20 mesh sieve 6. Acetic Acid  Mixed (device: FM - VG -01, POWREX , JAPAN ) Granules (spray dried + glucose: 228.846 g) Put the granules established in step 5 into the machine and add Acetic acid while operating blade: 150rpm, chopper: 2000rpm glacial Acetic acid 4.58 g

Example  2

Using the same composition and manufacturing method as in Example 1, except that the binder solution was sprayed using a nozzle sprayer having a round six-hole orifice instead of the nozzle sprayer having a single hole orifice. Solid formulations were prepared.

Example  3

In the preparation method of Example 2, the same composition and preparation as in Example 1, except that 40% glucose solution (10 g of glucose + 15 g of distilled water) was used as the binder solution, and the amount of glucose mixed in the spray dried product was 18.846 g. Solid formulations were prepared using the method.

Comparative example  One

Sodium chloride 255.24 g, potassium chloride 6.264 g and sodium acetate 34.242 g, calcium chloride 9.264 g, magnesium chloride 4.272 g, glucose 42 g, acetic acid 4.58 g were placed in a V-mixer (V-mixer, Erweka, Germany) and mixed for 30 minutes.

Comparative example  2

255.24 g of sodium chloride, 6.264 g of potassium chloride and 34.242 g of sodium acetate, 9.264 g of calcium chloride, 4.272 g of magnesium chloride, and 42 g of glucose were added to a V-mixer (V-mixer, Erweka, Germany) and mixed for 30 minutes, followed by a dry granulator (TG- 2000, Erweka, Germany). This assembly is called fitz-mill, Fitzpatrick, USA) and 4.58 g of acetic acid were added dropwise through a tube for 8 minutes to mix.

Comparative example  3

A jet mill was used to grind 255.24 g of sodium chloride, 34.242 g of sodium acetate and 9.264 g of calcium chloride, 4.272 g of magnesium chloride, 6.264 g of potassium chloride, and 42 g of glucose. This was put into a granulator (FM-VG-01, powrec, Japan; Vertical granulator), and 4.58 g of acetic acid was added dropwise using a tube and mixed for 8 minutes.

Comparative example  4

Using a jet mill, 255.24 g of sodium chloride, 34.242 g of sodium acetate and 9.264 g of calcium chloride, 4.272 g of magnesium chloride, 6.264 g of potassium chloride, and 42 g of glucose were ground and a granulator (FM-VG-01, powrec, Japan; 15g of distilled water was added dropwise through a tube while mixing into a vertical granulator to prepare granules. 4.58 g of acetic acid was added dropwise and mixed for 8 minutes.

Comparative example  5

255.24 g of sodium chloride, 6.264 g of potassium chloride and 34.242 g of sodium acetate, 9.264 g of calcium chloride, and 4.272 g of magnesium chloride were dissolved in 886.62 g of water, and the solution was spray dried under the same conditions as in Example 1 to obtain 200 g of a spray dried product.

Test Example  1. Content Uniformity Analysis

Seven samples were randomly sampled from the above examples and comparative examples, and each sample was subjected to ion chromatography (device: Metrohm 761 Compact IC, Metrohm 813 Compact Autosampler, Metrohm 753 Suppressor Module, cation column: Metrohm C2 100, anion column: Mertohm A Supp5 100 * 4mm, Switzerland) to measure the concentration of ions are shown in Table 4 below.

Cation (K, Ca, Mg, Na) standard sampling conditions were as follows. To confirm the concentration of the cation to be analyzed, potassium chloride (Potassium chloride), calcium chloride (Calcium chloride), magnesium chloride (Magnesium chloride), sodium chloride (Sodium chloride) is put in a volumetric flask (volumetric flask) and dissolved in water of a predetermined concentration A standard solution was prepared for 3 to 5 points, and the concentration of the sample was determined using a calibration curve using the values obtained through the experiment.

Anion (Cl, Acetate) standard sampling conditions were as follows. In order to confirm the concentration of the cation to be analyzed, sodium chloride and acetic acid were added to a volumetric flask and dissolved in water to prepare 3 to 5 points of a standard solution having a predetermined concentration. Using the obtained values, the concentration of the sample was determined by using a calibration curve. In addition, by measuring the specific light intensity of each sample to determine the glucose content and the standard deviation is shown in Table 4 below.

Test sample Na ⁺ Mg ^{2 +} K ⁺ Ca ^{2 +} Cl ^- CH3COO ^- Glucose Example 1 101.56 ± 1.7 100.90 ± 1.7 100.33 ± 0.5 101.25 ± 1.6 99.97 ± 0.3 97.09 ± 2.3 94.22 ± 2.5 Example 2 101.09 ± 1.8 99.25 ± 1.7 101.36 ± 0.9 100.26 ± 1.2 99.12 ± 0.6 99.14 ± 0.9 105.88 ± 3.2 Example 3 101.47 ± 0.5 101.69 ± 0.6 99.27 ± 0.9 100.03 ± 0.2 101.86 ± 0.2 99.57 ± 0.3 102.01 ± 1.0 Comparative Example 1 102.69 ± 1.5 126.84 ± 11.6 88.43 ± 21.5 115.61 ± 8.9 106.67 ± 1.9 91.04 ± 6.8 90.11 ± 7.0 Comparative Example 2 101.99 ± 2.2 93.42 ± 6.4 91.89 ± 11.3 92.58 ± 6.0 102.79 ± 2.0 94.32 ± 5.2 92.17 ± 5.1 Comparative Example 3 101.70 ± 0.6 106.21 ± 6.1 93.26 ± 8.6 98.21 ± 9.9 97.99 ± 3.6 94.60 ± 7.3 105.77 ± 10.8 Comparative Example 4 99.76 ± 0.7 92.33 ± 4.0 95.78 ± 5.5 98.21 ± 2.5 99.30 ± 3.0 95.57 ± 4.0 102.81 ± 3.4 * Unit: nEq / l

As shown in the results of Table 4, the ion concentration of the example was shown to be uniform compared to the ion concentration of the comparative example, compared to the comparative example of a simple mixture and / or granulated material of the pulverized or unpulverized electrolyte, and the spray dried of the electrolyte. , Examples of the present invention can be seen that it can provide a dialysis solvent to achieve excellent content uniformity.

Test Example  2. Repose  And density measurement

In order to check the fluidity, the angle of repose (flow angle) was measured by using an angle measuring device (GTB, Erweka, Germany), and the density was measured by USP Method 1 using a density measuring device (SVM202, Erweka, Germany). It was.

Test sample Repose angle (°) Density (g / ml) Example 1 37.5 0.793 Example 2 37 0.817 Example 3 35 0.834 Comparative Example 1 55 1.050 Comparative Example 2 46 0.946 Comparative Example 3 42 0.790 Comparative Example 5 48 0.340

Typically, in the case of a solid agent, when the angle of repose is 40 ° or less, it is determined that the fluidity is good, and as shown in Table 5, the angle of repose was less than 40 ° in all of the examples. The smaller the angle of repose, the better the flowability of the granules. In addition, in the case of the spray drying of Comparative Example 5, the density is 0.34 g / ml, the solid dialysis agent to reduce problems such as logistics or storage due to the increase in volume, which is a disadvantage of the liquid dialysis agent is less, In the case of the Example, a density is 2 times or more (that is, 0.79-0.83 g / ml) compared with the comparative example 5.

On the other hand, Comparative Examples 1 to 3, in which the electrolyte components were mixed and milled as they were, were found to have a poor angle of repose, even though the density was relatively good.

Test Example  3. Measurement of particle size distribution

Examples and comparative examples were applied to a sieve analysis (Sieve analysis VT, Erweka, Germany), and after the standard size of the various sizes were installed in the instrument and operated for 10 minutes at 200 rpm and weighed the weight of the powder remaining in each sieve Conversion particle size distribution results are shown in Table 6 below.

Particle size (mesh) More than 20 20-40 40 to 60 60-100 100-200 Less than 200 Particle Size (㎛) 850 or more 425 to 850 250-425 150 to 250 75 to 150 75 or less Example 1 0% 36.04% 30.32% 11.08% 14.19% 8.37% Example 2 0% 26.76% 27.06% 28.81% 12.91% 4.46% Example 3 0% 27.19% 35.18% 31.44% 4.46% 1.73% Comparative Example 2 0% 15.64% 16.52% 14.76% 33.25% 19.83% Comparative Example 3 0% 0.13% 1.37% 4.17% 28.28% 65.54% Comparative Example 4 0% 40.94% 14.70% 6.46% 19.39% 18.51%

As shown in the results of Table 6, in the case of the Example, the formation of fine powder was suppressed and the ratio of the granules of 20-100 mesh size having an excellent dissolution rate was higher than 75%.

Test Example  4. Melt rate measurement

The dissolution rate of an Example and a comparative example was measured by the following method. The dissolution rate was measured using a particle size analyzer (Mastersizer X, Malvern, UK), after 15 g of a dialysis solvent was added to the flow cell, and then the time point at which the particles completely dissolved and disappeared from the time when the particles of the formulation began to dissolve. It is shown in Table 7 below.

Dissolution rate (s) Example 1 110 Example 2 90 Example 3 75 Comparative Example 3 160 Comparative Example 4 130 Comparative Example 5 140

As shown in Table 7, it can be seen that the dissolution rate of the Example was superior to the comparative example.

Test Example  5. Hygroscopicity  Measure

Example 3, Comparative Examples 3 and 4 were sufficiently dried in a drying desiccator at 25 ° C. for 24 hours, and each was spread out thinly in Petri dishes at 5 g and left for 18 hours at 25 ° C. and 60% relative humidity. The water content before and after the test was measured using a Karl Fischer moisture analyzer (Metrohm, Switzerland) and is shown in Table 8 below.

Before the test After the test (18 hours) Hygroscopicity (18 hours) Example 3 0.33% 4.66% 4.33% Comparative Example 3 0.38% 13.26% 12.88% Comparative Example 4 0.39% 12.64% 12.25%

As shown in Table 8, compared with Comparative Examples 3 and 4, which are granulated salts, the hygroscopicity of Example 3, which was a granulated spray dried product, was low. Thus, Example 3, which is a formulation of the present invention, was found to have a low likelihood of formation of masses caused by solidification or aggregation.

Claims (13)

Preparing an aqueous electrolyte solution, and then preparing a spray dried product thereof; A second step of preparing granules by spraying a binder solution on the spray dried material of the first step; And A third step of drying and granulating the granules prepared in the second step and mixing by spraying a pH adjuster Method for producing a solid preparation for dialysis, comprising a. The method according to claim 1, wherein the powder particle size of the spray dried manufactured in the first step is characterized in that 20 ~ 75㎛, solid preparation for dialysis. The method of claim 1, wherein the spray dried the electrolyte solution inlet temperature (In-Let temp.) 100 ~ 300 ℃, Out-Let temp. 100 ~ 200 ℃, air injection rate 600 ~ 1000 A process for producing a solid preparation for dialysis, characterized in that it is prepared by spray drying under the condition of l / h. The method according to claim 1 or 2, further comprising the step of further mixing the glucose powder in the spray drying of the first step, before performing the second step. The method for producing a dialysis solid preparation according to claim 1 or 2, wherein the preparation produced by the production method is 75% or more of all preparations having particles having a particle size of 20 to 100 mesh. The method of claim 1 or 2, wherein the electrolyte is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate and mixtures thereof. The method of claim 1 or 2, wherein the binder solution is water or an aqueous glucose solution. The method of claim 7, wherein the binder solution is an aqueous solution of 0-50% glucose. The method of claim 1 or 2, wherein the addition amount of the binder solution is 3 to 10% by weight based on the total weight of the spray dried product or the mixture of the spray dried product and the glucose powder. The method according to claim 1, wherein the pH adjuster Organic acids including acetic acid, oxalic acid, succinic acid, citric acid, tartaric acid, and maleic acid; And A method for producing a solid preparation for dialysis, characterized in that at least one selected from the group consisting of inorganic acids containing hydrochloric acid. 15 g of the solid preparation for dialysis is introduced into a flow cell using a particle size analyzer (Matersizer X, Malvern, UK), and then the particles of the preparation are dissolved. Solid preparation for dialysis, the time for which the particles completely melt away from the time starting point is less than 110 seconds. A solid preparation for dialysis prepared by the process according to claim 1 or 2, comprising a) an electrolyte component and b) a pH adjuster. 13. The dialysis solid preparation of claim 12, further comprising c) glucose.