Tiopronin-containing composition as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tiopronin-containing composition as well as a preparation method and application thereof. The preparation method comprises the following steps: granulating by adopting isopropanol as a granulating solution, drying and tabletting to obtain a tablet core with extremely low water content, and meanwhile, dissolving a mixture of an amine alkyl methacrylate copolymer and hydroxypropylcellulose in isopropanol as an isolating layer solution to coat the tablet core, so that the stability of the tablet core is improved; and finally, calcium carbonate, cane sugar and the like are adopted for sugar coating, so that unpleasant odor is effectively covered, the compliance of a patient is improved, the preparation is suitable for large-scale production, the medicine taking convenience and the medicine administration safety of the patient are improved, and therefore, the preparation has a good practical application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a composition containing sulfopronin, a preparation method thereof and an application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.

[0003] Tiopronin is a glycine derivative containing a thiol group, and its chemical name is N-(2-mercaptopropionyl)-glycine. Tiopronin is a compound developed by Santen Pharmaceutical Co., Ltd. in Japan. It has been used as a liver disease treatment agent since 1970. The product name of Tiopronin tablets was 100, and in 1979, the efficacy and effect of increasing mercury excretion in early senile cortical cataracts and mercury poisoning were added. The re-evaluation was completed in 1995. The specification is 100mg, and the license holder is Mylan Pharmaceutical Co., Ltd. In July 2023, the license holder transferred from Mylan Pharmaceutical Co., Ltd. to Viatris Pharmaceuticals (VIATRIS) Co., Ltd. for production and sales.

[0004] The choice of dosage form for tiopronin must be carefully considered based on the patient's specific condition and treatment needs. Injections are suitable for acute symptoms and critically ill patients, while tablets and enteric-coated tablets are more suitable for the long-term treatment of chronic conditions. Due to the poor stability of tiopronin, standard tablets must be stored in dark, cool, and dry conditions. Furthermore, tiopronin itself has a certain odor, so the development of a dosage form with excellent stability and the ability to mask the unpleasant odor is urgently needed in clinical practice. Summary of the Invention

[0005] To address the shortcomings of the prior art, the present invention aims to provide a composition containing sulfopronin, its preparation method, and its application. Specifically, the present invention utilizes isopropyl alcohol as a granulation solution for granulation, followed by drying and tableting to produce a tablet core with an extremely low water content. Furthermore, a mixture of aminoalkyl methacrylate copolymer and hydroxypropyl cellulose dissolved in isopropyl alcohol is used as a barrier layer solution to coat the tablet core, improving its stability. Finally, a sugar coating using calcium carbonate, sucrose, or the like is applied to effectively mask unpleasant odors and improve patient compliance. The present invention was completed based on these research findings.

[0006] In order to achieve the above technical objectives, the technical solutions provided by the present invention are as follows:

[0007] The first aspect of the present invention provides the use of a composition of an aminoalkyl methacrylate copolymer and hydroxypropyl cellulose as an isolation layer material in the preparation of tiopronin tablets.

[0008] In the composition, the mass ratio of the aminoalkyl methacrylate copolymer to the hydroxypropyl cellulose is 1-10:1-25, preferably 1:1.

[0009] Specifically, the application includes: dissolving methacrylate aminoalkyl copolymer and hydroxypropyl cellulose in an isolation layer solvent for coating, thereby significantly improving the stability of the tablet core.

[0010] The isolation layer solvent may be any one or more of acetone, dichloromethane, and isopropyl alcohol; among them, isopropyl alcohol is preferred.

[0011] Furthermore, in the tiopronin tablets, the wetting agent can also be any one or more of acetone, dichloromethane, and isopropyl alcohol; among which isopropyl alcohol is preferred.

[0012] A second aspect of the present invention provides a tiopronin tablet comprising at least an active ingredient, tiopronin, and an isolation layer material, wherein the isolation layer material is a composition of an aminoalkyl methacrylate copolymer and hydroxypropyl cellulose; the mass ratio of tiopronin, aminoalkyl methacrylate copolymer, and hydroxypropyl cellulose is 100-200:1-10:1-25, preferably 20:1:1.

[0013] Furthermore, the composition of the tiopronin tablet includes: active ingredient tiopronin, diluent, disintegrant, binder, wetting agent, lubricant, anti-adherent, isolation layer material, isolation layer solvent, sugar coating layer material, powder coating layer material, coating solvent and polishing agent.

[0014] Wherein, the diluent can be any one or both of lactose and corn starch;

[0015] The disintegrant may be low-substituted hydroxypropyl cellulose;

[0016] The binder may be any one or more of povidone K30 and methylcellulose;

[0017] The wetting agent and isolation layer solvent can be any one or more of acetone, dichloromethane, and isopropyl alcohol; preferably isopropyl alcohol;

[0018] The lubricant can be magnesium stearate;

[0019] The sugar coating material may be sucrose;

[0020] The powder coating material may be any one or more of calcium carbonate, talc, and corn starch;

[0021] The coating solvent can be water (such as purified water);

[0022] The polishing agent may be carnauba wax.

[0023] Furthermore, the tiopronin tablets are made from the following raw materials in parts by mass:

[0024] 100-200 parts of tiopronin;

[0025] Lactose 20-100 parts;

[0026] 0-20 parts corn starch;

[0027] Low-substituted hydroxypropyl cellulose 0-20 parts;

[0028] Povidone K30 0-10 parts;

[0029] 20-100 parts of isopropyl alcohol;

[0030] 10-60 parts of methylcellulose;

[0031] 0-5 parts of magnesium stearate;

[0032] 1-10 parts of aminoalkyl methacrylate copolymer;

[0033] 1-25 parts of hydroxypropyl cellulose;

[0034] 2-20 parts of talcum powder;

[0035] 100-500 parts of isopropyl alcohol;

[0036] 30-300 parts of sucrose;

[0037] 10-200 parts of calcium carbonate;

[0038] 30-150 parts water;

[0039] 0-10 parts of carnauba wax.

[0040] The third aspect of the present invention provides a method for preparing the above-mentioned tiopronin tablets, which comprises the following steps:

[0041] (1) Weigh the raw materials and excipients; sieve and mix tiopronin, lactose, corn starch, low-substituted hydroxypropyl cellulose, and methylcellulose;

[0042] (2) adding povidone K30 to isopropyl alcohol, stirring and dissolving the mixture as a binder, and adding the mixture to the mixed raw material obtained in step (1) for wet granulation to obtain wet granules;

[0043] (3) drying, sizing, mixing and tableting the wet granules;

[0044] (4) adding methacrylate copolymer and hydroxypropyl cellulose to the isopropyl alcohol solution and continuously stirring until completely dissolved, adding talc to the remaining isopropyl alcohol solution, stirring and dispersing, grinding, and finally stirring to coat the tablets obtained after tableting;

[0045] (5) Powder coating: dissolving sucrose in hot water and then adding calcium carbonate to obtain a powder coating solution, and applying a powder coating to the coated sheet;

[0046] (6) Sugar coating: adding sucrose to hot water to dissolve it to obtain a sugar coating solution, and then applying sugar coating to the powder-coated sheet;

[0047] (7) Add carnauba wax for polishing.

[0048] In the step (3), the sieve aperture of the whole granules is not greater than 2.0 mm, preferably 1.0 mm.

[0049] In the step (4), the mass ratio of the isopropyl alcohol used to dissolve the methacrylate copolymer and hydroxypropyl cellulose to the remaining isopropyl alcohol is 2-8:1, preferably 4:1.

[0050] In the steps (5) and (6), the temperature of the hot water is 80-90° C.; the mass ratio of sucrose to hot water is 1-10:1-5; more preferably, it is 7:3.

[0051] Beneficial technical effects of one or more of the above technical solutions:

[0052] The above technical solution uses isopropyl alcohol as a granulation solution for granulation, and then compresses the tablets after drying to obtain a tablet core with extremely low water content. A mixture of an aminoalkyl methacrylate copolymer and hydroxypropyl cellulose dissolved in isopropyl alcohol is used as an isolation layer solution to coat the tablet core to improve the stability of the tablet core. Finally, calcium carbonate, sucrose, etc. are used for sugar coating to effectively mask the unpleasant odor, which is conducive to improving patient compliance, making it suitable for mass production, improving the convenience of patients taking the medicine and the safety of administration, and therefore having good practical application value. DETAILED DESCRIPTION

[0053] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0054] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0055] Unless otherwise defined herein, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art. Although methods and materials similar to or equivalent to the methods and materials described herein can also be used in the practice of the present invention, preferred methods and materials are described herein. In addition, as used herein, the terms "one," "an" or "a kind of" include multiple or multiple, unless the context clearly indicates otherwise. The numerical ranges throughout the application documents include any subranges therein and any numerical values incremented by the smallest subunit of a given value therein. Unless otherwise clearly stated, the numerical values throughout the application documents represent approximate measurements or limitations of the range of embodiments including slight deviations from a given value and having approximately the values mentioned and having the exact values mentioned. Except for the working examples provided at the end of the detailed description, all numerical values of the parameters (e.g., quantities or conditions) in this application document (including the appended claims) should be understood to be modified by the term "approximately" in all cases, regardless of whether "approximately" actually appears before the numerical value. "Approximately" means that the numerical value described allows for slight imprecision (some close to precision in the value; approximately or reasonably close to the value; approximately). If the imprecision provided by "about" is not understood in this ordinary sense in the art, then "about" as used herein at least represents the variation that can be produced by ordinary methods of measuring and using these parameters. For example, "about" can include a variation of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5%.

[0056] The present invention will be further described below in conjunction with the examples. The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. Based on the examples in the present invention, any variation of the present invention by those skilled in the art without making any creative premise falls within the scope of protection of the present invention. Meanwhile, in the examples of the present invention, unless otherwise specified, all preparation raw materials are commercially available products well known to those skilled in the art.

[0057] Example 1

[0058] The formulation composition of a batch of 3,000 tiopronin sugar-coated tablets is shown in the following table:

[0059] Table 1 Example 1 Prescription composition

[0060]

[0061] The preparation method of the above-mentioned tiopronin tablets comprises the following steps:

[0062] 1. Weighing and sieving: Weigh the raw materials and excipients according to the batch amount. Add 300g of tiopronin, 150g of lactose, 27g of corn starch, 15g of low-substituted hydroxypropyl cellulose, and 66.3g of methyl cellulose to a granulator in sequence and sieve.

[0063] 2. Mixing: Place the sieved tiopronin, lactose, corn starch, low-substituted hydroxypropyl cellulose and methyl cellulose in a wet mixing granulator and mix for 5 minutes at a stirring speed of 100 rpm and a cutting blade of 700 rpm.

[0064] 3. Slurrying and granulation: Add 6 g of povidone K30 to 120 g of isopropyl alcohol, stir to dissolve, and then add the mixture as a binder into a wet granulator for granulation. Turn on the stirring speed of 100 rpm and the cutting blade of 1200 rpm. The slurrying time is 2 to 5 minutes and the granulation time is 5 minutes.

[0065] 4. Drying: Transfer the wet particles into the FBD pot for drying, adjust the air volume appropriately, start heating after ventilation for 5 minutes, set the air inlet temperature to 40℃±5℃, keep the pot boiling, shovel the pot when necessary, and dry until the moisture content is ≤1.5%. The detection temperature is 75℃.

[0066] 5. Granulation: Use a 1.0 mm sieve to granulate the dry granules at a granulation speed of about 500 rpm.

[0067] 6. Total mixing: Add the granulated dry granules into the hopper mixer and mix for 10 minutes at a mixing speed of 10 rpm.

[0068] 7. Tablet pressing: Use rotary tablet press for tablet pressing

[0069] 8. Isolation layer coating: Slowly add 15g of methacrylate copolymer and 15g of hydroxypropyl cellulose to 600g of isopropyl alcohol solution, continue stirring until completely dissolved, add 27g of talc to the remaining 150g of isopropyl alcohol solution, stir and disperse, and pass through a colloid mill for at least 2 times. After combining, stir for 30 minutes and start coating. The inlet air temperature is 45±10℃. When the coating weight gain reaches 8.5-12%, stop coating.

[0070] 9. Powder coating: weigh 60g purified water and heat it to 80-90℃, add 140g sucrose, stir for 10-30 minutes to completely dissolve the sucrose, add 90g calcium carbonate and continue stirring for 20-30min. After preparation, filter the coating solution into a clean container with a 60-mesh sieve and continue to keep warm (60-70℃). Add slurry: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating. When the tablet bed temperature is below 40℃, add the powder coating liquid. Homogenize: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, and homogenize for 5-15min. Drying: turn on the main machine: 2-12rpm, turn on the exhaust (set the air intake volume: 2000m 3 / h), start hot air (set air inlet temperature: 50-60°C), drying time: 5-25 minutes; cooling: start the main machine (2-12rpm), turn off the exhaust, hot air, and heating, and cool until the tablet bed temperature is below 40°C. Repeat the above steps. Stop powder coating when the average tablet weight reaches 260mg-330mg.

[0071] 10. Sugar coating: weigh 30g purified water and heat it to 80-90℃, add 70g sucrose, stir for 10-30 minutes to completely dissolve the sucrose, without any lumps, keep warm during the process to keep the sucrose solution clear. Add slurry: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, when the tablet bed temperature is below 40℃, add the powder coating liquid; Homogenize: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, homogenize for 5-15 minutes. Drying: turn on the main machine: 2-12rpm, turn on the exhaust (set the air intake volume: 2000m 3 / h), start hot air (set air inlet temperature: 50-60°C), drying time: 5-25 minutes; cooling: start the main machine (2-12rpm), turn off the exhaust, hot air, and heating, and cool until the tablet bed temperature is below 40°C. Repeat the above steps. Stop sugar coating when the average tablet weight reaches 280mg-345mg.

[0072] 11. Polishing: Turn off the exhaust, hot air and heating, sprinkle 3g of carnauba wax into the high-efficiency coating machine, and polish until the surface of the tablet is bright.

[0073] Finally, sulfamethoxazole sugar-coated tablets with good appearance and no bad odor were prepared.

[0074] Comparative Example 1

[0075] The wetting agent and isolation layer solvent were changed from isopropyl alcohol to purified water. The formulation composition of a batch of 3,000 sulforhinolone sugar-coated tablets is shown in the following table:

[0076] Table 2 Comparative Example 1 Prescription Composition

[0077]

[0078]

[0079] The preparation method of the above-mentioned tiopronin tablets comprises the following steps:

[0080] 1. Weighing and sieving: Weigh 300g of tiopronin, 150g of lactose, 27g of corn starch, 15g of low-substituted hydroxypropyl cellulose, and 66.3g of methyl cellulose according to the batch amount, add them into a granulator in sequence, and sieve the granules.

[0081] 2. Mixing: Place the sieved tiopronin, lactose, corn starch, low-substituted hydroxypropyl cellulose and methyl cellulose in a wet mixing granulator and mix for 5 minutes at a stirring speed of 100 rpm and a cutting blade of 700 rpm.

[0082] 3. Slurrying and granulation: Add 6 g of povidone K30 to 60 g of purified water, stir and dissolve, and add it into a wet granulator as a binder for granulation. Turn on the stirring speed of 100 rpm and the cutting knife of 1200 rpm. The slurrying time is 2 to 5 minutes and the granulation time is 5 minutes.

[0083] 4. Drying: Transfer the wet particles into the FBD pot for drying, adjust the air volume appropriately, start heating after ventilation for 5 minutes, set the air inlet temperature to 40℃±5℃, keep the pot boiling, shovel the pot when necessary, and dry until the moisture content is ≤1.5%. The detection temperature is 75℃.

[0084] 5. Granulation: Use a 1.0 mm sieve to granulate the dry granules at a granulation speed of about 500 rpm.

[0085] 6. Total mixing: Add the granulated dry granules into the hopper mixer and mix for 10 minutes at a mixing speed of 10 rpm.

[0086] 7. Tablet pressing: Use a rotary tablet press for tablet pressing.

[0087] 8. Isolation layer coating: Slowly add 15g of methacrylate amine alkyl copolymer and 15g of hydroxypropyl cellulose to 200g of purified water solution, continue stirring until completely dissolved, add 27g of talc to the remaining 100g of purified water solution, stir and disperse, and pass through a colloid mill for at least 2 times. After combining, stir for 30min and start coating. The inlet air temperature is 45±10℃. When the coating weight gain reaches 8.5-12%, stop coating.

[0088] 9. Powder coating: weigh 60g purified water and heat it to 80-90℃, add 140g sucrose, stir for 10-30 minutes to completely dissolve the sucrose, add 90g calcium carbonate and stir for 20-30min. After preparation, filter the coating solution into a clean container with a 60-mesh sieve and continue to keep warm (60-70℃). Add slurry: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating. When the tablet bed temperature is below 40℃, add the powder coating liquid. Homogenize: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, and homogenize for 5-15min. Drying: turn on the main machine: 2-12rpm, turn on the exhaust (set the air intake volume: 2000m 3 / h), start hot air (set air inlet temperature: 50-60°C), drying time: 5-25 minutes; cooling: start the main machine (2-12rpm), turn off the exhaust, hot air, and heating, and cool until the tablet bed temperature is below 40°C. Repeat the above steps. Stop powder coating when the average tablet weight reaches 260mg-330mg.

[0089] 10. Sugar coating: weigh 30g purified water and heat it to 80-90℃, add 70g sucrose, stir for 10-30 minutes to completely dissolve the sucrose, without any lumps, keep warm during the process to keep the sucrose solution clear. Add slurry: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, when the tablet bed temperature is below 40℃, add the powder coating liquid; Homogenize: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, homogenize for 5-15 minutes. Drying: turn on the main machine: 2-12rpm, turn on the exhaust (set the air intake volume: 2000m 3 / h), start hot air (set air inlet temperature: 50-60°C), drying time: 5-25 minutes; cooling: start the main machine (2-12rpm), turn off the exhaust, hot air, and heating, and cool until the tablet bed temperature is below 40°C. Repeat the above steps. Stop sugar coating when the average tablet weight reaches 280mg-345mg.

[0090] 11. Polishing: Turn off the exhaust, hot air and heating, sprinkle 3g of carnauba wax into the high-efficiency coating machine, and polish until the surface of the tablet is bright.

[0091] Finally, sulfamethoxazole sugar-coated tablets with good appearance and no bad odor were prepared.

[0092] Comparative Example 2

[0093] The isolation layer in the formula was deleted and the aminoalkyl methacrylate copolymer was used to prepare a composition. The formula composition of a batch of 3,000 Tiopronin tablets is shown in the following table:

[0094] Table 2 Comparative Example 2 Prescription Composition

[0095]

[0096]

[0097] The preparation method of the above-mentioned tiopronin tablets comprises the following steps:

[0098] 1. Weighing and sieving: Weigh the raw materials and excipients according to the batch amount. Add 300g of tiopronin, 150g of lactose, 27g of corn starch, 15g of low-substituted hydroxypropyl cellulose, and 66.3g of methyl cellulose to a granulator in sequence and sieve.

[0099] 2. Mixing: Place the sieved tiopronin, lactose, corn starch, low-substituted hydroxypropyl cellulose and methyl cellulose in a wet mixing granulator and mix for 5 minutes at a stirring speed of 100 rpm and a cutting blade of 700 rpm.

[0100] 3. Slurrying and granulation: Add 6 g of povidone K30 to 120 g of isopropyl alcohol, stir and dissolve, and add it into a wet granulator as a binder for granulation. Turn on the stirring speed of 100 rpm and the cutting knife of 1200 rpm. The slurrying time is 2 to 5 minutes and the granulation time is 5 minutes.

[0101] 4. Drying: Transfer the wet particles into the FBD pot for drying, adjust the air volume appropriately, start heating after ventilation for 5 minutes, set the air inlet temperature to 40℃±5℃, keep the pot boiling, shovel the pot when necessary, and dry until the moisture content is ≤1.5%. The detection temperature is 75℃.

[0102] 5. Granulation: Use a 1.0 mm sieve to granulate the dry granules at a granulation speed of about 500 rpm.

[0103] 6. Total mixing: Add the granulated dry granules into the hopper mixer and mix for 10 minutes at a mixing speed of 10 rpm.

[0104] 7. Tablet pressing: Use rotary tablet press for tablet pressing

[0105] 8. Isolation layer coating: Slowly add 30g of hydroxypropyl cellulose to 600g of isopropyl alcohol solution and continue stirring until completely dissolved. Add 27g of talc to the remaining 150g of isopropyl alcohol solution, stir and disperse, and pass through a colloid mill for at least 2 times. After combining, stir for 30 minutes and start coating. The inlet air temperature is 45±10℃. When the coating weight gain reaches 8.5-12%, stop coating.

[0106] 9. Powder coating: weigh 60g purified water and heat it to 80-90℃, add 140g sucrose, stir for 10-30 minutes to completely dissolve the sucrose, add 90g calcium carbonate and continue stirring for 20-30min. After preparation, filter the coating solution into a clean container with a 60-mesh sieve and continue to keep warm (60-70℃). Add slurry: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating. When the tablet bed temperature is below 40℃, add the powder coating liquid. Homogenize: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, and homogenize for 5-15min. Drying: turn on the main machine: 2-12rpm, turn on the exhaust (set the air intake volume: 2000m 3 / h), start hot air (set air inlet temperature: 50-60°C), drying time: 5-25 minutes; cooling: start the main machine (2-12rpm), turn off the exhaust, hot air, and heating, and cool until the tablet bed temperature is below 40°C. Repeat the above steps. Stop powder coating when the average tablet weight reaches 260mg-330mg.

[0107] 10. Sugar coating: weigh 30g purified water and heat it to 80-90℃, add 70g sucrose, stir for 10-30 minutes to completely dissolve the sucrose, without any lumps, keep warm during the process to keep the sucrose solution clear. Add slurry: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, when the tablet bed temperature is below 40℃, add the powder coating liquid; Homogenize: turn on the main machine: 2-12rpm, turn off the exhaust, turn off the hot air, turn off the heating, homogenize for 5-15 minutes. Drying: turn on the main machine: 2-12rpm, turn on the exhaust (set the air intake volume: 2000m 3 / h), start hot air (set air inlet temperature: 50-60°C), drying time: 5-25 minutes; cooling: start the main machine (2-12rpm), turn off the exhaust, hot air, and heating, and cool until the tablet bed temperature is below 40°C. Repeat the above steps. Stop sugar coating when the average tablet weight reaches 280mg-345mg.

[0108] 11. Polishing: Turn off the exhaust, hot air and heating, sprinkle 3g of carnauba wax into the high-efficiency coating machine, and polish until the surface of the tablet is bright.

[0109] Finally, sulfamethoxazole sugar-coated tablets with good appearance and no bad odor were prepared.

[0110] Comparative Example 3

[0111] The formula composition of a batch of 3,000 Tiopronin tablets is shown in the following table:

[0112] Table 4 Comparative Example 3 Prescription Composition

[0113]

[0114]

[0115] The preparation method of the above-mentioned tiopronin tablets comprises the following steps:

[0116] 1. Weighing and sieving: Weigh the raw materials and excipients according to the batch amount. Add 300g of tiopronin, 150g of lactose, 27g of corn starch, 15g of low-substituted hydroxypropyl cellulose, and 66.3g of methyl cellulose to a granulator and sieve.

[0117] 2. Mixing: Place the sieved tiopronin, lactose, corn starch, low-substituted hydroxypropyl cellulose and methyl cellulose in a wet mixing granulator and mix for 5 minutes at a stirring speed of 100 rpm and a cutting blade of 700 rpm.

[0118] 3. Slurrying and granulation: Add 6 g of povidone K30 to 120 g of isopropyl alcohol, stir to dissolve, and then add the mixture as a binder into a wet granulator for granulation. Turn on the stirring speed of 100 rpm and the cutting blade of 1200 rpm. The slurrying time is 2 to 5 minutes and the granulation time is 5 minutes.

[0119] 4. Drying: Transfer the wet particles into the FBD pot for drying, adjust the air volume appropriately, start heating after ventilation for 5 minutes, set the air inlet temperature to 40℃±5℃, keep the pot boiling, shovel the pot when necessary, and dry until the moisture content is ≤1.5%. The detection temperature is 75℃.

[0120] 5. Granulation: Use a 1.0mm sieve to granulate the dry granules at a speed of about 500rpm

[0121] 6. Total mixing: Add the whole dry granules into the hopper mixer and mix for 10 minutes. The mixing speed is 10 rpm.

[0122] 7. Tablet pressing: Use rotary tablet press for tablet pressing

[0123] Finally, ordinary tiopronin tablets with good appearance were prepared.

[0124] Key attribute tests of the compositions of various examples and comparative examples:

[0125] The properties, odor, solubility / dissolution curve, etc. of the reference preparation, the examples and the comparative example compositions were tested. The test results are shown in the following table:

[0126] Table 5 Composition test results-1

[0127]

[0128] Table 6 Total impurity test results of the composition-2

[0129]

[0130] From the prescriptions and preparation processes of the examples and comparative examples, it can be seen that the related substances in Comparative Example 1, in which purified water is used as a wetting agent, increase significantly, and a small amount of the tablets are bluish-white in appearance; the dissolution curve of Comparative Example 2, in which the aminoalkyl methacrylate copolymer is deleted from the isolation layer, becomes significantly faster, and the related substances also show a significant growth trend in the accelerated 6-month period; the uncoated sulfopronin tablets in Comparative Example 3 have a significant odor, and the related substances increase significantly during the stability period.

[0131] From the above results, it can be seen that the formulation of Example 1 is the optimal formulation of Tiopronin Tablets.

[0132] It should be noted that the above examples are only intended to illustrate the technical solutions of the present invention and are not intended to limit the same. Although the present invention has been described in detail with reference to the examples given, those skilled in the art may modify or replace the technical solutions of the present invention as needed without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. Use of a composition of aminoalkyl methacrylate copolymer and hydroxypropyl cellulose as an isolation layer material in the preparation of tiopronin tablets.

2. The use according to claim 1, characterized in that In the composition, the mass ratio of the aminoalkyl methacrylate copolymer to the hydroxypropyl cellulose is 1-10:1-25.

3. The use according to claim 1, characterized in that The application comprises: dissolving methacrylate aminoalkyl copolymer and hydroxypropyl cellulose in an isolation layer solvent for coating; Wherein, the isolation layer solvent is any one or more of acetone, dichloromethane, and isopropyl alcohol; among which isopropyl alcohol is preferred; Furthermore, in the tiopronin tablets, the wetting agent is any one or more of acetone, dichloromethane, and isopropyl alcohol; among them, isopropyl alcohol is preferred.

4. A tiopronin tablet, characterized in that: The invention comprises at least an active ingredient, tiopronin, and an isolation layer material, wherein the isolation layer material is a composition of methacrylate aminoalkyl copolymer and hydroxypropyl cellulose; the mass ratio of tiopronin, methacrylate aminoalkyl copolymer and hydroxypropyl cellulose is 100-200:1-10:1-25.

5. The tiopronin tablet according to claim 4, wherein The raw materials of the tiopronin tablets include: active ingredient tiopronin, diluent, disintegrant, binder, wetting agent, lubricant, anti-adhesive agent, isolation layer material, isolation layer solvent, sugar coating layer material, powder coating layer material, coating solvent and polishing agent.

6. The tiopronin tablet according to claim 5, characterized in that The diluent is any one or both of lactose and corn starch; The disintegrant is low-substituted hydroxypropyl cellulose; The binder is any one or more of povidone K30 and methylcellulose; The wetting agent and isolation layer solvent are any one or more of acetone, dichloromethane, and isopropyl alcohol; preferably isopropyl alcohol; The lubricant is magnesium stearate; The sugar coating material is sucrose; The powder coating layer material is any one or more of calcium carbonate, talcum powder, and corn starch; The coating solvent is water; The polishing agent is carnauba wax.

7. The tiopronin tablet according to claim 6, wherein The tiopronin tablets are made from the following raw materials in parts by mass:

8. The method for preparing the tiopronin tablets according to any one of claims 4 to 7, characterized in that: It includes the following steps: (1) Weigh the raw materials and excipients; sieve and mix tiopronin, lactose, corn starch, low-substituted hydroxypropyl cellulose, and methylcellulose; (2) adding povidone K30 to isopropyl alcohol, stirring and dissolving the mixture as a binder, and adding the mixture to the mixed raw material obtained in step (1) for wet granulation to obtain wet granules; (3) drying, sizing, mixing and tableting the wet granules; (4) adding methacrylate copolymer and hydroxypropyl cellulose to the isopropyl alcohol solution and continuously stirring until completely dissolved, adding talc to the remaining isopropyl alcohol solution, stirring and dispersing, grinding, and finally stirring to coat the tablets obtained after tableting; (5) Powder coating: dissolving sucrose in hot water and then adding calcium carbonate to obtain a powder coating solution, and applying a powder coating to the coated sheet; (6) Sugar coating: adding sucrose to hot water to dissolve it to obtain a sugar coating solution, and then applying sugar coating to the powder-coated sheet; (7) Add carnauba wax for polishing.

9. The preparation method according to claim 8, wherein In the step (3), the sieve aperture of the whole granules is not greater than 2.0 mm, preferably 1.0 mm; In the step (4), the mass ratio of the isopropyl alcohol used to dissolve the methacrylate copolymer and the hydroxypropyl cellulose to the remaining isopropyl alcohol is 2-8:

1.

10. The preparation method according to claim 9, characterized in that In steps (5) and (6), the hot water temperature is 80-90°C.

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