A kind of 13 C methacetin orally disintegrating tablets and their preparation method and application

Abstract

The present invention discloses a 13 C-methacetin orally disintegrating tablet and its preparation method and application, belonging to the technical field of pharmaceutical preparations. The 13 C-methacetin orally disintegrating tablet is prepared from 13 C-methacetin and excipients by freeze-drying or direct powder compression, which improves the stability of the raw material drug 13 C-methacetin and improves the 13 solubility of C-methacetin. The above 13 C-methacetin orally disintegrating tablet has the characteristics of rapid disintegration in the mouth or rapid disintegration with only a very small amount of water, which is convenient for taking and improves the compliance in clinical use. It can be used for preparing drugs, reagents or test kits for disease diagnosis, evaluation of liver reserve function, and evaluation before and after liver surgery, etc.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular, to a 13 C-methacetin orally disintegrating tablet and its preparation method and application. Background Art

[0002] The liver is an important metabolic organ of the human body. Although there are many liver function test indicators currently used in clinical practice, there are few tests that can quantitatively reflect the liver reserve and compensatory ability in the early stage of liver cirrhosis. 13 The 13C-methacetin breath test is a new method for detecting liver reserve function that has emerged recently. Through experiments, it has been found that 13 the 13C-methacetin breath test value can distinguish liver cirrhosis from non-cirrhosis and has very high value in clinical practice.

[0003] Among them, 13 13C-methacetin, chemically named p-acetamidophenol (methoxy-13C), has the following structural formula:

[0004] 13 13C-methacetin is for diagnostic use and needs to be rapidly absorbed in the body. Therefore, this product needs to be dissolved in water as soon as possible when taken. To ensure 13 the quality stability of the 13C-methacetin preparation product, as well as the safety and effectiveness during the taking and absorption processes, it is of great significance to develop a 13 13C-methacetin dosage form with excellent solubility and stability.

[0005] In view of this, the present invention is specifically proposed. Summary of the Invention

[0006] One of the purposes of the present invention is to provide a 13 13C-methacetin orally disintegrating tablet, which has excellent solubility and stability and can be rapidly dissolved when taken.

[0007] Another purpose of the present invention is to provide a preparation method of the above-mentioned 13 13C-methacetin orally disintegrating tablet.

[0008] Another purpose of the present invention is to provide an application of the above-mentioned 13 13C-methacetin orally disintegrating tablet.

[0009] This application can be achieved as follows:

[0010] In a first aspect, this application provides a 13 13C-methacetin orally disintegrating tablet, which is prepared from 13 13C-methacetin and excipients by a freeze-drying method or a direct powder compression method.

[0011] In an alternative embodiment, the excipients include at least one of an excipient, a disintegrant, a flavoring agent, a lubricant, and a preservative.

[0012] In an alternative embodiment, the excipient includes at least one of polyvinylpyrrolidone K30, polyethylene glycol 4000, polyethylene glycol 6000, citric acid, mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose, gelatin, Tween 80, and poloxamer 188;

[0013] and / or, the disintegrant includes at least one of crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl cellulose;

[0014] and / or, the flavoring agent includes at least one of aspartame, stevioside, sucralose, and essence;

[0015] and / or, the lubricant includes at least one of stearic acid, magnesium stearate, calcium stearate, and sodium stearyl fumarate;

[0016] and / or, the preservative includes at least one of methylparaben and its sodium salt, ethylparaben and its sodium salt, propylparaben and its sodium salt, sodium benzoate, and potassium sorbate.

[0017] In an alternative embodiment, each 13 C mepivacaine orally disintegrating tablet weighs 50 - 100 mg.

[0018] In an alternative embodiment, each 13 C mepivacaine orally disintegrating tablet weighs 75 mg.

[0019] In an alternative embodiment, 13 the disintegration or dissolution time of the C mepivacaine orally disintegrating tablet in the oral cavity or in 1 - 2 mL of water does not exceed 30 s.

[0020] In an alternative embodiment, each 13 C mepivacaine orally disintegrating tablet contains 2 - 20 wt% of a disintegrant;

[0021] and / or, each 13 C mepivacaine orally disintegrating tablet contains 0.1 - 2 wt% of a lubricant;

[0022] and / or, each 13 C mepivacaine orally disintegrating tablet contains no more than 2.0 wt% of a flavoring agent;

[0023] and / or, each 13 C mepivacaine orally disintegrating tablet contains no more than 1.0 wt% of a preservative.

[0024] In a second aspect, the present application provides the above 13Preparation method of c-methacetin orally disintegrating tablets, comprising the following steps: preparing c-methacetin and auxiliary materials into tablets by freeze-drying method or powder direct compression method. 13 Prepare c-methacetin and auxiliary materials into tablets.

[0025] In an alternative embodiment, when using the freeze-drying method, dissolve c-methacetin and auxiliary materials in water to prepare a freeze-drying intermediate solution, and then fill, freeze-dry and seal. 13 Dissolve c-methacetin and auxiliary materials in water to prepare a freeze-drying intermediate solution, then fill, freeze-dry and seal.

[0026] In an alternative embodiment, the excipients used to prepare the freeze-drying intermediate solution include at least one of polyvinylpyrrolidone K30, polyethylene glycol 4000, polyethylene glycol 6000, mannitol, sorbitol, xylitol, lactose, gelatin, poloxamer 188.

[0027] In an alternative embodiment, the weight ratio of c-methacetin to excipients used to prepare the freeze-drying intermediate solution is 1:0.5 - 1:10. 13 The weight ratio of c-methacetin to excipients is 1:0.5 - 1:10.

[0028] In an alternative embodiment, the total concentration of c-methacetin and auxiliary materials in the freeze-drying intermediate solution is 10 - 30%. 13 The total concentration of c-methacetin and auxiliary materials is 10 - 30%.

[0029] In an alternative embodiment, when using the powder direct compression method, first prepare a solid dispersion of c-methacetin and part of the excipients, and then add the remaining auxiliary materials to press into tablets. 13 Prepare a solid dispersion of c-methacetin and part of the excipients, and then add the remaining auxiliary materials to press into tablets.

[0030] In an alternative embodiment, the solid dispersion is prepared by solvent method or spray drying method.

[0031] In an alternative embodiment, the particle size of the solid dispersion < 300μm.

[0032] In an alternative embodiment, the excipients used to prepare the solid dispersion include at least one of polyvinylpyrrolidone K30, polyethylene glycol 4000, polyethylene glycol 6000, poloxamer 188.

[0033] In an alternative embodiment, the weight ratio of c-methacetin to excipients in the solid dispersion is 1:0.5 - 1:10. 13 The weight ratio of c-methacetin to excipients is 1:0.5 - 1:10.

[0034] In an alternative embodiment, the remaining auxiliary materials contain excipients, and the excipients in the remaining auxiliary materials include at least one of citric acid, mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose.

[0035] In an alternative embodiment, the excipients in the remaining auxiliary materials account for 13 10 - 70wt% of c-methacetin orally disintegrating tablets.

[0036] Third aspect, the present application provides the 13 application of the C - mephenytoin orally disintegrating tablet, for example, it can be used to prepare drugs, reagents or kits for disease diagnosis, liver reserve function assessment, and assessment before and after liver surgery.

[0037] In an alternative embodiment, the disease includes at least one of cirrhosis, primary biliary cirrhosis, simple steatosis, chronic liver disease staging, alcoholic liver disease, degree or staging of liver fibrosis, non - alcoholic fatty liver, neonatal cholestasis, biliary atresia, intrahepatic inflammation, acute liver failure, and hepatocellular carcinoma;

[0038] and / or, the liver reserve function assessment includes at least one of the evaluation of liver function in related diseases, the assessment of chemotherapy - induced liver injury, the assessment of predicting chronic liver failure death, and the assessment of liver detoxification ability;

[0039] and / or, the assessment before and after surgery includes at least one of the assessment of regeneration after hepatectomy, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and the assessment before and after related surgeries.

[0040] The beneficial effects of the present application include:

[0041] The 13 C - mephenytoin orally disintegrating tablet provided by the present application is prepared from 13 C - mephenytoin and excipients by freeze - drying or direct powder compression methods, which improves the stability of the active pharmaceutical ingredient 13 C - mephenytoin and improves the 13 solubility of C - mephenytoin. The above - mentioned 13 C - mephenytoin orally disintegrating tablet has the characteristics of rapid disintegration in the oral cavity or rapid disintegration with only a very small amount of water, which is convenient for taking and improves the compliance in clinical use. It can be used to prepare drugs, reagents or kits for disease diagnosis, liver reserve function assessment, and assessment before and after liver surgery, etc. Specific embodiments

[0042] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. For those not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0043] The following specifically describes the 13 C - mephenytoin orally disintegrating tablet provided by the present application, its preparation method, and its application.

[0044] The present application proposes a 13 C - mephenytoin orally disintegrating tablet, which is composed of 13C Methacetin and excipients are prepared by freeze-drying or powder direct compression.

[0045] The so-called "orodisintegrating tablets" refer to tablets that do not require water or only require a small amount of water, do not need to be chewed, and quickly disintegrate when encountering saliva in the mouth. With the power of swallowing, the medicine can enter the stomach and take effect.

[0046] This application will be 13 C Methacetin is prepared into orally disintegrating tablets, which are easy to take, quick to take effect, high bioavailability, good taste, etc. In addition, by adopting freeze-drying or powder direct compression, the raw material drug 13 The stability and solubility of C-methacetin are conducive to improving its compliance in clinical use.

[0047] For reference, the above 13 C. The auxiliary materials used in the orodisintegrating methacetin tablets may illustratively but not limitatively include at least one of an excipient, a disintegrant, a flavoring agent, a lubricant, and a preservative.

[0048] Among them, the excipients may illustratively but not limitatively include at least one of povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, citric acid, mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose, gelatin, Tween 80 and poloxamer 188.

[0049] The disintegrant may illustratively but not limitatively include at least one of crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose.

[0050] The flavoring agent may illustratively but not limitatively include at least one of aspartame, stevioside, sucralose and flavors, which only requires a small amount to improve the mouthfeel of the orodisintegrating tablet and enhance the adaptability of clinical application.

[0051] The lubricant may illustratively but not limitatively include at least one of stearic acid, magnesium stearate, calcium stearate, and sodium stearyl fumarate.

[0052] Preservatives may exemplarily but not limitatively include at least one of methylparaben and its sodium salt, ethylparaben and its sodium salt, propylparaben and its sodium salt, sodium benzoate and potassium sorbate, which can inhibit the growth of microorganisms in the preparation, improve the stability of the product, and ensure the quality of the product within the shelf life.

[0053] In some optional embodiments, the above auxiliary materials are water-soluble substances. In particular, when freeze-dried, the excipients, flavoring agents and preservatives are all water-soluble substances.

[0054] As a reference ground, each 13The weight of the C-methacetin orally disintegrating tablets can be, for example, 50 - 100 mg, such as 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, etc. In some preferred embodiments, each tablet 13 The weight of the C-methacetin orally disintegrating tablets can be 75 mg. When taking, one tablet can be taken each time.

[0055] In this application, each tablet 13 The C-methacetin orally disintegrating tablets may contain 2 - 20 wt% (such as 2 wt%, 5 wt, 8 wt%, 10 wt%, 12 wt%, 15 wt%, 18 wt% or 20 wt%, etc.) of disintegrants.

[0056] Each tablet 13 The C-methacetin orally disintegrating tablets may contain 0.1 - 2 wt% (such as 0.1 wt%, 0.2 wt%, 0.5 wt%, 1 wt%, 1.5 wt% or 2 wt%, etc.) of lubricants.

[0057] Each tablet 13 The C-methacetin orally disintegrating tablets may contain no more than 2.0 wt% (such as 2 wt%, 1.5 wt%, 1 wt%, 0.8 wt%, 0.5 wt%, 0.2 wt% or 0.1 wt%, etc.) of flavoring agents.

[0058] Each tablet 13 The C-methacetin orally disintegrating tablets may contain no more than 1.0 wt% (such as 1 wt%, 0.8 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt% or 0.1 wt%, etc.) of preservatives.

[0059] As mentioned above, the 13 disintegration or dissolution time of the C-methacetin orally disintegrating tablets in the oral cavity or in 1 - 2 mL of water does not exceed 30 s. That is to say, the 13 C-methacetin orally disintegrating tablets provided in this application only require a very small amount of water to rapidly disintegrate, and can disintegrate in the oral cavity by saliva or a very small amount of water during clinical oral administration, being easy to swallow and having good compliance.

[0060] Correspondingly, this application also provides a preparation method of the above-mentioned 13 C-methacetin orally disintegrating tablets, including the following steps: preparing the C-methacetin and excipients into tablets by freeze-drying or direct powder compression 13 methods.

[0061] When using the freeze-drying method, dissolve 13 the C-methacetin and excipients in water to make a freeze-drying intermediate solution, and then fill, freeze-dry and seal.

[0062] The excipients used in preparing the freeze-dried intermediate solution may include at least one of povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, mannitol, sorbitol, xylitol, lactose, gelatin, and poloxamer 188.

[0063] Those used in preparing the freeze-dried intermediate solution 13 The weight ratio of C-methacetin to the excipient is 1:0.5 - 1:10, such as 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, etc., and it can also be any other value within the range of 1:0.5 - 1:10. In the freeze-dried intermediate solution 13 The total concentration of C-methacetin and the auxiliary materials can be 10 - 30%, such as 10%, 15%, 20%, 25%, or 30%, etc. Among them, for the freeze-dried intermediate solution, by volume 13 The total amount of C-methacetin and the auxiliary materials is by mass.

[0064] Filling can be to fill the freeze-dried intermediate solution into an aluminum-plastic blister, and each blister can be filled with 3 mL of the freeze-dried intermediate solution.

[0065] The process and conditions of freeze-drying can be referred to as follows:

[0066] Freeze-drying stage Shelf temperature Time Vacuum degree Pre-freezing -40°C to -45°C 4-6h / Vacuum pumping -40°C to -45°C / <50Pa Shelf temperature rise Rise to 0 - 5°C 6-10h <50Pa Sublimation drying 0-5℃ 6-10h <50Pa Shelf temperature rise Rise to 30 - 35°C 1.5-2h <50Pa Desorption drying 30-35℃ 2.5-3h <20Pa Freeze-drying end / / /

[0067] After drying, the aluminum-plastic blister and the aluminum foil can be heat-sealed.

[0068] Continuing from the above, in the above freeze-drying preparation process, the excipient serves as a freeze-drying skeleton material. As the water sublimes during the freeze-drying process, a porous blocky solid is formed. 13 C-methacetin is dispersed in the skeleton and is in an amorphous state, which can improve 13 the solubility of C-methacetin and enable it to dissolve rapidly in the mouth.

[0069] When the direct powder compression method is adopted, first 13 prepare C-methacetin and a part of the excipient into a solid dispersion, and then add the remaining auxiliary materials to press into tablets.

[0070] For reference, the preparation of the solid dispersion can be carried out by the solvent method or the spray drying method.

[0071] The excipients used in preparing the above solid dispersion may include at least one of povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, and poloxamer 188. In the solid dispersion 13The weight ratio of C - methacetin to the excipient is 1:0.5 - 1:10, such as 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, etc., and can also be any other value within the range of 1:0.5 - 1:10.

[0072] Subsequently, the solid dispersion is crushed or sieved into particles or powders with a particle size < 300 μm, and then the remaining excipients are added and mixed evenly, and then pressed into tablets.

[0073] The remaining excipients mentioned above may also contain excipients. For the sake of easy distinction, the excipient used in the preparation of the solid dispersion can be called "the first excipient", and the excipient in the remaining excipients can be called "the second excipient". Exemplarily, the second excipient may include at least one of citric acid, mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose. The second excipient may account for 13 10 - 70 wt% of the C - methacetin orally disintegrating tablets, such as 10 wt%, 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt% or 70 wt%, etc.

[0074] The flavoring agent and preservative used in the above - mentioned direct powder compression process may be the same as those used in the freeze - drying process. And, the excipients used in the freeze - drying process may not contain disintegrants and lubricants.

[0075] In addition, this application also provides the above - mentioned 13 Application of the C - methacetin orally disintegrating tablets, for example, can be used to prepare drugs, reagents or kits for disease diagnosis, liver reserve function evaluation, and evaluation before and after liver surgery.

[0076] By way of reference, the disease may exemplarily include at least one of cirrhosis, primary biliary cirrhosis, simple steatosis, chronic liver disease staging, alcoholic liver disease, degree or staging of liver fibrosis, non - alcoholic fatty liver, neonatal cholestasis, biliary atresia, intrahepatic inflammation, acute liver failure, and hepatocellular carcinoma;

[0077] The liver reserve function evaluation may exemplarily include at least one of the evaluation of liver function of related diseases, the evaluation of chemotherapy - induced liver injury, the evaluation of predicting chronic liver failure death, and the evaluation of liver detoxification ability.

[0078] The evaluation before and after surgery may exemplarily include at least one of the evaluation of regeneration after hepatectomy, the evaluation of the urgency of liver transplantation, the evaluation of postoperative liver failure, and the evaluation before and after related surgeries.

[0079] The features and properties of the present invention will be further described in detail below in conjunction with examples.

[0080] Example 1

[0081] This example provides a13 C Methacetin orally disintegrating tablets, the formula of which is shown in Table 1.

[0082] Table 1 Formula

[0083]

[0084] The 13 Preparation process of the C Methacetin orally disintegrating tablets is as follows:

[0085] (1) Take 2500 mL of purified water and heat it to 60 °C;

[0086] (2) Weigh the prescribed amounts of 13 C Methacetin, mannitol, polyethylene glycol 4000, poloxamer 188, aspartame, strawberry essence and sodium benzoate, add them to the above purified water, stir to dissolve, and then add purified water to make the volume up to 3000 mL;

[0087] (3) Fill the above solution into an aluminum-plastic blister, with 3 mL filled in each blister;

[0088] (4) Transfer it to a freeze dryer for freeze-drying, and the freeze-drying parameters are shown in Table 2 below.

[0089] Table 2 Freeze-drying parameters

[0090] Freeze-drying stage Shelf temperature Time Vacuum degree Pre-freezing -40℃ 4h / Vacuum pumping -40℃ / <40Pa Shelf temperature rise Rise to 5°C 8h <40Pa Sublimation drying 5℃ 8h <40Pa Shelf temperature rise Rise to 35°C 1.5h <40Pa Desorption drying 35℃ 2.5h <20Pa Freeze-drying end / / /

[0091] (5) Heat-seal the freeze-dried sample with aluminum foil to obtain 13 C Methacetin orally disintegrating tablets.

[0092] Example 2

[0093] This example provides a 13 C Methacetin orally disintegrating tablets, the formula of which is shown in Table 3.

[0094] Table 3 Formula

[0095]

[0096] The 13 Preparation process of the C Methacetin orally disintegrating tablets is as follows:

[0097] (1) Take 2000 mL of purified water and heat it to 60 °C;

[0098] (2) Weigh the prescribed amounts of 13 C Methacetin, polyvinylpyrrolidone K30, lactose, gelatin, stevioside, mint essence, sodium methylparaben and sodium propylparaben, add them to the above purified water, stir to dissolve, and then add purified water to make the volume up to 2500 mL;

[0099] (3) Fill the above solution into aluminum-plastic blisters, with 2.5 mL filled in each blister;

[0100] (4) Transfer to a freeze dryer for freeze-drying, and the freeze-drying parameters are shown in Table 4 below.

[0101] Table 4 Freeze-drying parameters

[0102]

[0103]

[0104] (5) Heat-seal the freeze-dried sample with aluminum foil to obtain 13 C Methacetin orally disintegrating tablets.

[0105] Example 3

[0106] This example provides a 13 C Methacetin orally disintegrating tablet, and its formula is shown in Table 5.

[0107] Table 5 Formula

[0108]

[0109] The 13 preparation process of C Methacetin orally disintegrating tablets is as follows:

[0110] (1) Weigh the prescribed amounts of 13 C Methacetin, polyvinylpyrrolidone K30, and poloxamer 188, add them to 300 mL of ethanol, stir to dissolve, and set aside;

[0111] (2) Spray-dry the above ethanol solution in a spray dryer to form solid dispersion particles with a particle size less than 300 μm;

[0112] (3) Add the above solid dispersion particles to the prescribed amounts of microcrystalline cellulose, crospovidone, aspartame, strawberry essence, sodium benzoate, and magnesium stearate, and mix evenly;

[0113] (4) Press the above mixed powder into tablets, control the tablet weight to be 400 mg ± 20 mg, and the hardness to be 60 - 80 N to obtain 13 C Methacetin orally disintegrating tablets.

[0114] Example 4

[0115] This example provides a 13 C Methacetin orally disintegrating tablet, and its formula is shown in Table 6.

[0116] Table 6 Formula

[0117]

[0118] The13 The preparation process of C - methacetin orally disintegrating tablets is as follows:

[0119] (1) Weigh the prescribed amounts of 13 C - methacetin, polyethylene glycol 6000, poloxamer 188, methylparaben, and ethylparaben, add them to 300 mL of ethanol, stir to dissolve, and set aside;

[0120] (2) Rotate - evaporate the ethanol from the above - mentioned ethanol solution in a rotary evaporator to form a solid dispersion;

[0121] (3) Grind the above - mentioned solid dispersion at low temperature and pass through a 60 - mesh sieve;

[0122] (4) Add the powder of the above - mentioned solid dispersion to the prescribed amounts of microcrystalline cellulose, lactose, croscarmellose sodium, low - substituted hydroxypropyl cellulose, sucralose, orange essence, and stearic acid, and mix evenly;

[0123] (5) Compress the above - mentioned mixed powder into tablets, control the tablet weight to be 400 mg ± 20 mg, and the hardness to be 60 - 80 N, then we get 13 C - methacetin orally disintegrating tablets.

[0124] Comparative example

[0125] This comparative example provides a 13 C - methacetin granule, and its formula is shown in Table 7.

[0126] Table 7 Formula

[0127]

[0128] The 13 The preparation process of C - methacetin granule is as follows:

[0129] (1) Crush the raw and auxiliary materials, pass through an 80 - mesh sieve, weigh and set aside;

[0130] (2) Add 13 C - methacetin, mannitol, polyethylene glycol 4000, and disodium hydrogen phosphate dodecahydrate to a wet granulator, mix evenly, and add ethanol to granulate;

[0131] (3) Pass the above - mentioned wet granules through a swing granulator, and the screen mesh size is 16 - mesh;

[0132] (4) Dry the prepared granules in a vacuum drying oven at 50 °C for 4 h under vacuum;

[0133] (5) Screen the dried granules through a 14 - mesh screen and remove the fine powder through an 80 - mesh sieve;

[0134] (6) Fill the granules into bottles, with a filling amount of 5 g / bottle, seal, and then we get.

[0135] Test Examples

[0136] The medicaments prepared in the above Examples 1-4 and Comparative Examples were compared, and the results are shown in Table 8 below.

[0137] Table 8 Comparison Table

[0138]

[0139] It should be noted that "Impurity A" in the above table is p-anisidine, a degradation impurity of mefasudil. The amide structure of mefasudil raw material medicine may be partially degraded in the presence of high-temperature water to form p-anisidine.

[0140] As can be seen from Table 8:

[0141] ① In terms of quality: The 13 C mefasudil orally disintegrating tablets provided in the examples of the present application did not detect the related substance Impurity A, and the related substance Impurity A in the comparative example was higher than that in the orally disintegrating tablet samples of each example. The main reason is that the processes of each example of the orally disintegrating tablets are relatively mild, and the process is at low temperature or normal temperature, while the drying process of the comparative example is 50 °C, and the temperature is relatively high. Therefore, the quality of the 13 C mefasudil orally disintegrating tablets in the examples of the present application is better.

[0142] ② In terms of clinical use: The 13 C mefasudil orally disintegrating tablets in the examples of the present application can quickly disintegrate with only a small amount of water. Clinically, oral administration can be disintegrated in the mouth by saliva or only a small amount of water, which is easy to swallow and has good compliance; while the comparative example needs to be stirred in warm water for several minutes to dissolve before it can be taken. It can be seen that the 13 C mefasudil orally disintegrating tablets in the examples of the present application are convenient to take, do not need to be dissolved and prepared clinically, can reduce the burden on medical staff, and have good compliance for patients, with obvious advantages.

[0143] In summary, the 13 C mefasudil orally disintegrating tablets provided in the present application are prepared from 13 C mefasudil and excipients by freeze-drying or direct powder compression, which improves the stability of the raw material medicine 13 C mefasudil and improves the 13 solubility of 13 C mefasudil. The above

[0144] C mefasudil orally disintegrating tablets have the characteristics of rapid disintegration in the mouth or rapid disintegration with only a very small amount of water, which is convenient to take and improves the compliance in clinical use. It can be used to prepare drugs, reagents or kits for disease diagnosis, liver reserve function evaluation, and evaluation before and after liver surgery, etc.The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A 13 cimetidine orally disintegrating tablet, characterized in that Each tablet 13 The weight of the C-methacetin orally disintegrating tablet is 50-100 mg; the 13 disintegration or dissolution time of the C-methacetin orally disintegrating tablet in the oral cavity or in 1-2 mL of water does not exceed 10 s; The 13 Preparation of the C-methacetin orally disintegrating tablets comprises the following steps: Dissolve 13 C mepivacaine and excipients in water to prepare a freeze-dried intermediate solution, and then fill, lyophilize, and seal; wherein, the excipients used to prepare the freeze-dried intermediate solution are excipients, flavoring agents, and preservatives; the excipients include at least one of polyvinylpyrrolidone K30, polyethylene glycol 4000, polyethylene glycol 6000, mannitol, sorbitol, xylitol, lactose, gelatin, and poloxamer 188; the 13 weight ratio of C mepivacaine to the excipient is 1:0.5 - 1:10; in the freeze-dried intermediate solution 13 the total concentration of C mepivacaine and excipients is 10 - 30%; each tablet 13 contains no more than 2.0 wt% of the flavoring agent and no more than 1.0 wt% of the preservative; The stages of freeze-drying include pre-freezing, vacuum pumping, the first stage of shelf temperature increase, sublimation drying, the second stage of shelf temperature increase, and desorption drying; the shelf temperature for pre-freezing is -40°C to -45°C, and the time is 4 - 6 h; the shelf temperature for vacuum pumping is -40°C to -45°C, and the vacuum degree is < 50 Pa; the temperature for the first stage of shelf temperature increase rises to 0 - 5°C, the time is 6 - 10 h, and the vacuum degree is < 50 Pa; the temperature for sublimation drying rises to 0 - 5°C, the time is 6 - 10 h, and the vacuum degree is < 50 Pa; the temperature for the second stage of shelf temperature increase rises to 30 - 35°C, the time is 1.5 - 2 h, and the vacuum degree is < 50 Pa; the temperature for desorption drying rises to 30 - 35°C, the time is 2.5 - 3 h, and the vacuum degree is < 20 Pa.

2. According to claim 1 13 C methacetin orally disintegrating tablets, characterized in that The taste-correcting agent includes at least one of aspartame, stevioside, sucralose, and essence. And / or, the preservative includes at least one of methylparaben and its sodium salt, ethylparaben and its sodium salt, propylparaben and its sodium salt, sodium benzoate, and potassium sorbate.

3. According to claim 1 13 C mephenytoin orally disintegrating tablets, characterized in that Each tablet 13 The weight of each orally disintegrating tablet of C methacetin is 75 mg.

4. The 13 preparation method of c-methacetin orally disintegrating tablets, characterized in that It includes the following steps: Dissolve 13 C mephenytoin and excipients in water to prepare a freeze-dried intermediate solution, and then fill, freeze-dry, and seal; wherein, the excipients used to prepare the freeze-dried intermediate solution are excipients, flavoring agents, and preservatives; the excipients include at least one of povidone K30, polyethylene glycol 4000, polyethylene glycol 6000, mannitol, sorbitol, xylitol, lactose, gelatin, and poloxamer 188; the 13 weight ratio of C mephenytoin to the excipient used to prepare the freeze-dried intermediate solution is 1:0.5 - 1:10; the 13 total concentration of C mephenytoin and excipients in the freeze-dried intermediate solution is 10 - 30%; each 13 C mephenytoin orally disintegrating tablet contains no more than 2.0 wt% of the flavoring agent and no more than 1.0 wt% of the preservative; The stages of freeze-drying include pre-freezing, vacuum pumping, the first stage of shelf temperature increase, sublimation drying, the second stage of shelf temperature increase, and desorption drying; the shelf temperature for pre-freezing is -40°C to -45°C, and the time is 4 - 6 h; the shelf temperature for vacuum pumping is -40°C to -45°C, and the vacuum degree is < 50 Pa; the temperature for the first stage of shelf temperature increase rises to 0 - 5°C, the time is 6 - 10 h, and the vacuum degree is < 50 Pa; the temperature for sublimation drying rises to 0 - 5°C, the time is 6 - 10 h, and the vacuum degree is < 50 Pa; the temperature for the second stage of shelf temperature increase rises to 30 - 35°C, the time is 1.5 - 2 h, and the vacuum degree is < 50 Pa; the temperature for desorption drying rises to 30 - 35°C, the time is 2.5 - 3 h, and the vacuum degree is < 20 Pa.

5. The use of the orally disintegrating tablet of C-methacetin according to any one of claims 1 to 3, characterized in that, 13 The 13 C methacetin orally disintegrating tablets are used for preparing drugs, reagents or test kits for disease diagnosis, liver reserve function assessment, and assessment before and after liver surgery. ​ 6. The application according to claim 5, wherein The disease includes at least one of liver cirrhosis, primary biliary cirrhosis, simple steatosis, chronic liver disease staging, alcoholic liver disease, the degree or staging of liver fibrosis, non-alcoholic fatty liver, neonatal cholestasis, biliary atresia, intrahepatic inflammation, acute liver failure, and hepatocellular carcinoma. And / or, the assessment of liver reserve function includes at least one of the evaluation of liver function in related diseases, the assessment of chemotherapy-induced liver injury, the assessment of predicting death from chronic liver failure, and the assessment of liver detoxification ability. And / or, the assessment before and after surgery includes at least one of the assessment of liver regeneration after hepatectomy, the assessment of the urgency of liver transplantation, the assessment of postoperative liver failure, and the assessment before and after related surgeries.

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