A veterinary gs-441524 tablet and a preparation method thereof

Abstract

The application relates to the field of veterinary drugs, in particular to a veterinary GS-441524 tablet and a preparation method thereof. In the application, GS-441524 raw medicine, a filling agent, a disintegrating agent, a lubricant and a stabilizer are used as raw materials, the combination of mannitol and microcrystalline cellulose is selected as the filling agent, and coating is carried out, so that a new type of veterinary GS-441524 tablet is prepared. The application reduces the medicine loss caused by the thermal decomposition of API in the tabletting process, and improves the uniformity and stability of the medicine in the tablet.

Description

Technical Field

[0001] This application relates to the field of veterinary drugs, and in particular to a veterinary GS-441524 tablet and its preparation method. Background Technology

[0002] GS-441524, chemically named (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carboxynitrile, is a nucleoside analog antiviral drug initially developed by Gilead Sciences for the inhibition of RNA virus replication. Currently, GS-441524 is the drug of choice for FIP (feline infectious peritonitis virus). Intracellularly, it is phosphorylated by a kinase to its active form, acting on viral RNA polymerase and subsequently blocking viral RNA synthesis. It can also be used for various viral infections.

[0003] Currently, the main dosage form of GS-441524 is injection. However, the use of injection-form veterinary drugs presents certain difficulties, requiring professional operation, which creates a certain barrier to entry in the practical use of GS-441524 formulations. Some research and development has been undertaken on oral formulations of GS-441524. However, due to the low oral bioavailability of tablets and the light and heat instability of GS-441524 during manufacturing, friction between raw materials during tablet preparation can lead to heat generation in the system. Insufficient heat dissipation can result in low uniformity of tablet content. Summary of the Invention

[0004] To achieve the above objectives, this application provides a veterinary GS-441524 tablet and its preparation method, which can reduce the loss of active ingredients caused by excessive heating of API during tablet preparation, and improve the uniformity and stability of the formulation.

[0005] First, the veterinary GS-441524 tablets involved in this application consist of a core and a coating. Per 100 parts by weight of GS-441524 active pharmaceutical ingredient, the core comprises the following components in parts by weight:

[0006] 50-500 parts of filler

[0007] 15-30 parts of disintegrant

[0008] Stabilizer 5-15 parts

[0009] 2-10 parts of lubricant

[0010] The filler includes mannitol and microcrystalline cellulose, wherein the mass ratio of mannitol to microcrystalline cellulose is 1:0.5 to 3.

[0011] The coating is 5 to 15 parts by weight.

[0012] In the above scheme, a combination of mannitol and microcrystalline cellulose is used as a filler. Mannitol provides good lubrication properties and good dispersibility of the active pharmaceutical ingredient (API) of GS-441524. Furthermore, the API is less affected by friction in the mannitol system, reducing API loss due to heat generation during the process. Further, in the above scheme, the stabilizer is preferably citric acid, and / or the disintegrant is preferably sodium carboxymethyl starch.

[0013] Preferably, the filler comprises 100-300 parts by weight, and the filler further comprises triethyl glycerol, wherein the mass fraction of triethyl glycerol is 1 / 40 to 1 / 10 of the total mass of the filler. In the above scheme, triethyl glycerol and mannitol can jointly reduce the deterioration of the active pharmaceutical ingredient during tableting. The introduction of triethyl glycerol not only significantly improves the recovery rate of API in the system, but also greatly improves the uniformity between tablets, making different tablets have more similar properties.

[0014] Preferably, the lubricant is a combination of magnesium stearate and colloidal silica, wherein the mass ratio of magnesium stearate to colloidal silica is 1:0.25-2. Magnesium stearate provides good surface activity, which can improve the uniformity of dispersion of each component, while colloidal silica provides lubrication at the physical level, providing good lubricity in the early stage of tableting, reducing friction, and reducing the heat generated during tableting.

[0015] In addition, this application also provides a method for preparing the above-mentioned veterinary GS-441524 tablets, comprising the following steps:

[0016] S1. Mix GS-441524 active pharmaceutical ingredient, microcrystalline cellulose, disintegrant, filler, stabilizer and at least a portion of lubricant;

[0017] S2. Add mannitol to the above system and mix again;

[0018] S3. Add the remaining lubricant to the above system, mix and compress into sheets;

[0019] S4. Coat the tablets obtained by compression in step S3 with a film to obtain GS-441524 tablets.

[0020] Preferably, in step S3, triethyl glycerol is also added. More preferably, in step S1, the colloidal silica portion of the lubricant is added, and in step S3, the magnesium stearate portion of the lubricant is added.

[0021] In the above scheme, different lubricants and fillers are added in stages. In step S1, colloidal silica and microcrystalline cellulose are added first. In this step, the entire system is in a dry state for initial mixing. Colloidal silica reduces the friction between solid particles. Since all components are in a solid state in step S1, the system has low viscosity, high fluidity, and can be mixed more uniformly. In step S2, mannitol is added and further mixed. The purpose of this step is mainly to mix and disperse the API with mannitol, while slightly increasing the viscosity of the system, allowing the API to disperse and be adsorbed into the fillers and lubricants. Mannitol can also better disperse the disintegrant, providing space for disintegration. In step S3, the remaining lubricant, namely magnesium stearate, is added, along with triethyl glycerol. The main purpose of this step is to shape the small particles formed in step S2. Magnesium stearate and triethyl glycerol coat the shaped particles, providing cohesive viscosity for the sheet while reducing friction between the shaped particles, thus providing better sheet formation.

[0022] Preferably, in step S3, magnesium stearate and triethyl glycerol are dispersed in water and then added to the mixture obtained in step S2 by spraying, wherein the ratio of the volume of water to the sum of the masses of magnesium stearate and triethyl glycerol is 2-5 mL / g. More preferably, in this step, the spraying temperature is controlled at 0-4°C.

[0023] In this scheme, magnesium stearate and triethyl glycerol are first dispersed in an aqueous system, and then added to the system in the form of a spray to bind them together. On the one hand, this makes the cohesion of the particles stronger, and the particles are less likely to disintegrate in subsequent preparation. On the other hand, it can also play a role in distributing and cooling, which also improves the overall quality.

[0024] In summary, this application improves the preparation method of veterinary GS-441524 tablets by modifying the addition method of lubricant and filler, reducing the heat generation during the preparation process, and improving the dispersion uniformity of API in the tablets, so that the final product has a stable appearance, good recovery rate and uniformity. Attached Figure Description

[0025] Figure 1 This is the high performance liquid chromatography spectrum of GS-441524 in this application. Detailed Implementation

[0026] The solution in this application will be further described through the following specific implementation methods.

[0027] The detection method for the samples prepared in the following examples is as follows:

[0028] 1. Sample morphology inspection: Overall inspection of the sample's color, shape, and whether it is cracked.

[0029] 2. The dissolution test and high performance liquid chromatography method of the Chinese Pharmacopoeia 2015 edition, Part II were used for testing. Ten tablets of each sample were taken for testing. The average API content and dissolution rate at 15 min were measured, and the homogeneity was determined by the CV% value of the API content.

[0030] The specific detection method using high-performance liquid chromatography is as follows:

[0031] Place one tablet of the product in a 100ml volumetric flask, add 30ml of DMSO, sonicate for 20min, then add 50ml of 0.4% phosphoric acid solution, sonicate for 10min, cool, and dilute to volume with 0.4% phosphoric acid solution. Then perform high-performance liquid chromatography (HPLC) detection under the following conditions:

[0032] Chromatographic column: Fuli Instruments Polypark C18-AQ (5µm, 4.6*150mm)

[0033] Mobile phase: Methanol-0.1 t% phosphoric acid aqueous solution (volume ratio 5:95)

[0034] Peak emission time: 8~9 min

[0035] Flow rate: 1.5 ml / min

[0036] Column temperature: 35℃

[0037] Injection volume: 2ul

[0038] Wavelength: 240nm.

[0039] Example 1: This example provides a veterinary GS-441524 tablet, the overall formula of which is as follows:

[0040] API (i.e., GS-441524, hereinafter the same): 20g;

[0041] Filler: 60g, specific components are as follows:

[0042] Mannitol 28.5g;

[0043] Microcrystalline cellulose 28.5g;

[0044] 3g of triethyl glycerol;

[0045] Disintegrant: 4g, specifically sodium carboxymethyl starch;

[0046] Stabilizer: 2g, specifically citric acid;

[0047] Lubricant: 1g, specific ingredients are as follows:

[0048] Magnesium stearate 0.5g;

[0049] 0.5g of colloidal silica.

[0050] In addition, it also contains a coating material, the amount of which is 2g. Any commercially available enteric coating material can be used. Specifically, in this embodiment and the following embodiments, the coating material used is HPMCAS, which contains 5% by weight of pork liver powder.

[0051] All of the above solid materials have passed through a 60-mesh sieve.

[0052] Specifically, in Example 1, the tablet preparation method is as follows:

[0053] S1. In a mixer, add API, microcrystalline cellulose, disintegrant, filler, stabilizer, and colloidal silica, and mix for 10 minutes.

[0054] S2. Add mannitol to the above mixture and continue mixing for 20 minutes;

[0055] S3. Disperse magnesium stearate and triethyl glycerol in 14 ml of water to form a uniform suspension. Then, control the temperature at 4°C and add the suspension to the system by spraying. Continue mixing for 5 min.

[0056] S4. Transfer the above mixture to a three-dimensional mixer, compress it into tablets to a hardness of 60N, and then perform film coating to obtain the final tablets. It should be noted that the above mass only represents the theoretical mass ratio. In fact, in this embodiment and the following embodiments, each tablet finally obtained contains 110mg of API.

[0057] Example 2: Based on Example 1, this example adjusts the total amount of filler added and the ratio of the three fillers. The experimental results of Example 1 and Example 2 are shown in Table 1 and Table 2.

[0058]

[0059]

[0060] In the table above, the recovery rate refers to the ratio of the measured API content to the theoretical content.

[0061] The data in the table above shows that the amount of filler added affects the overall dissolution rate. Excessive filler (refer to experimental groups 2-4) leads to a significant decrease in dissolution rate and a lower average recovery rate. This is likely because excessive filler reduces the uniformity of particle distribution within the system, resulting in a higher CV value. Conversely, lower filler levels, such as in experimental groups 2-3, tend to result in greater variance between tablets, leading to a higher CV value. Furthermore, insufficient filler can result in a lack of API protection, further reducing the overall recovery rate.

[0062] Furthermore, by comparing experimental groups 2-7 and 2-11 with other experimental groups, it can be seen that when the amount of triethyl glycerol is too small or not added at all, the dispersibility and heat accumulation of the system are improved to a certain extent, resulting in a significant decrease in the recovery rate of the system. On the other hand, when the amount of triethyl glycerol added is too large, it will also lead to poor tablet shape and easy cracking.

[0063] Regarding the ratio of mannitol to microcrystalline cellulose, experiments showed that a mass ratio of 1:0.5 to 3 yielded good detection results. As shown in experimental group 2-16, excessive addition of microcrystalline cellulose led to a decrease in solubility and recovery rate, and the poor dispersion performance of microcrystalline cellulose on APIs resulted in a significant loss of system homogeneity. Similarly, as shown in experimental group 2-13, excessive addition of mannitol significantly resulted in an unformed system.

[0064] Example 3: In this example, based on Example 1, the total amount and specific components of the lubricant were adjusted, and the experimental results are shown in Tables 3 and 4.

[0065]

[0066]

[0067] The experimental results in Tables 3 and 4 show that the overall ratio of colloidal silica and magnesium stearate should be appropriate. Generally, an excess of either magnesium stearate or colloidal silica will lead to significant lubrication deficiency in the system, resulting in a marked decrease in the overall recovery rate. Furthermore, excessive lubricant will also lead to lower cohesion in the system, making the resulting tablets more prone to cracking.

[0068] Example 4: This example adjusts the overall preparation process based on Example 1, as follows:

[0069] Experimental group 4-1: Combine steps S1 and S2 into S1': In a mixer, add API, microcrystalline cellulose, disintegrant, filler, mannitol, stabilizer and colloidal silica, and mix for 30 min.

[0070] Experimental group 4-2: The order of adding mannitol and microcrystalline cellulose was changed. Mannitol was added in step S1 and microcrystalline cellulose was added in step S2.

[0071] Experimental group 4-3: Adjust steps S1 and S2. Do not add microcrystalline cellulose in step S1, and add microcrystalline cellulose in step S2.

[0072] Experimental group 4-4: For step S3, instead of spraying, magnesium stearate and triethyl glycerol were directly added to the mixer and mixed for another 5 minutes.

[0073] For experimental groups 4-5, the addition step of triethyl glycerol was adjusted, and triethyl glycerol was added in step S1.

[0074] For experimental groups 4-6, the addition step of triethyl glycerol was adjusted, and triethyl glycerol was added in step S2.

[0075] For experimental groups 4-7, the steps for adding magnesium stearate were adjusted, and magnesium stearate was added in step S1.

[0076] For experimental groups 4-8, the steps for adding magnesium stearate were adjusted, and magnesium stearate was added in step S2.

[0077] In experimental groups 4-9, room temperature spraying was used in step S3.

[0078] The experimental results for Example 4 are shown in Table 5.

[0079]

[0080]

[0081] The above experimental results show that the order and conditions of each step in this application have a significant impact on the final experimental results. Specifically, the addition of microcrystalline cellulose in step S1 can disperse and load API in the early stage. In experimental group 4-2, it can be seen that if microcrystalline cellulose is added in step S2, it will lead to a significant decrease in uniformity and a certain loss in morphology.

[0082] In step S3, spraying provides better cooling performance compared to direct addition. Considering that a preliminary homogeneous mixture is formed in steps S1 and S2 with the addition of mannitol, adding magnesium stearate or triethyl glycerol in steps S1 or S2 would prevent them from adhering to the surface of the pre-formed particles, thus increasing friction between particles. This would make the prepared tablets more susceptible to damage and would also fail to protect the API during tableting. Furthermore, spraying at a lower temperature (typically 4°C) can further remove heat from the system, slightly improving the system recovery rate.

[0083] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A veterinary GS-441524 tablet, comprising a core and a coating, characterized in that, According to 100 parts by weight of GS-441524 active pharmaceutical ingredient, the core comprises the following components in parts by weight: 200-400 parts of filler 15-30 parts of disintegrant Stabilizer 5-15 parts 2-10 parts of lubricant The filler comprises mannitol and microcrystalline cellulose, wherein the mass ratio of mannitol to microcrystalline cellulose is 1:0.5 to 3. The coating is 5 to 15 parts by weight; The filler also contains triethyl glycerol, wherein the mass fraction of triethyl glycerol is 1 / 40 to 1 / 10 of the total mass of the filler; The lubricant is a combination of magnesium stearate and colloidal silica, wherein the mass ratio of magnesium stearate to colloidal silica is 1:0.25-2. The GS-441524 veterinary tablets contain the following steps: S1. Mix GS-441524 active pharmaceutical ingredient, microcrystalline cellulose, disintegrant, stabilizer and colloidal silica; S2. Add mannitol to the mixture obtained in step S1 and mix again; S3. Disperse magnesium stearate and triethyl glycerol in water, and then add them to the mixture obtained in step S2 by spraying. The ratio of the volume of water to the sum of the masses of magnesium stearate and triethyl glycerol is 2 to 5 mL / g, and the spraying temperature is 0 to 4℃. S4. Coat the tablets obtained by compression in step S3 with a film to obtain GS-441524 tablets.

2. The veterinary GS-441524 tablets according to claim 1, characterized in that, The stabilizer is citric acid, and / or the disintegrant is sodium carboxymethyl starch.

3. The veterinary GS-441524 tablets according to claim 1, characterized in that, The mixing time in step S2 is controlled to be 5-15 min, and the mixing time in step S3 is controlled to be 10-30 min.

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