A tablet of tecovirimat and a method of making the same

Abstract

This invention provides a tecoviride tablet and its preparation method. The tecoviride tablet comprises the following components in parts by weight: 10 parts tecoviride; 8-100 parts dispersant; 5-10 parts alkalinity regulator; 5-15 parts disintegrant; 5-15 parts filler; 3-5 parts binder; and 2-4 parts lubricant. The preparation method includes the following steps: S1. Weighing each component in the prescribed amount; S2. Crushing the tecoviride and mixing it with the dispersant and alkalinity regulator to obtain a mixture, and then grinding the mixture; S3. Adding the disintegrant and filler to the ground mixture and mixing well, then adding it to a binder solution prepared with the binder to prepare wet granules, and drying to obtain dry granules; S4. Adding the lubricant to the dry granules and mixing well, then granulating and compressing to obtain tecoviride tablets. Using this invention avoids the use of cyclodextrin in drug preparation and can improve the dissolution rate of poorly soluble drugs, thereby improving bioavailability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a tecoviril tablet and its preparation method. Background Technology

[0002] Tecovirimat (code name ST-246, chemical name 4-trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-vinylidenecyclopropano[f]isoindole-2(1H)-yl)-benzamide) is a highly active small molecule viral inhibitor. Its mechanism of action is to prevent viral release into cells by binding to viral genes. The structural formula of tecovirimat is shown in Formula 1.

[0003]

[0004] The orthopoxvirus genus comprises many viruses that cause serious diseases in both humans and animals. Viruses in this genus, including cowpox, monkeypox, and smallpox, can all infect humans. Ticoviri exhibits strong activity against orthopoxviruses such as smallpox virus, monkeypox virus, and cowpox virus. At a concentration of 0.01 μmol / L, it can inhibit 50% of monkeypox virus replication in vitro. Furthermore, tecoviri is well-tolerated in animals with intact or partially compromised immune systems. Combining tecoviri with smallpox vaccine can effectively prevent and treat adverse reactions caused by the latter, reduce damage levels, and accelerate wound healing.

[0005] Tecoviride has extremely poor water solubility, which limits its clinical application. To improve the water solubility and dissolution rate of tecoviride, CN107638571A proposes an oral tecoviride composition and its preparation method. This involves adding cyclodextrin and meglumine to tecoviride to prepare a ternary composition, which improves the dissolution of the oral tecoviride composition. However, due to the use of cyclodextrin for drug inclusion, cyclodextrin carries certain potential risks and its application in pharmaceuticals may cause adverse reactions in humans. Summary of the Invention

[0006] In view of this, the present invention aims to provide a tecoviride tablet and its preparation method, which avoids the use of cyclodextrin and can improve the dissolution of poorly soluble drugs, thereby improving bioavailability.

[0007] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0008] On one hand, the present invention provides a tecoviride tablet comprising the following components in parts by weight: 10 parts tecoviride; 8-100 parts dispersant; 5-10 parts alkaline regulator; 5-15 parts disintegrant; 5-15 parts filler; 3-5 parts binder; and 2-4 parts lubricant.

[0009] Furthermore, the dispersion carrier is selected from at least one of poloxamer 188, polyvinyl alcohol, copolyvinyl ketone, and hydroxypropyl methylcellulose.

[0010] Furthermore, the alkalinity regulator is selected from at least one of sodium bicarbonate, sodium carbonate, and potassium hydroxide.

[0011] Furthermore, the disintegrant is selected from at least one of sodium carboxymethyl starch, croscarmellose sodium, and low-substituted hydroxypropyl cellulose.

[0012] Furthermore, the filler is selected from at least one of lactose, starch, and microcrystalline cellulose.

[0013] Furthermore, the adhesive is selected from at least one of polyvinylpyrrolidone and methylcellulose.

[0014] Furthermore, the lubricant is selected from at least one of talc, magnesium stearate, and micronized silica gel.

[0015] On the other hand, the present invention also proposes a method for preparing tecoviride tablets, the method comprising the following steps:

[0016] S1. Weigh out the prescribed amounts of each component;

[0017] S2. After pulverizing Tecoviril, mix it with a dispersing carrier and an alkaline regulator to obtain a mixture, and then grind the mixture;

[0018] S3. After grinding, add the disintegrant and filler to the mixture and mix well. Then add the mixture to the adhesive solution prepared by the adhesive to prepare wet granules. After drying, dry granules are obtained.

[0019] S4. The dry granules are added to a lubricant, mixed evenly, granulated, and compressed into tablets to obtain tecoviril tablets.

[0020] Furthermore, the preparation method of the tecoviride tablets includes the following steps:

[0021] S1. Weigh out the prescribed amounts of each component;

[0022] S2. After pulverizing Tecoviril, mix it with a dispersant, an alkaline regulator, and a disintegrant to obtain a mixture, and then grind the mixture.

[0023] S3. After mixing the ground mixture with the filler, add it to the adhesive solution prepared by the adhesive to prepare wet particles, and dry them to obtain dry particles;

[0024] S4. The dry granules are added to a lubricant, mixed evenly, granulated, and compressed into tablets to obtain tecoviril tablets.

[0025] Compared with existing technologies, the tecoviride tablet and its preparation method described in this invention have the following advantages:

[0026] (1) The present invention provides a tecoviride tablet and its preparation method, which avoids the use of cyclodextrin, reduces the potential risks of cyclodextrin as a pharmaceutical excipient, and facilitates large-scale production and application.

[0027] (2) The tecoviride tablet and its preparation method of the present invention help to increase the pH value of the surface microenvironment of tecoviride during dissolution, thereby improving the dissolution of the drug. Detailed Implementation

[0028] The present invention will be further described below with reference to specific embodiments. First, it should be noted that the data in the following experimental examples were obtained by the inventors through numerous experiments. Due to space limitations, only a portion of these data is shown in the specification, and those skilled in the art can understand and implement the present invention based on this data. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the contents of this invention, those skilled in the art can make various modifications or alterations to the invention, and these modifications or alterations also fall within the scope of protection of this application.

[0029] This invention proposes a tecoviride tablet comprising the following components in parts by weight: 10 parts tecoviride; 8-100 parts dispersant; 5-10 parts alkaline regulator; 5-15 parts disintegrant; 5-15 parts filler; 3-5 parts binder; and 2-4 parts lubricant.

[0030] The preparation method of the tecoviride tablets includes the following steps:

[0031] S1. Weigh out the prescribed amounts of each component;

[0032] S2. After pulverizing Tecoviril, mix it with a dispersing carrier and an alkaline regulator to obtain a mixture, and then grind the mixture;

[0033] S3. After grinding, add the disintegrant and filler to the mixture and mix well. Then add the mixture to the adhesive solution prepared by the adhesive to prepare wet granules. After drying, dry granules are obtained.

[0034] S4. The dry granules are added to a lubricant, mixed evenly, granulated, and compressed into tablets to obtain tecoviril tablets.

[0035] Example 1

[0036] Prescription information effect Content (g) Tcovery raw materials 100 Polosham 188 Dispersion carrier 540 Sodium carbonate Alkalinity regulator 80 Sodium carboxymethyl starch Disintegrant 100 lactose filler 100 Polyvinylpyrrolidone adhesives 50 talcum powder lubricant 30

[0037] Weigh the ingredients according to the prescription amount in the table above. Grind tecoviride through a 40-60 mesh sieve, then mix it with poloxamer 188 and sodium carbonate to obtain a mixture. Grind the mixture for 3-5 minutes. Dissolve 50g of polyvinylpyrrolidone in 950g of water to form a 5% polyvinylpyrrolidone binder solution. Add sodium carboxymethyl starch and lactose to the ground mixture and mix evenly. Use the above binder solution to make wet granules, and dry granules. Add talc to the dry granules, mix evenly, and then granulate and compress to obtain tecoviride tablets.

[0038] Example 2

[0039] The raw materials and dosages used in Example 2 and Example 1 were the same. Tecoviride was pulverized and passed through a 40-60 mesh sieve, then mixed with poloxamer 188, sodium carbonate, and sodium carboxymethyl starch to obtain a mixture. The mixture was ground for 3-5 minutes. 50g of polyvinylpyrrolidone was dissolved in 950g of water to form a 5% polyvinylpyrrolidone binder solution. Lactose was added to the ground mixture and mixed thoroughly. Wet granules were prepared using the binder solution, and dried to obtain dry granules. The dry granules were then mixed with talc, sized, and compressed into tablets to obtain tecoviride tablets.

[0040] Example 3

[0041]

[0042]

[0043] Weigh the ingredients according to the prescription amount in the table above. Grind tecoviride through a 40-60 mesh sieve, then mix it with polyvinyl alcohol, sodium bicarbonate, and croscarmellose sodium to obtain a mixture. Grind the mixture for 3-5 minutes. Add 30g of methylcellulose to 345g of water to form an 8% methylcellulose binder solution. Add starch to the ground mixture and mix evenly. Use the above binder solution to prepare wet granules, and dry them to obtain dry granules. Add magnesium stearate to the dry granules, mix evenly, and then granulate and compress to obtain tecoviride tablets.

[0044] Example 4

[0045] Prescription information effect Content (g) Tcovery raw materials 100 Copolyvinylpyrrolidone Dispersion carrier 530 potassium hydroxide Alkalinity regulator 100 Low-substituted hydroxypropyl cellulose Disintegrant 50 microcrystalline cellulose filler 150 Methylcellulose adhesives 50 Micronized silica lubricant 20

[0046] Weigh the ingredients according to the prescription amount in the table above. Grind tecoviride through a 40-60 mesh sieve, then mix it with copovidone, potassium hydroxide, and low-substituted hydroxypropyl cellulose to obtain a mixture. Grind the mixture for 3-5 minutes. Add 50g of methylcellulose to 450g of water to form a 10% methylcellulose binder solution. Add microcrystalline cellulose to the ground mixture and mix evenly. Use the above binder solution to prepare wet granules, and dry granules. Add microcrystalline silica gel to the dry granules, mix evenly, and then granulate and compress to obtain tecoviride tablets.

[0047] Example 5

[0048] Prescription information effect Content (g) Tcovery raw materials 100 Copolyvinylpyrrolidone Dispersion carrier 530 potassium hydroxide Alkalinity regulator 100 Sodium carboxymethyl starch Disintegrant 50 microcrystalline cellulose filler 150 Methylcellulose adhesives 50 Micronized silica lubricant 20

[0049] Weigh the ingredients according to the prescription amount in the table above. Crush tecoviride and pass it through a 40-60 mesh sieve. Then mix it with copovidone, potassium hydroxide, and sodium carboxymethyl starch to obtain a mixture. Grind the mixture for 3-5 minutes. Add 50g of methylcellulose to 450g of water to form a 10% methylcellulose binder solution. Add microcrystalline cellulose to the ground mixture and mix evenly. Use the above binder solution to make wet granules. Dry granules are obtained after drying. Add micronized silica gel to the dry granules, mix evenly, and then granulate and compress to obtain tecoviride tablets.

[0050] Furthermore, as part of an embodiment of the present invention, the present invention also provides a tecoviride tablet comprising the following components in parts by weight: 10 parts tecoviride; 8-100 parts dispersant; 5-10 parts alkalinity modifier; 5-15 parts disintegrant; 5-15 parts filler; 3-5 parts binder; 2-4 parts lubricant; and 5-10 parts excipient. The excipient is meglumine.

[0051] The preparation method of the tecoviride tablets includes the following steps:

[0052] S1. Weigh out the prescribed amounts of each component;

[0053] S2. After pulverizing Tecoviril, mix it with a dispersant, an alkaline regulator, and a disintegrant to obtain a mixture, and then grind the mixture.

[0054] S3. After mixing the ground mixture with filler, add it to the adhesive solution prepared with binder and additives to prepare wet granules, and dry granules are obtained after drying.

[0055] S4. The dry granules are added to a lubricant, mixed evenly, granulated, and compressed into tablets to obtain tecoviril tablets.

[0056] Example 6

[0057] Prescription information effect Content (g) Tcovery raw materials 100 Copolyvinylpyrrolidone Dispersion carrier 480 potassium hydroxide Alkalinity regulator 100 Low-substituted hydroxypropyl cellulose Disintegrant 50 microcrystalline cellulose filler 150 Methylcellulose adhesives 50 Micronized silica lubricant 20 meglumine Additives 50

[0058] Weigh the ingredients according to the prescription amount in the table above. Grind tecoviride through a 40-60 mesh sieve, then mix it with copovidone, potassium hydroxide, and low-substituted hydroxypropyl cellulose to obtain a mixture. Grind the mixture for 3-5 minutes. Add 50g of methylcellulose and 50g of meglumine to 400g of water to form a 10% methylcellulose binder solution. Add microcrystalline cellulose to the ground mixture and mix evenly. Use the above binder solution to prepare wet granules, and dry granules. Add microcrystalline silica gel to the dry granules, mix evenly, and then granulate and compress to obtain tecoviride tablets.

[0059] Example 7

[0060]

[0061]

[0062] Weigh the ingredients according to the prescription amount in the table above. Crush tecoviride and pass it through a 40-60 mesh sieve. Then mix it with copovidone, potassium hydroxide, and sodium carboxymethyl starch to obtain a mixture. Grind the mixture for 3-5 minutes. Add 50g of methylcellulose and 100g of meglumine to 350g of water to form a 10% methylcellulose binder solution. Add microcrystalline cellulose to the ground mixture and mix evenly. Use the above binder solution to make wet granules. Dry granules are obtained after drying. Add microcrystalline silica gel to the dry granules, mix evenly, and then granulate and compress to obtain tecoviride tablets.

[0063] Comparative Example 1

[0064] Comparative Example 1 is a ternary composition (tecoviride / meglumine / cyclodextrin) prepared using the method of Example 1 in CN107638571A. Specifically, 200g of meglumine and 600g of hydroxypropyl-β-cyclodextrin were dissolved in water and mixed evenly, and then 100g of tecoviride was added and stirred in a water bath. The resulting solution was freeze-dried to remove moisture. Lactose, hydroxypropyl methylcellulose, and sodium carboxymethyl starch were added and mixed, and then passed through an 80-mesh sieve and mixed evenly. Ethanol was then added as a wetting agent. The above mixture was made into a soft mass, passed through a 20-mesh sieve to form wet granules, and the wet granules were dried at 60°C to obtain dry granules. The prescribed amount of micronized silica powder was added to the dry granules, and the mixture was passed through a 16-mesh sieve, granulated, and compressed into tablets.

[0065] Dissolution test

[0066] Experimental Method: Using 1000 ml of water as the dissolution medium, the dissolution test was performed according to the method (Chinese Pharmacopoeia 2015, General Chapter 0931, Method II) at 100 rpm. 5 ml of solution was collected at 5, 10, 20, 30, and 45 min, filtered through a 0.45 μm microporous membrane to obtain the test solution. Separately, 5 mg of tecovirex raw material was accurately weighed as a reference standard and placed in a 100 ml volumetric flask. The volume was then diluted to the mark with the dissolution medium to obtain the reference solution. High-performance liquid chromatography (HPLC) was used to determine the peak areas of the test solution and the reference solution at 224 nm. The dissolution amount at different time points was calculated using the external standard method, and the cumulative dissolution percentage was calculated. The specific results are shown in Table 1.

[0067] Table 1. Cumulative dissolution percentage (%)

[0068] Group 5min 10min 20min 30min 45min Example 1 58.4 80.2 93.9 99.9 99.9 Example 2 60.5 81.8 95.4 99.9 99.9 Example 3 61.2 81.9 95.6 99.9 99.9 Example 4 62.5 82.5 96.0 99.9 99.9 Example 5 60.3 82.0 95.4 99.9 99.9 Example 6 62.0 82.3 96.1 99.9 99.9 Example 7 61.4 81.5 95.9 99.9 99.9 Comparative Example 1 56.3 78.9 91.2 97.8 99.9

[0069] As shown in Table 1, the dissolution effect of the tecoviril tablets obtained in Examples 1-7 using the method of this application in the initial stage was better than that of Comparative Example 1. For tecoviril, a drug with low water solubility, improving dissolution can improve bioavailability. Tecoviril has poor water solubility, and its solubility increases with increasing pH. Based on these properties of tecoviril, this application adds an alkaline regulator to adjust the pH value of tecoviril. At the same time, a dispersion carrier is used to disperse tecoviril and improve its hydrophilicity. Under the mechanical action of grinding, the contact surface between tecoviril, the dispersion carrier, and the alkaline regulator is improved, resulting in sufficient contact and high dispersion between tecoviril and the dispersion carrier, and between tecoviril and the alkaline regulator. This helps to increase the pH value of the surface microenvironment of tecoviril during dissolution, thereby improving drug dissolution.

[0070] Moreover, compared to Comparative Example 1, which requires the addition of cyclodextrin for inclusion to solubilize the drug, the method of this application can avoid the use of cyclodextrin, reducing the potential risks of cyclodextrin as a drug excipient.

[0071] Example 1 involved grinding tecoviride, a dispersing carrier, and an alkaline regulator before adding sodium carboxymethyl starch as a disintegrant. Example 2 involved grinding tecoviride, a dispersing carrier, an alkaline regulator, and the disintegrant together. The dissolution effect of Example 2 was superior to that of Example 1. This is because adding the disintegrant during the grinding process allows the finely ground tecoviride and disintegrant to be fully dispersed and continuously tumble and come into contact with each other, which helps to fully exert the disintegrant's effect and allows tecoviride to dissolve rapidly.

[0072] Content determination

[0073] Comparative Example 2

[0074] Comparative Example 2 and its formulation and dosage are the same as in Example 6. Tecoviride was pulverized and passed through a 40-60 mesh sieve, then mixed with copovidone, potassium hydroxide, and low-substituted hydroxypropyl cellulose to obtain a mixture. The mixture was ground for 3-5 minutes. 50g of methylcellulose was added to 400g of water to form a methylcellulose binder solution. The ground mixture was then mixed with microcrystalline cellulose and meglumine, and wet granules were prepared using the binder solution. After drying, dry granules were obtained. The dry granules were mixed with micronized silica gel, granulated, and compressed into tablets to obtain tecoviride tablets.

[0075] Experimental Methods: Five tablets from the same batch prepared in Examples 1-7 and Comparative Example 1 were placed in 200 mL volumetric flasks, diluted to the mark with the mobile phase, and shaken well. 1 mL of this solution was then accurately transferred to a 10 mL volumetric flask and diluted to the mark with the mobile phase. A commercially available tecovirex tablet solution of similar concentration was prepared using the same method as a reference solution. The solution was filtered through a 0.45 μm microporous membrane and then analyzed. The drug content was calculated using the external standard method. Chromatographic conditions were as follows: ZORBAX Eclipse XDB-C18 column (4.6 mm × 250 mm, 5 μm), mobile phase: acetonitrile; sodium dihydrogen phosphate solution = 50:50, column temperature = 25℃, flow rate = 1 mL / min, wavelength = 224 nm, injection volume = 20 μL. Specific results are shown in Table 2.

[0076] Table 2. Tecoviride content

[0077]

[0078]

[0079] Table 2 shows that the tecoviride tablets prepared in Comparative Example 1 exhibited significant differences in tecoviride content across five samples taken from the same batch, ranging from a minimum of 92.5% to a maximum of 100.9%. This is detrimental to ensuring drug content uniformity in large-scale pharmaceutical production and may affect efficacy. A possible reason is incomplete inclusion of cyclodextrin during the encapsulation process, resulting in some tablets having higher drug content than others. In Example 6, compared to Example 4, meglumine was added during the preparation of the binder solution, improving the uniformity of tecoviride content in the tablets. Similarly, in Example 7, compared to Example 5, meglumine was added during the preparation of the binder solution, further improving the uniformity of tecoviride content. The tablet content in the same batch showed minimal variation and was more conducive to pharmaceutical manufacturing. Adding meglumine to the binder solution can improve the uniformity of drug content in the tablets. Comparative Example 2, which changed the order of meglumine addition, showed less uniformity in drug content compared to Example 6, indicating that the order of meglumine addition also affects content uniformity.

[0080] Tablet friability and appearance

[0081] The tecoviride tablets prepared in Examples 1-7 and Comparative Example 1 were tested according to Appendix XG of the 2010 edition of the Chinese Pharmacopoeia, Part II. The specific results are shown in Table 3.

[0082] Table 3. Friability and Appearance

[0083] friability Example 1 0.55%, without cracks or shattering. Example 2 0.50%, without cracks or shattered pieces. Example 3 0.42%, with no cracks or fragments. Example 4 0.13%, with no cracks or fragments. Example 5 0.48%, with no cracks or shattered pieces. Example 6 0.18%, with no cracks or fragments. Example 7 0.45%, without cracks or shattered pieces. Comparative Example 1 0.85%, showing signs of breakage, cracking, and fragmentation.

[0084] As shown in Table 3, the tablets prepared in Examples 4 and 6 exhibited the best friability, thus improving the quality of the tecoviril tablets. The applicant hypothesizes that, compared to other disintegrants, the low-substituted hydroxypropyl cellulose used in Examples 4 and 6 has a coarser structure. During the grinding process, tecoviril formed a relatively fine structure, and with the pushing action of grinding, this structure allowed for better interlocking of the tecoviril particles with the coarse, gapped low-substituted hydroxypropyl cellulose particles, helping to reduce impact or abrasion on the tecoviril. Products with satisfactory friability are more likely to ensure the stability of the drug.

[0085] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A tecovirex tablet, characterized in that, The tecoviride tablets comprise the following components in parts by weight: 10 parts tecoviride; 48 parts copovidone; 10 parts potassium hydroxide; 5 parts low-substituted hydroxypropyl cellulose; 15 parts microcrystalline cellulose; 5 parts methylcellulose; 2 parts micronized silica; and 5 parts meglumine. The method for preparing tecoviride tablets includes the following steps: S1. Weigh out the prescribed amounts of each component; S2. After pulverizing tecoviride, mix it with copovidone, potassium hydroxide, and low-substituted hydroxypropyl cellulose to obtain a mixture, and then grind the mixture. S3. After grinding the mixture, add microcrystalline cellulose and mix well. Then add the mixture to a binder solution prepared with methylcellulose and meglumine to prepare wet granules. After drying, dry granules are obtained. S4. The dry granules are added to micronized silica gel, mixed evenly, granulated, and compressed into tablets to obtain tecoviril tablets.

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