Sitafloxacin tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations. Specifically, the invention relates to a sitafloxacin tablet and a preparation method thereof. The sitafloxacin tablet comprises (1) a solid dispersion which comprises (a) an active component which is sitafloxacin sesquihydrate and accounts for 15%-30% of the total weight of the tablet, (b) a solid dispersion carrier which is copovidone and accounts for 45%-65% of the total weight of the tablet, and (c) a stabilizer which is colloidal silicon dioxide and accounts for 0.1%-2.2% of the total weight of the tablet; (2) a filler accounting for 10-40% of the total weight of the tablet; (3) an adhesive accounting for 1%-5% of the total weight of the tablet; (4) a disintegrating agent accounting for 0.5-3% of the total weight of the tablet; and (5) a lubricant accounting for 0.2%-1.0% of the total weight of the tablet.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations. Specifically, the present invention relates to a sitafloxacin tablet and a preparation method thereof. Background Art

[0002] Sitafloxacin is a fluoroquinolone antibacterial drug developed by Daiichi Sankyo, used for the treatment of bacterial infections caused by severe and drug-resistant bacteria. The chemical name of sitafloxacin is (-)-7-[(7S)-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, and its sesquihydrate is used clinically.

[0003] Sitafloxacin sesquihydrate is poorly soluble in water, very slightly soluble in absolute ethanol, slightly soluble in methanol, and soluble in 0.1 mol / L hydrochloric acid solution or 0.1 mol / L sodium hydroxide solution. It belongs to BCS class II compounds. After oral administration, it dissolves slowly in the body and is difficult to completely dissolve, resulting in low drug bioavailability and unsatisfactory antibacterial effect. Therefore, the preparation of a suitable sitafloxacin preparation has always been a challenging task.

[0004] CN103156821A discloses a preparation method of sitafloxacin tablets by wet granulation. Although this method meets the requirements such as dissolution, it has high requirements for the particle size of the raw material drug, and both the raw material and the excipient need to pass through an 80-mesh sieve, making production difficult to achieve.

[0005] CN101496789B discloses a sitafloxacin sustained-release pellet and a preparation method thereof, which improves the bioavailability by a divided-dose dispersion dosage form, but there is no successful case in immediate-release preparations. Moreover, sitafloxacin is poorly soluble in water and common organic solvents, making the process difficult to achieve and prone to solvent residues.

[0006] CN113181125B discloses a preparation method of sitafloxacin tablets by stepwise adding refined sitafloxacin powder and mannitol for co-grinding. Although the amount of excipient used in this method is small, grinding easily leads to agglomeration, thus affecting the dissolution rate.

[0007] CN105663054B discloses a sitafloxacin granule, and the preparation contains sitafloxacin, a diluent, a lubricant, and a coating component. Although this method can meet the dissolution requirements when sitafloxacin becomes a drug, the granule has a large volume and high storage requirements.

[0008] Therefore, it is still necessary to optimize the formulation of sitafloxacin preparations and find a simplified preparation process. Summary of the Invention

[0009] In a first aspect, the present invention provides a sitafloxacin tablet, characterized in that the tablet comprises: a solid dispersion, the solid dispersion comprising: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 15%-30% of the total weight of the tablet, and (b) a solid dispersion carrier, which is copovidone, accounting for 35%-65% of the total weight of the tablet; and may further comprise a filler, a binder, a disintegrant, and a lubricant.

[0010] In one embodiment of the first aspect, the active ingredient accounts for 18% to 27% of the total weight of the tablet, preferably 20%-25%.

[0011] In one embodiment of the first aspect, the solid dispersion carrier accounts for 45%-65% of the total weight of the tablet, preferably 48%-62%, more preferably 50%-60%.

[0012] In one embodiment of the first aspect, the filler is selected from one or more of mannitol, starch, lactose, and microcrystalline cellulose, preferably selected from one or two of mannitol and starch. The amount of the filler may account for 10%-40% of the total weight of the tablet, preferably 12%-35%, more preferably 15%-32.5%, further preferably 15%-30%, for example, about 25%. In a preferred embodiment, the filler is mannitol and starch. In a more preferred embodiment, the filler is mannitol and starch, mannitol accounting for 5%-20% of the total weight of the tablet, and starch accounting for 5%-20% of the total weight of the tablet. In a further preferred embodiment, the filler is mannitol and starch, mannitol accounting for 10-16.5% of the total weight of the tablet, and starch accounting for 10-16.5% of the total weight of the tablet, preferably 5%-10%.

[0013] The starch as the filler may be selected from corn starch, potato starch, and wheat starch, preferably corn starch.

[0014] In one embodiment of the first aspect, the binder is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Preferably, the binder is hydroxypropyl cellulose. The amount of the binder may account for 1%-5% of the total weight of the tablet, preferably 2%-4%, more preferably about 3%.

[0015] In one embodiment of the first aspect, the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, and cross-linked polyvinylpyrrolidone. Preferably, the disintegrant is low-substituted hydroxypropyl cellulose. The amount of the disintegrant may account for 0.5%-3% of the total weight of the tablet, preferably 1%-2%, more preferably 1.2%-1.8%, further preferably about 1.5%.

[0016] In one embodiment of the first aspect, the lubricant is selected from one or more of magnesium stearate, calcium stearate, and sodium fumarate; preferably, the lubricant is selected from one or more of magnesium stearate and calcium stearate; more preferably, the lubricant is magnesium stearate. The amount of the lubricant can be 0.2% - 1.0% of the total weight of the tablets, preferably 0.3% - 0.7%, and more preferably about 0.5%.

[0017] The inventors surprisingly found that further including a specific amount of colloidal silica in the solid dispersion has additional unexpected technical effects. Colloidal silica can not only improve the flowability of the feeding during hot melt extrusion in the process of preparing the solid dispersion by the hot melt extrusion method, but also improve the chemical stability of the active ingredient. The specific amount of colloidal silica refers to that the amount of colloidal silica is 0.1% - 2.2% of the total weight of the tablets, preferably 0.2% - 2.0%.

[0018] In one embodiment, the sitafloxacin tablets comprise: (1) A solid dispersion, which comprises: (a) an active ingredient, being sitafloxacin sesquihydrate, accounting for 20% - 25% of the total weight of the tablets; (b) a solid dispersion carrier, being copovidone, accounting for 50% - 60% of the total weight of the tablets; (c) a stabilizer, being colloidal silica, accounting for 0.2% - 2.0% of the total weight of the tablets; (2) Fillers, being mannitol and starch, where mannitol accounts for 10% - 16.5% of the total weight of the tablets, and starch accounts for 5% - 16% of the total weight of the tablets, preferably 10% - 16%; (3) A binder, being hydroxypropyl cellulose, accounting for about 3% of the total weight of the tablets; (4) A disintegrant, being low-substituted hydroxypropyl cellulose, accounting for about 1.5% of the total weight of the tablets; (5) A lubricant, being magnesium stearate, accounting for about 0.5% of the total weight of the tablets.

[0019] Optionally, the sitafloxacin tablets of the present invention can have a film coating to mask unpleasant tastes, make the tablets aesthetically pleasing, provide identification for the tablets, etc. Suitable coating materials and methods for film coating that can achieve the above purposes are well known in the art. For example, the film coating premix 03F480031-CN (its composition: hydroxypropyl methylcellulose 2910 (viscosity 3 - 15 mPa·s): titanium dioxide: polyethylene glycol 6000: talc powder = 48:20:8:4) commercially available from Shanghai Colorcon Coating Technology Co., Ltd. can be used to coat the tablets of the present invention. The film coating can increase the weight of the tablets by about 5%.

[0020] On the other hand, the present invention provides a method for preparing the sitafloxacin tablets of the present invention, which is characterized in that the method comprises: Step (1). Mix a specified amount of the active ingredient, the solid dispersion carrier, and optionally colloidal silicon dioxide to obtain a mixture. Step (2). Add the mixture obtained in step (1) to a hot melt extrusion device, perform hot melt extrusion, and crush the obtained extruded material to obtain a solid dispersion. Step (3). Mix the solid dispersion obtained in step (2) evenly with a specified amount of filler, disintegrant, binder, and lubricant, and press into tablets.

[0021] The method may optionally further include: Step (4). Coating the tablets obtained in step (3) with a film coating to obtain sitafloxacin film-coated tablets.

[0022] In one embodiment, in step (2), the hot melt extrusion is carried out under the following conditions: the screw speed is 120 - 400 rpm, the hot melt extrusion temperature is 130 - 200 °C, and the feeding speed is 0.8 - 3.0 kg / h.

[0023] In one embodiment, in step (3), the hardness of the tablet cores obtained after pressing is 40 N - 90 N.

[0024] The sitafloxacin tablets of the present invention have increased sitafloxacin dissolution rate, and thus have better absorption and higher bioavailability in vivo. In addition, the tablets of the present invention can be prepared by a simple and easy-to-operate hot melt extrusion method. Compared with the prior art, this preparation method does not use organic solvents and can meet the dissolution requirements on the basis of reducing energy consumption and improving production capacity.

[0025] In addition, the inventors of the present invention surprisingly found that when preparing sitafloxacin tablets by using the hot melt extrusion process of the present invention, adding colloidal silicon dioxide significantly improves the stability of sitafloxacin, and the related substances are significantly reduced.

[0026] Unless otherwise clearly stated to the contrary, the percentages given in this application are all weight percentages.

[0027] Those skilled in the art can understand that the sum of the weight percentages of the components of the composition ≤ 100% (i.e., less than or equal to 100%).

[0028] As used herein, the term "about" means an expansion of the value given after it by ±10%, preferably ±5%. For example, "about 5%" means 4.5% to 5.5%, preferably 4.75% to 5.25%.

[0029] As used herein, the term "solid dispersion carrier" refers to an auxiliary material that can disperse a drug inside or on its surface by physical or chemical methods to form a solid dispersion. The formation of a solid dispersion usually promotes the release characteristics of the drug.

[0030] As used herein, the term "copovidone" refers to the product obtained by copolymerizing 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 3:2. Calculated on the anhydrous basis, the nitrogen (N) content is 7.0% to 8.0%, and the copolymer contains 35.3% to 41.4% of vinyl acetate (C4H6O2). Copovidone is commercially available, for example, from BASF Pharma under the trade name Kollidon ® Commercially available, such as Kollidon ® VA64

[0031] As used herein, the term "hydroxypropyl cellulose" refers to partially substituted 2-hydroxypropyl ether cellulose. Calculated on the dried basis, the hydroxypropoxy group (-OCH2CHOHCH3) content is 53.4% to 80.5%. Hydroxypropyl cellulose is commercially available, for example, from Nippon Soda Co., Ltd., such as HPC-L, etc.

[0032] As used herein, the term "low-substituted hydroxypropyl cellulose" refers to low-substituted 2-hydroxypropyl ether cellulose, which is prepared by alkalizing cellulose and then carrying out an etherification reaction with propylene oxide under high-temperature conditions, followed by neutralization, recrystallization, washing, drying, pulverization, and sieving. Calculated on the dried basis, the hydroxypropoxy group (-OCH2CHOHCH3) content is 5.0% to 16.0%. Low-substituted hydroxypropyl cellulose is commercially available, for example, from Shin-Etsu Chemical Co., Ltd. under the trade name L-HPC ® Commercially available, such as L-HPC ® LH-21, etc.

[0033] As used herein, "hydroxypropyl methylcellulose" refers to 2-hydroxypropyl ether methylcellulose, which is a semi-synthetic product and can be prepared by two methods: (1) treating cotton linter or wood pulp fiber with caustic soda and then reacting successively with chloromethane and propylene oxide, followed by refining and pulverization; (2) treating methylcellulose of an appropriate grade with sodium hydroxide and reacting with propylene oxide under high temperature and high pressure until the desired degree is reached, followed by refining. The molecular weight range is 10,000 to 1,500,000.

[0034] As used herein, the term "colloidal silica" is a white, porous powder prepared by reacting silicon tetrachloride in a hydrogen and oxygen flame. Calculated on the ignited basis, the SiO2 content should be 99.0% to 100.5%. Colloidal silica is commercially available, for example, from Evonik Operations GmbH under the trade name Aerosil®, such as Aerosil®200, etc.

[0035] As used herein, the term "optionally" or "optional" means that the subsequent described event or situation may or may not occur, and includes the case where the event or situation occurs and the case where the event or situation does not occur. For example, "optionally includes" means that the steps described later may or may not be present. Detailed Description

[0036] Embodiment 1. A sitafloxacin tablet, characterized in that the tablet comprises: (1) A solid dispersion, the solid dispersion comprising: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 15% - 30% of the total weight of the tablet, (b) a solid dispersion carrier, the solid dispersion carrier being copovidone, accounting for 45% - 65% of the total weight of the tablet, (c) a stabilizer, the stabilizer being colloidal silicon dioxide, accounting for 0.1% - 2.2% of the total weight of the tablet; (2) A filler, accounting for 10% - 40% of the total weight of the tablet; (3) A binder, accounting for 1% - 5% of the total weight of the tablet; (4) A disintegrant, accounting for 0.5% - 3% of the total weight of the tablet; (5) A lubricant, accounting for 0.2% - 1.0% of the total weight of the tablet.

[0037] Embodiment 2. The sitafloxacin tablet according to Embodiment 1, wherein the active ingredient accounts for 18% - 27% of the total weight of the tablet, and the solid dispersion carrier accounts for 48% - 62% of the total weight of the tablet.

[0038] Embodiment 3. The sitafloxacin tablet according to Embodiment 1, wherein the active ingredient accounts for 20% - 25% of the total weight of the tablet, the solid dispersion carrier accounts for 50% - 60% of the total weight of the tablet, the stabilizer accounts for 0.2% - 2% of the total weight of the tablet, the filler accounts for 15% - 32.5% of the total weight of the tablet, the binder accounts for about 3% of the total weight of the tablet, the disintegrant accounts for about 1.5% of the total weight of the tablet, and the lubricant accounts for about 0.5% of the total weight of the tablet, where the term "about" means that the value given after it is extended by ±10%.

[0039] Embodiment 4. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein the filler is selected from one or more of mannitol, starch, lactose, and microcrystalline cellulose; the binder is selected from one or more of hydroxypropyl cellulose, povidone, and hydroxypropyl methylcellulose; the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, and cross-linked povidone; The lubricant is selected from one or more of magnesium stearate, calcium stearate, and sodium stearyl fumarate.

[0040] Embodiment 5. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein the filler is mannitol and starch, and mannitol accounts for 5%-20% of the total weight of the tablet, and starch accounts for 5%-20% of the total weight of the tablet; the binder is hydroxypropyl methylcellulose; the disintegrant is low-substituted hydroxypropyl cellulose; the lubricant is magnesium stearate.

[0041] Embodiment 6. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein the filler is mannitol and starch, and mannitol accounts for 10-16.5% of the total weight of the tablet, and starch accounts for 5%-16% of the total weight of the tablet; the binder is hydroxypropyl methylcellulose; the disintegrant is low-substituted hydroxypropyl cellulose; the lubricant is magnesium stearate.

[0042] Embodiment 7. The sitafloxacin tablet according to Embodiment 1, the tablet comprising: (1) A solid dispersion, the solid dispersion comprising: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 20%-25% of the total weight of the tablet; (b) a solid dispersion carrier, which is copovidone, accounting for 50%-60% of the total weight of the tablet; (c) a stabilizer, which is colloidal silicon dioxide, accounting for 0.2%-2.0% of the total weight of the tablet; (2) A filler, which is mannitol and starch, mannitol accounting for 10%-16.5% of the total weight of the tablet, and starch accounting for 5%-16% of the total weight of the tablet; (3) A binder, which is hydroxypropyl cellulose, accounting for 3% of the total weight of the tablet; (4) A disintegrant, which is low-substituted hydroxypropyl cellulose, accounting for 1.5% of the total weight of the tablet; (5) A lubricant, which is magnesium stearate, accounting for 0.5% of the total weight of the tablet.

[0043] Embodiment 8. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein the tablet has a film coating.

[0044] Embodiment 9. The sitafloxacin tablet according to Embodiment 4, wherein the tablet has a film coating.

[0045] Embodiment 10. The sitafloxacin tablet according to Embodiment 5, wherein the tablet has a film coating.

[0046] Embodiment 11. The sitafloxacin tablet according to Embodiment 6, wherein the tablet has a film coating.

[0047] Embodiment 12. The sitafloxacin tablet according to Embodiment 7, wherein the tablet has a film coating.

[0048] Embodiment 13. A method for preparing the sitafloxacin tablet according to any one of Embodiments 1 to 12, characterized in that the method comprises: Step (1). Mix a specified amount of the active ingredient, the solid dispersion carrier, and the stabilizer to obtain a mixture; Step (2). Add the mixture obtained in Step (1) to a hot melt extrusion device, perform hot melt extrusion, and crush the obtained extruded material to obtain a solid dispersion; Step (3). Uniformly mix the solid dispersion obtained in Step (2) with a specified amount of filler, disintegrant, binder, and lubricant, and press into tablets; The method may optionally further comprise: Step (4). Coat the tablets obtained in Step (3) with a film coating.

[0049] Embodiment 14. According to the method of Embodiment 13, wherein, In Step (2), the hot melt extrusion is carried out under the following conditions: the screw rotation speed is 120 - 400 rpm, the hot melt extrusion temperature is 130 - 200 °C, and the feeding speed is 0.8 - 3.0 kg / h; And / or, In Step (3), the hardness of the tablets obtained after tableting is 40 N - 90 N.

[0050] Embodiment 15. A sitafloxacin tablet prepared by the method of Embodiment 13 or 14.

[0051] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to embodiments. It should be understood that the embodiments described herein are only used to explain the present invention and are not used to limit the protection scope of the present invention.

[0052] Specific information of the excipients used in the examples: polyvinylpyrrolidone (PVP K15), copovidone (Kollidon ® VA64), hydroxypropyl cellulose (HPC-L), low-substituted hydroxypropyl cellulose (LH-21), mannitol (PEARLITOL ® 160 C), corn starch (Type B), hypromellose acetate succinate (AS MF), colloidal silicon dioxide (Aerosil® 200).

[0053] Example 1 The components and their weight percentages of the tablets of Example 1 are as follows: sitafloxacin sesquihydrate, 25%; copovidone, 50%; mannitol, 10%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0054] The sitafloxacin tablets are prepared as follows: Step (1). Mix a specified amount of sitafloxacin and copovidone to obtain a mixture; Step (2). Add the mixture obtained in step (1) to a hot melt extrusion device for hot melt extrusion operation. The screw speed is 120 - 200 rpm, the hot melt extrusion temperature is 130 - 200 °C, and the feeding speed is 0.8 - 1.2 kg / h to obtain an extruded material. The extruded material is subjected to hammer milling to obtain a solid dispersion; Step (3). Add the solid dispersion obtained in step (2) and a specified amount of mannitol, starch, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose to a mixing device for mixing for 5 - 30 min, then add magnesium stearate and mix for another 5 - 10 min to obtain a mixed material. The mixed material is tableted using a rotary tablet press, and the hardness of the tablet core is 30 N - 100 N; Step (4). Coating the tablets obtained in step (3) with a film coating premix 03F480031-CN (its composition: hydroxypropyl methylcellulose 2910 (viscosity 3 - 15 mPa·s): titanium dioxide: polyethylene glycol 6000: talc powder = 48:20:8:4) to obtain film-coated sitafloxacin tablets. The film coating causes the tablets to gain weight by about 5%.

[0055] Example 2 The components and their weight percentages of the tablets of Example 2 are as follows: sitafloxacin sesquihydrate, 25%; hypromellose acetate succinate, 50%; mannitol, 10%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0056] The sitafloxacin tablets are prepared by the same method as in Example 1, except that in step (1), a specified amount of hypromellose acetate succinate is used to replace a specified amount of copovidone.

[0057] Example 3 The components and their weight percentages of the tablets of Example 3 are as follows: sitafloxacin sesquihydrate, 25%; povidone, 50%; mannitol, 10%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0058] The sitafloxacin tablets were prepared by the same method as in Example 1, except that in step (1), a specified amount of povidone was used to replace a specified amount of copovidone.

[0059] Example 4 The components and their weight percentages of the tablets of Example 4 are as follows: sitafloxacin sesquihydrate, 25%; copovidone, 37.5%; mannitol, 16.5%; corn starch, 16%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0060] The sitafloxacin tablets were prepared by the same method as in Example 1, except that the drug loading of the solid dispersion obtained in step (1) was 40%.

[0061] Example 5 The components and their weight percentages of the tablets of Example 5 are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 50%; mannitol, 15%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0062] The sitafloxacin tablets were prepared by the same method as in Example 1, except that the drug loading of the solid dispersion obtained in step (1) was 28.6%.

[0063] Example 6 The components and their weight percentages of the tablets of Example 6 are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 60%; mannitol, 10%; corn starch, 5%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0064] The sitafloxacin tablets were prepared by the same method as in Example 1, except that the drug loading of the solid dispersion obtained in step (1) was 25%.

[0065] Example 7: Dissolution test Dissolution tests were performed on the tablets of Examples 1-6 and the original developed formulation, Grepitto® (National Medicine Approval No. HJ20190022, Daiichi Sankyo Co., Ltd.).

[0066] Dissolution was determined with reference to the dissolution and release determination method (Method 2 of General Chapter 0931, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0067] Apparatus: High performance liquid chromatograph and dissolution tester.

[0068] Dissolution medium: pH = 6.8 phosphate buffer solution.

[0069] Volume of dissolution medium: 900 mL.

[0070] Rotation speed: 50 rpm.

[0071] Sampling times: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0072] Take the tablets of Examples 1-6 and the original developed formulation, according to the dissolution and release determination method (Second Method of General Chapter 0931, Volume IV, Chinese Pharmacopoeia 2020 Edition), take 900 mL of pH = 6.8 phosphate buffer solution as the dissolution medium, paddle method at 50 revolutions per minute, operate according to the law, take the solution for determination according to the sampling time, and the dissolution data are shown in Table 1: Table 1. Dissolution (%) of Tablets of Examples 1-6 and the Original Developed Formulation Test sample 5 min 10 min 15 min 20 min 30 min 45 min 60 min Example 1 25 54 73 80 86 92 98 Example 2 20 48 66 75 80 86 94 Example 3 14 40 52 63 70 79 86 Example 4 17 45 63 73 80 88 94 Example 5 25 56 75 83 88 94 99 Example 6 24 56 74 85 87 95 99 Original developed formulation 22 50 67 75 82 87 95 It can be seen from the data in the above table that the tablets of Examples 1, 5, and 6 achieved a dissolution of more than 85% in vitro within 30 min, and had a better dissolution rate than the original developed formulation [the original developed formulation reached more than 85% only at 45 min]. The tablets of Examples 1, 5, and 6 had a high dissolution rate and good dissolution effect, so they had a higher bioavailability and were more conducive to absorption in vivo.

[0073] Example 8 The components and their weight percentages of the tablets of Example 8 are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 50%; colloidal silicon dioxide, 0.2%; mannitol, 14.8%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0074] Prepare sitafloxacin tablets as follows: Step (1). Mix the specified amounts of sitafloxacin, copovidone, and colloidal silicon dioxide to obtain a mixture. Step (2). Add the mixture obtained in step (1) to a hot melt extrusion device for hot melt extrusion operation, the screw speed is 120 - 200 rpm, the hot melt extrusion temperature is 130 - 200 °C, the feeding speed is 0.8 - 1.2 kg / h, to obtain an extruded material, and the extruded material is subjected to hammer milling to obtain a solid dispersion. Step (3). Add the solid dispersion obtained in step (2) and the specified amounts of mannitol, starch, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose to a mixing device for mixing for 5 - 30 min, then add magnesium stearate and mix for another 5 - 10 min to obtain a mixed material, and the mixed material is tableted using a rotary tablet press, and the hardness of the tablet core is 30 N - 100 N. Step (4). The tablets obtained in step (3) are film-coated with a film coating premix 03F480031-CN (composition: hypromellose 2910 (viscosity 3 - 15 mPa·s): titanium dioxide: polyethylene glycol 6000: talc = 48:20:8:4) to obtain sitafloxacin film-coated tablets, and the film coating causes the tablets to gain weight by about 5%.

[0075] Example 9 The components of the tablets of Example 9 and their weight percentages are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 50%; colloidal silicon dioxide, 0.5%; mannitol, 14.5%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0076] Sitafloxacin tablets are prepared by using the specified amounts of the components according to the method of Example 8.

[0077] Example 10 The components of the tablets of Example 10 and their weight percentages are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 50%; colloidal silicon dioxide, 2.0%; mannitol, 13.0%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0078] Sitafloxacin tablets are prepared by using the specified amounts of the components according to the method of Example 8.

[0079] Example 11 The components of the tablets of Example 11 and their weight percentages are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 50%; colloidal silicon dioxide, 2.5%; mannitol, 12.5%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; magnesium stearate, 0.5%.

[0080] Sitafloxacin tablets are prepared by using the specified amounts of the components according to the method of Example 8.

[0081] The preparation processes of Examples 8 - 11 show that adding colloidal silicon dioxide to the hot melt material improves the feeding fluidity during hot melt extrusion.

[0082] Example 12: Dissolution test According to the same method as in Example 7, dissolution tests are carried out on the tablets of Examples 8 - 11 and the original research formulation Grepitant® (National Medicine Approval No. HJ20190022, Daiichi Sankyo Co., Ltd.). The dissolution data are shown in Table 2: Table 2. Dissolution (%) of Examples 8 - 11 Test sample 5 min 10 min 15 min 20 min 30 min 45 min 60 min Example 5 25 56 75 83 88 94 99 Example 8 25 54 73 82 86 92 98 Example 9 24 55 74 83 87 93 97 Example 10 24 53 74 83 86 91 97 Example 11 16 45 59 64 73 76 80 Original developed formulation 22 50 67 75 82 87 95 As can be seen from the data in the above table, Examples 8-10 still maintained good dissolution effects [the dissolution rate could reach over 85% in 30 minutes in vitro], but Example 11 showed poor dissolution results.

[0083] Example 13: Stability test Take the tablets of Examples 5, 8-10 and the original developed preparation, and place them under the conditions required by the Guidelines for Stability Testing of Drug Substances and Preparations (the Guidelines for Stability Testing of Drug Substances and Preparations, Part IV of the Chinese Pharmacopoeia 2020 Edition, 9001 Guidelines for Stability Testing of Drug Substances and Preparations, Pharmaceutical Preparations) at 40 °C / RH 75% for 3 months for accelerated test investigation. The dissolution and related substance test results are shown in Table 3.

[0084] Table 3. Stability test results of the tablets of Examples 5, 8-10 and the original developed preparation Test sample Investigation item Day 0 1st month 2nd month 3rd month Example 5 Dissolution rate (%) 88 87 88 88 Example 5 Related substances (%) 0.39 0.38 0.39 0.38 Example 8 Dissolution rate (%) 86 87 88 87 Example 8 Related substances (%) 0.35 0.36 0.35 0.35 Example 9 Dissolution rate (%) 87 86 87 88 Example 9 Related substances (%) 0.14 0.14 0.13 0.14 Example 10 Dissolution rate (%) 86 86 85 86 Example 10 Related substances (%) 0.13 0.12 0.13 0.13 Original developed formulation Dissolution rate (%) 82 80 77 76 Original developed formulation Related substances (%) 0.32 0.34 0.37 0.37 Conclusion: After being placed at 40 °C / RH 75% for 3 months, the dissolution rates of the tablets of Examples 5, 8-10 were basically unchanged compared with those on the 0th day, showing excellent stability. In contrast, the dissolution rate of the original developed preparation decreased by 6%. In addition, it was surprisingly observed that the contents of related substances in Examples 5 and 8 were slightly higher than those of the original developed preparation, while the contents of related substances in the tablets of Examples 9 and 10 were reduced by more than 50% compared with those of the original developed preparation. Moreover, after being placed at 40 °C / RH 75% for 3 months, the related substances of the preparations of Examples 9 and 10 remained unchanged, while the content of related substances of the original developed preparation increased by 15.63%.

[0085] The experimental results showed that a specific amount of colloidal silica not only improved the feeding fluidity during hot melt extrusion, but also significantly improved the chemical stability of the tablets.

[0086] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A sitafloxacin tablet, characterized in that: The tablet comprises: (1) a solid dispersion, the solid dispersion comprising: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 15%-30% of the total weight of the tablet, (b) a solid dispersion carrier, which is copovidone, accounting for 45%-65% of the total weight of the tablet, and (c) a stabilizer, which is colloidal silicon dioxide, accounting for 0.1%-2.2% of the total weight of the tablet; (2) fillers, accounting for 10% to 40% of the total tablet weight; (3) Binder, accounting for 1%-5% of the total tablet weight; (4) disintegrant, accounting for 0.5% to 3% of the total tablet weight; (5) Lubricant, accounting for 0.2%-1.0% of the total weight of the tablet.

2. The sitafloxacin tablet according to claim 1, wherein The active ingredient accounts for 18%-27% of the total weight of the tablet, and the solid dispersion carrier accounts for 48%-62% of the total weight of the tablet.

3. The sitafloxacin tablet according to claim 1, wherein The active ingredient accounts for 20%-25% of the total weight of the tablet, the solid dispersion carrier accounts for 50%-60% of the total weight of the tablet, the stabilizer accounts for 0.2%-2% of the total weight of the tablet, the filler accounts for 15%-32.5% of the total weight of the tablet, the binder accounts for about 3% of the total weight of the tablet, the disintegrant accounts for about 1.5% of the total weight of the tablet, and the lubricant accounts for about 0.5% of the total weight of the tablet, wherein the term "about" indicates that the numerical value given thereafter is extended by ±10%.

4. The sitafloxacin tablet according to any one of claims 1 to 3, wherein The filler is selected from one or more of mannitol, starch, lactose and microcrystalline cellulose; The binder is selected from one or more of hydroxypropyl cellulose, povidone, and hypromellose; The disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and cross-linked polyvinylpyrrolidone; The lubricant is selected from one or more of magnesium stearate, calcium stearate, and hard sodium fumarate.

5. The sitafloxacin tablet according to any one of claims 1 to 3, wherein The fillers are mannitol and starch, and mannitol accounts for 5%-20% of the total weight of the tablet, and starch accounts for 5%-20% of the total weight of the tablet; The binder is hypromellose; The disintegrant is low-substituted hydroxypropyl cellulose; The lubricant is magnesium stearate.

6. The sitafloxacin tablet according to any one of claims 1 to 3, wherein The fillers are mannitol and starch, and mannitol accounts for 10-16.5% of the total weight of the tablet, and starch accounts for 5%-16% of the total weight of the tablet; The binder is hypromellose; The disintegrant is low-substituted hydroxypropyl cellulose; The lubricant is magnesium stearate.

7. The sitafloxacin tablet according to claim 1, comprising: (1) a solid dispersion, the solid dispersion comprising: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 20%-25% of the total weight of the tablet; (b) a solid dispersion carrier, which is copovidone, accounting for 50%-60% of the total weight of the tablet; (c) a stabilizer, which is colloidal silicon dioxide, accounting for 0.2%-2.0% of the total weight of the tablet; (2) fillers, which are mannitol and starch, with mannitol accounting for 10%-16.5% of the total weight of the tablet and starch accounting for 5%-16% of the total weight of the tablet; (3) Binder, which is hydroxypropylcellulose, accounting for 3% of the total tablet weight; (4) disintegrant, which is low-substituted hydroxypropyl cellulose, accounting for 1.5% of the total weight of the tablet; (5) Lubricant: magnesium stearate, accounting for 0.5% of the total weight of the tablet.

8. The sitafloxacin tablet according to any one of claims 1 to 3, wherein the tablet has a film coating.

9. The sitafloxacin tablet according to claim 4, wherein the tablet has a film coating.

10. The sitafloxacin tablet according to claim 5, wherein the tablet has a film coating.

11. The sitafloxacin tablet according to claim 6, wherein the tablet has a film coating.

12. The sitafloxacin tablet according to claim 7, wherein the tablet has a film coating.

13. A method for preparing the sitafloxacin tablet according to any one of claims 1 to 12, characterized in that: The method comprises: Step (1). Mixing a specified amount of an active ingredient, a solid dispersion carrier, and a stabilizer to obtain a mixture; Step (2) The mixture obtained in step (1) is added to a hot melt extrusion device, hot melt extrusion, the extruded material obtained is crushed to obtain a solid dispersion; Step (3) The solid dispersion obtained in step (2) is mixed with a specified amount of a filler, a disintegrant, a binder, a lubricant, and tableted; The method optionally further comprises: Step (4). Film-coating the tablets obtained in step (3).

14. The method according to claim 13, wherein: In step (2), the hot melt extrusion is carried out under the following conditions: the screw speed is 120-400 rpm, the hot melt extrusion temperature is 130-200° C., and the feeding speed is 0.8-3.0 kg / h; and / or, In step (3), the hardness of the tablets obtained after tableting is 40N-90N.

15. A sitafloxacin tablet prepared by the method of claim 13 or 14.