Sitafloxacin tablet and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations. Specifically, the present invention relates to a sitafloxacin tablet and a preparation method thereof. The sitafloxacin tablet comprises: (1) a solid dispersion, wherein the solid dispersion comprises: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 15%-30% of the total weight of the tablet, (b) a solid dispersion carrier, wherein the solid dispersion carrier is copovidone, accounting for 45%-65% of the total weight of the tablet, (c) a stabilizer, wherein the stabilizer is 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; 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, and in particular to a sitafloxacin tablet and a preparation method thereof. Background Art

[0002] Sitafloxacin is a fluoroquinolone antibacterial drug developed by Daiichi Sankyo Co., Ltd. in Japan for the treatment of severe and drug-resistant bacterial infections. Its chemical name 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 anhydrous ethanol, slightly soluble in methanol, and soluble in 0.1 mol / L hydrochloric acid or 0.1 mol / L sodium hydroxide solutions. It belongs to the BCS Class II compound and dissolves slowly and incompletely in the body after oral administration, resulting in low bioavailability and unsatisfactory antibacterial efficacy. Therefore, the preparation of a suitable sitafloxacin formulation has always been a challenging task.

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

[0005] CN101496789B discloses a sitafloxacin sustained-release micropill and a preparation method thereof, which aims to improve bioavailability by dispersing the dosage form in divided doses. However, there have been no successful cases in immediate-release preparations. In addition, sitafloxacin is poorly soluble in water and common organic solvents, making the process difficult to implement and prone to solvent residue.

[0006] CN113181125B discloses a method for preparing sitafloxacin tablets by stepwise addition of refined sitafloxacin powder and grinding with mannitol. Although this method uses a small amount of excipients, grinding easily leads to agglomeration, thereby affecting the dissolution rate.

[0007] CN105663054B discloses a sitafloxacin granule preparation, which comprises sitafloxacin, a diluent, a lubricant, and a coating component. Although this method can meet the dissolution requirements of sitafloxacin when it is prepared as a drug, the granules are relatively large in size and have high storage requirements.

[0008] Therefore, there is still a need to optimize the formulation of sitafloxacin and find a simplified formulation 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, wherein the solid dispersion comprises: (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%, preferably 20%-25% of the total weight of the tablet.

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

[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 both of mannitol and starch. The amount of the filler can 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 accounts for 5%-20% of the total weight of the tablet, and starch accounts for 5%-20% of the total weight of the tablet. In a further preferred embodiment, the filler is mannitol and starch, mannitol accounts for 10-16.5% of the total weight of the tablet, and starch accounts for 10-16.5% of the total weight of the tablet, preferably 5%-10%.

[0013] The starch used as the filler can 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, povidone, and hypromellose. Preferably, the binder is hydroxypropyl cellulose. The binder may be used in an amount of 1% to 5%, preferably 2% to 4%, and more preferably about 3% of the total weight of the tablet.

[0015] In one embodiment of the first aspect, the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and cross-linked polyvinylpyrrolidone. Preferably, the disintegrant is low-substituted hydroxypropyl cellulose. The amount of the disintegrant can account for 0.5%-3% of the total weight of the tablet, preferably 1%-2%, more preferably 1.2%-1.8%, and 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 hard 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 lubricant can account for 0.2%-1.0% of the total weight of the tablet, preferably 0.3%-0.7%, and more preferably about 0.5%.

[0017] The inventors surprisingly discovered that further including a specific amount of colloidal silicon dioxide in a solid dispersion has additional, unexpected technical benefits. Colloidal silicon dioxide not only improves the flowability of the solid dispersion during hot-melt extrusion, but also improves the chemical stability of the active ingredient. The specific amount of colloidal silicon dioxide refers to an amount of colloidal silicon dioxide of 0.1% to 2.2%, preferably 0.2% to 2.0%, based on the total weight of the tablet.

[0018] In one embodiment, the sitafloxacin tablet comprises:

[0019] (1) a 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; and (c) a stabilizer, which is colloidal silicon dioxide, accounting for 0.2%-2.0% of the total weight of the tablet;

[0020] (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, preferably 10%-16%;

[0021] (3) binder, which is hydroxypropylcellulose, accounting for approximately 3% of the total tablet weight;

[0022] (4) disintegrant, which is low-substituted hydroxypropyl cellulose, accounting for approximately 1.5% of the total tablet weight;

[0023] (5) Lubricant, magnesium stearate, accounting for about 0.5% of the total weight of the tablet.

[0024] Optionally, the sitafloxacin tablets of the present invention may be film-coated to mask unpleasant tastes, enhance tablet aesthetics, or allow for tablet labeling. Suitable coating materials and film-coating methods for achieving these objectives are well known in the art. For example, the tablets of the present invention can be coated using the film-coating premix 03F480031-CN (composition: hydroxypropyl methylcellulose 2910 (viscosity 3-15 mPa·s): titanium dioxide: polyethylene glycol 6000: talc = 48:20:8:4) commercially available from Shanghai Colorcon Coating Technology Co., Ltd. This film coating can increase tablet weight by approximately 5%.

[0025] In another aspect, the present invention provides a method for preparing the sitafloxacin tablets of the present invention, characterized in that the method comprises:

[0026] Step (1) mixing a specified amount of the active ingredient, a solid dispersion carrier and optionally colloidal silicon dioxide to obtain a mixture;

[0027] Step (2) The mixture obtained in step (1) was added to a hot melt extrusion device, hot melt extrusion, the resulting extruded material was crushed to obtain a solid dispersion;

[0028] Step (3). The solid dispersion obtained in step (2) is mixed evenly with a specified amount of filler, disintegrant, binder, and lubricant, and tabletted.

[0029] The method may optionally further comprise:

[0030] Step (4). The tablets obtained in step (3) are film-coated to obtain sitafloxacin film-coated tablets.

[0031] In one embodiment, in step (2), the hot melt extrusion is carried out under the following conditions: screw speed is 120-400 rpm, hot melt extrusion temperature is 130-200° C., and feeding speed is 0.8-3.0 kg / h.

[0032] In one embodiment, in step (3), the hardness of the tablet core obtained after tableting is 40N-90N.

[0033] The sitafloxacin tablets of the present invention have increased sitafloxacin solubility, thereby achieving better absorption and higher bioavailability in the body. Furthermore, 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, meeting dissolution requirements while reducing energy consumption and improving production capacity.

[0034] In addition, the inventors of the present invention unexpectedly discovered that when sitafloxacin tablets are prepared using the hot melt extrusion process of the present invention, the addition of colloidal silicon dioxide significantly improves the stability of sitafloxacin and significantly reduces related substances.

[0035] Unless expressly stated otherwise, all percentages given in this application are by weight.

[0036] Those skilled in the art will understand that the sum of the weight percentages of the components of the composition is ≤100% (ie, less than or equal to 100%).

[0037] The term "about" as used herein means that the numerical value given thereafter is extended by ±10%, preferably ±5%. For example, "about 5%" means 4.5% to 5.5%, preferably 4.75% to 5.25%.

[0038] The term "solid dispersion carrier" as used herein refers to an excipient that can disperse the drug within or on its surface by physical or chemical methods to form a solid dispersion. The formation of a solid dispersion generally promotes the release characteristics of the drug.

[0039] The term "copolyvidone" as used herein refers to a product obtained by copolymerizing 1-vinyl-2-pyrrolidone with vinyl acetate in a mass ratio of 3:2. The nitrogen (N) content, calculated as anhydrous, is 7.0% to 8.0%, and the copolymer contains 35.3% to 41.4% vinyl acetate (C4H6O2). Copolyvidone is commercially available, for example, from BASF Pharma under the trade name Kollidon ® Commercially available, for example, Kollidon ® VA64.

[0040] The term "hydroxypropyl cellulose" as used herein refers to a partially substituted 2-hydroxypropyl ether cellulose containing 53.4% ​​to 80.5% hydroxypropoxy groups (-OCH2CHOHCH3) on a dry basis. Hydroxypropyl cellulose is commercially available, for example, from Nippon Soda Co., Ltd., such as HPC-L.

[0041] The term "low-substituted hydroxypropyl cellulose" as used herein refers to low-substituted 2-hydroxypropyl ether cellulose, which is obtained by alkalizing cellulose and reacting it with propylene oxide at high temperature to undergo etherification reaction, followed by neutralization, recrystallization, washing, drying, crushing and screening. Calculated on a dry basis, it contains 5.0% to 16.0% hydroxypropoxy groups (-OCH2CHOHCH3). 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.

[0042] As used herein, "hydroxypropyl methylcellulose" refers to 2-hydroxypropyl ether methylcellulose, a semi-synthetic product that can be prepared by two methods: (1) treating cotton linter or wood pulp fiber with caustic soda, reacting it with methyl chloride and then propylene oxide, refining it, and grinding it; (2) treating a suitable grade of methyl cellulose with sodium hydroxide, reacting it with propylene oxide under high temperature and pressure to the desired concentration, and then refining it. The molecular weight range is 10,000 to 1,500,000.

[0043] As used herein, the term "colloidal silica" is a white, loose powder obtained by reacting silicon tetrachloride in a flame of hydrogen and oxygen. The SiO2 content, calculated as ignited, should be between 99.0% and 100.5%. Colloidal silica is commercially available, for example, from Evonik Operations GmbH under the trade name Aerosil®, such as Aerosil® 200.

[0044] The term "optionally" or "optionally" as used herein means that the event or circumstance described later may or may not occur, and includes both situations in which the event or circumstance occurs and situations in which the event or circumstance does not occur. For example, "optionally including" means that the steps described later may or may not exist. DETAILED DESCRIPTION

[0045] Embodiment 1. A sitafloxacin tablet, characterized in that the tablet comprises:

[0046] (1) a solid dispersion comprising: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 15% to 30% of the total weight of the tablet; (b) a solid dispersion carrier, which is copovidone, accounting for 45% to 65% of the total weight of the tablet; and (c) a stabilizer, which is colloidal silicon dioxide, accounting for 0.1% to 2.2% of the total weight of the tablet;

[0047] (2) fillers, which account for 10% to 40% of the total tablet weight;

[0048] (3) Binder, accounting for 1%-5% of the total tablet weight;

[0049] (4) disintegrant, accounting for 0.5%-3% of the total tablet weight;

[0050] (5) Lubricant, accounting for 0.2%-1.0% of the total weight of the tablet.

[0051] 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.

[0052] 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, wherein the term "about" indicates that the numerical value given thereafter is expanded by ±10%.

[0053] Embodiment 4. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein

[0054] The filler is selected from one or more of mannitol, starch, lactose and microcrystalline cellulose;

[0055] The binder is selected from one or more of hydroxypropyl cellulose, povidone, and hypromellose;

[0056] The disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and cross-linked polyvinylpyrrolidone;

[0057] The lubricant is selected from one or more of magnesium stearate, calcium stearate, and hard sodium fumarate.

[0058] Embodiment 5. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein

[0059] 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;

[0060] The binder is hypromellose;

[0061] The disintegrant is low-substituted hydroxypropyl cellulose;

[0062] The lubricant is magnesium stearate.

[0063] Embodiment 6. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein

[0064] 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;

[0065] The binder is hypromellose;

[0066] The disintegrant is low-substituted hydroxypropyl cellulose;

[0067] The lubricant is magnesium stearate.

[0068] Embodiment 7. The sitafloxacin tablet according to embodiment 1, comprising:

[0069] (1) a 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; and (c) a stabilizer, which is colloidal silicon dioxide, accounting for 0.2%-2.0% of the total weight of the tablet;

[0070] (2) Fillers, which are mannitol and starch, with mannitol accounting for 10%-16.5% of the total tablet weight and starch accounting for 5%-16% of the total tablet weight;

[0071] (3) binder, which is hydroxypropyl cellulose, accounting for 3% of the total tablet weight;

[0072] (4) disintegrant, low-substituted hydroxypropyl cellulose, accounting for 1.5% of the total tablet weight;

[0073] (5) Lubricant, magnesium stearate, accounting for 0.5% of the total weight of the tablet.

[0074] Embodiment 8. The sitafloxacin tablet according to any one of Embodiments 1 to 3, wherein the tablet has a film coating.

[0075] Embodiment 9. The sitafloxacin tablet of embodiment 4, wherein the tablet has a film coating.

[0076] Embodiment 10. The sitafloxacin tablet of embodiment 5, wherein the tablet has a film coating.

[0077] Embodiment 11. The sitafloxacin tablet of embodiment 6, wherein the tablet has a film coating.

[0078] Embodiment 12. The sitafloxacin tablet of embodiment 7, wherein the tablet has a film coating.

[0079] Embodiment 13. A method for preparing a sitafloxacin tablet according to any one of Embodiments 1 to 12, characterized in that the method comprises:

[0080] Step (1). Mixing a specified amount of the active ingredient, the solid dispersion carrier, and the stabilizer to obtain a mixture;

[0081] Step (2) The mixture obtained in step (1) was added to a hot melt extrusion device, hot melt extrusion, the resulting extruded material was crushed to obtain a solid dispersion;

[0082] Step (3) The solid dispersion obtained in step (2) is mixed with a specified amount of filler, disintegrant, binder, lubricant, and tableted;

[0083] The method optionally further comprises:

[0084] Step (4). Film-coating the tablets obtained in step (3).

[0085] Embodiment 14. The method according to embodiment 13, wherein

[0086] In step (2), the hot melt extrusion is carried out under the following conditions: screw speed is 120-400 rpm, hot melt extrusion temperature is 130-200° C., and feeding speed is 0.8-3.0 kg / h;

[0087] and / or,

[0088] In step (3), the hardness of the tablet obtained after tableting is 40N-90N.

[0089] Embodiment 15. A sitafloxacin tablet prepared by the method of embodiment 13 or 14.

[0090] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the embodiments described herein are only used to explain the present invention and are not intended to limit the scope of protection of the present invention.

[0091] Specific information of the excipients used in the examples: polyvinylpyrrolidone (PVP K15), copolyvinylpyrrolidone (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).

[0092] Example 1

[0093] The components of the tablet of Example 1 and their weight percentages are as follows: sitafloxacin sesquihydrate, 25%; copovidone, 50%; mannitol, 10%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; and magnesium stearate, 0.5%.

[0094] Sitafloxacin tablets were prepared as follows:

[0095] Step (1). Mixing a specified amount of sitafloxacin and copovidone to obtain a mixture;

[0096] Step (2). The mixture obtained in step (1) was added to a hot melt extrusion device for hot melt extrusion operation, the screw speed was 120 to 200 rpm, the hot melt extrusion temperature was 130 to 200 ° C, the feed rate was 0.8 to 1.2 kg / h, and the extruded material was hammer-milled to obtain a solid dispersion;

[0097] Step (3). The solid dispersion obtained in step (2) is added to a mixing device with a specified amount of mannitol, starch, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose and mixed for 5 to 30 minutes. Magnesium stearate is then added and mixed for another 5 to 10 minutes to obtain a mixture. The mixture is tableted using a rotary tablet press. The tablet core hardness is 30N to 100N.

[0098] Step (4). The tablets obtained in step (3) were film-coated with a film coating premix 03F480031-CN (composition: hydroxypropyl methylcellulose 2910 (viscosity 3-15 mPa‧s): titanium dioxide: polyethylene glycol 6000: talc = 48:20:8:4) to obtain sitafloxacin-coated tablets. Film coating resulted in a tablet weight increase of approximately 5%.

[0099] Example 2

[0100] The components of the tablet of Example 2 and their weight percentages are as follows: sitafloxacin sesquihydrate, 25%; hypromellose acetate succinate, 50%; mannitol, 10%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; and magnesium stearate, 0.5%.

[0101] Sitafloxacin tablets were prepared in the same manner as in Example 1, except that in step (1), a specified amount of copovidone was replaced with a specified amount of hypromellose acetate succinate.

[0102] Example 3

[0103] The components of the tablet of Example 3 and their weight percentages are as follows: sitafloxacin sesquihydrate, 25%; povidone, 50%; mannitol, 10%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; and magnesium stearate, 0.5%.

[0104] Sitafloxacin tablets were prepared in the same manner as in Example 1, except that in step (1), a prescribed amount of copovidone was replaced with a prescribed amount of povidone.

[0105] Example 4

[0106] The components of the tablet of Example 4 and their weight percentages are as follows: sitafloxacin sesquihydrate, 25%; copovidone, 37.5%; mannitol, 16.5%; corn starch, 16%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; and magnesium stearate, 0.5%.

[0107] Sitafloxacin tablets were prepared using the same method as in Example 1, except that the drug loading of the solid dispersion obtained in step (1) was 40%.

[0108] Example 5

[0109] The components of the tablet of Example 5 and their weight percentages are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 50%; mannitol, 15%; corn starch, 10%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; and magnesium stearate, 0.5%.

[0110] Sitafloxacin tablets were prepared using the same method as in Example 1, except that the drug loading of the solid dispersion obtained in step (1) was 28.6%.

[0111] Example 6

[0112] The components of the tablet of Example 6 and their weight percentages are as follows: sitafloxacin sesquihydrate, 20%; copovidone, 60%; mannitol, 10%; corn starch, 5%; hydroxypropyl cellulose, 3%; low-substituted hydroxypropyl cellulose, 1.5%; and magnesium stearate, 0.5%.

[0113] Sitafloxacin tablets were prepared using the same method as in Example 1, except that the drug loading of the solid dispersion obtained in step (1) was 25%.

[0114] Example 7: Dissolution Test

[0115] The tablets of Examples 1 to 6 and the original formulation of Grabitol® (National Medicine Standard No. HJ20190022, Daiichi Pharmaceutical Sankyo Co., Ltd.) were subjected to dissolution tests.

[0116] The dissolution rate was determined according to the dissolution and release method (Method 2, Part 4, General Chapter 0931, Chinese Pharmacopoeia 2020 Edition).

[0117] Instruments: High performance liquid chromatography and dissolution tester.

[0118] Dissolution medium: pH = 6.8 phosphate buffer solution.

[0119] Dissolution medium volume: 900 mL.

[0120] Speed: 50 rpm.

[0121] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0122] The tablets and original preparations of Examples 1-6 were taken, and the dissolution and release rate determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2) was used. 900 mL of pH = 6.8 phosphate buffer solution was used as the dissolution medium. The paddle method was operated at 50 revolutions per minute. The solution was taken according to the sampling time and the dissolution data were shown in Table 1:

[0123] Table 1. Dissolution rate (%) of the tablets of Examples 1-6 and the original formulation

[0124] Test samples 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 preparation 22 50 67 75 82 87 95

[0125] As can be seen from the data in the table above, the tablets of Examples 1, 5, and 6 achieved a dissolution rate of over 85% in vitro within 30 minutes, which is significantly better than the original formulation (which only reached over 85% after 45 minutes). The tablets of Examples 1, 5, and 6 have a high dissolution rate and excellent dissolution effect, resulting in higher bioavailability and better absorption in vivo.

[0126] Example 8

[0127] The components of the tablet of Example 8 and their weight percentages 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%; and magnesium stearate, 0.5%.

[0128] Sitafloxacin tablets were prepared as follows:

[0129] Step (1). Mixing a specified amount of sitafloxacin, copovidone and colloidal silicon dioxide to obtain a mixture;

[0130] Step (2). The mixture obtained in step (1) was added to a hot melt extrusion device for hot melt extrusion operation, the screw speed was 120 to 200 rpm, the hot melt extrusion temperature was 130 to 200 ° C, the feed rate was 0.8 to 1.2 kg / h, and the extruded material was hammer-milled to obtain a solid dispersion;

[0131] Step (3). The solid dispersion obtained in step (2) is added to a mixing device with a specified amount of mannitol, starch, hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose and mixed for 5 to 30 minutes. Magnesium stearate is then added and mixed for another 5 to 10 minutes to obtain a mixture. The mixture is tableted using a rotary tablet press. The tablet core hardness is 30N to 100N.

[0132] Step (4). The tablets obtained in step (3) were film-coated with a film coating premix 03F480031-CN (composition: hydroxypropyl methylcellulose 2910 (viscosity 3-15 mPa‧s): titanium dioxide: polyethylene glycol 6000: talc = 48:20:8:4) to obtain sitafloxacin-coated tablets. Film coating resulted in a tablet weight increase of approximately 5%.

[0133] Example 9

[0134] The components of the tablet 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%; and magnesium stearate, 0.5%.

[0135] Sitafloxacin tablets were prepared according to the method of Example 8 using the specified amounts of the components.

[0136] Example 10

[0137] The components of the tablet 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%; and magnesium stearate, 0.5%.

[0138] Sitafloxacin tablets were prepared according to the method of Example 8 using the specified amounts of the components.

[0139] Example 11

[0140] The components of the tablet 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%; and magnesium stearate, 0.5%.

[0141] Sitafloxacin tablets were prepared according to the method of Example 8 using the specified amounts of the components.

[0142] The preparation processes of Examples 8-11 show that adding colloidal silica to the hot melt material improves the material flowability during hot melt extrusion.

[0143] Example 12: Dissolution Test

[0144] The dissolution test was performed on the tablets of Examples 8-11 and the original formulation of Grabitol® (National Medicine Standard No. HJ20190022, Daiichi Pharmaceutical Sankyo Co., Ltd.) in the same manner as in Example 7. The dissolution data are shown in Table 2:

[0145] Table 2. Dissolution rate (%) of Examples 8-11

[0146] Test samples 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 preparation 22 50 67 75 82 87 95

[0147] As can be seen from the data in the above table, Examples 8-10 still maintain good dissolution effects [dissolution can reach more than 85% in vitro within 30 minutes], but Example 11 shows poor dissolution results.

[0148] Example 13: Stability test

[0149] The tablets and original preparations of Examples 5 and 8-10 were placed at 40 ° C / RH 75% for 3 months in accordance with the requirements of the Guiding Principles for Stability Testing of Raw Materials and Preparations (Guiding Principles 9001 of the Chinese Pharmacopoeia 2020 Edition, Part IV, Stability Testing of Raw Materials and Preparations, Pharmaceutical Preparations). The accelerated test was carried out, and the dissolution and related substance test results are shown in Table 3.

[0150] Table 3. Stability test results of the tablets of Examples 5, 8-10 and the original formulation

[0151] Test samples Inspection Project Day 0 Month 1 Month 2 Month 3 Example 5 Dissolution (%) 88 87 88 88 Example 5 Related substances (%) 0.39 0.38 0.39 0.38 Example 8 Dissolution (%) 86 87 88 87 Example 8 Related substances (%) 0.35 0.36 0.35 0.35 Example 9 Dissolution (%) 87 86 87 88 Example 9 Related substances (%) 0.14 0.14 0.13 0.14 Example 10 Dissolution (%) 86 86 85 86 Example 10 Related substances (%) 0.13 0.12 0.13 0.13 Original preparation Dissolution (%) 82 80 77 76 Original preparation Related substances (%) 0.32 0.34 0.37 0.37

[0152] Conclusion: After 3 months of storage at 40°C / RH75%, the dissolution rates of the tablets of Examples 5, 8-10 remained essentially unchanged compared to day 0, demonstrating excellent stability. In contrast, the dissolution rate of the original formulation decreased by 6%. Furthermore, surprisingly, the related substance content of Examples 5 and 8 was slightly higher than that of the original formulation, while the related substance content of the tablets of Examples 9 and 10 was reduced by over 50% compared to the original formulation. Furthermore, after 3 months of storage at 40°C / RH75%, the related substances in the formulations of Examples 9 and 10 remained unchanged, while the related substance content of the original formulation increased by 15.63%.

[0153] The experimental results show that a specific amount of colloidal silicon dioxide not only improves the feeding fluidity during hot melt extrusion, but also significantly improves the chemical stability of the tablets.

[0154] 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 and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A sitafloxacin tablet, characterized in that The tablet comprises: (1) a solid dispersion comprising: (a) an active ingredient, which is sitafloxacin sesquihydrate, accounting for 15% to 30% of the total weight of the tablet; (b) a solid dispersion carrier, which is copovidone, accounting for 45% to 65% of the total weight of the tablet; and (c) a stabilizer, which is colloidal silicon dioxide, accounting for 0.1% to 2.2% of the total weight of the tablet; (2) fillers, which account 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%-3% of the total tablet weight; (5) Lubricant, accounting for 0.2%-1.0% of the total weight of the tablet, The sum of the weight percentages of the above components is ≤100%, and The solid dispersion is prepared by hot melt extrusion.

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 expanded 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 sodium stearyl 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 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; and (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 tablet weight and starch accounting for 5%-16% of the total tablet weight; (3) binder, which is hydroxypropyl cellulose, accounting for 3% of the total tablet weight; (4) disintegrant, low-substituted hydroxypropyl cellulose, accounting for 1.5% of the total tablet weight; (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. 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 the active ingredient, the solid dispersion carrier, and the stabilizer to obtain a mixture; Step (2) The mixture obtained in step (1) was added to a hot melt extrusion device, hot melt extrusion, the resulting extruded material was crushed to obtain a solid dispersion; Step (3) The solid dispersion obtained in step (2) is mixed with a specified amount of filler, disintegrant, binder, 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: screw speed is 120-400 rpm, hot melt extrusion temperature is 130-200° C., and feeding speed is 0.8-3.0 kg / h; And / or, in step (3), the hardness of the tablet obtained after tableting is 40N-90N.

15. Sitafloxacin tablets prepared by the method of claim 13 or 14.