Tilgorazan amorphous solid dispersion, tigorazan-containing tablet core, tigorazan tablet and preparation process of tigorazan amorphous solid dispersion

Abstract

The invention discloses a tigorazan amorphous solid dispersion, a tigorazan-containing tablet core, a tigorazan tablet and a preparation process of the tigorazan amorphous solid dispersion. The invention specifically discloses a tigorasan solid dispersion. The tigorasan solid dispersion comprises tigorasan and a carrier, the tigorasan is one or more of a tigorasan A crystal form, a tigorasan B crystal form and a tigorasan amorphous form; the carrier comprises copovidone and polyethylene glycol; the mass ratio of the copovidone to the polyethylene glycol is 1: (0.5-2). The invention also provides a preparation method of the tigorazan solid dispersion, a tigorazan-containing tablet core and a preparation method thereof, and a tigorazan tablet and a preparation method thereof. According to the method disclosed by the invention, wet granulation is adopted, so that the preparation process is simpler, the product quality is easier to control, the production efficiency is improved, large-scale production is facilitated, and the prepared tigoraz tablets are good in content uniformity and good in stability.

Description

[0001] This application claims priority to Chinese patent application 2025112539088, filed on September 3, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical preparations, and more specifically, to ticoraxen amorphous solid dispersions, ticoraxen-containing tablet cores, ticoraxen tablets, and their preparation processes. Background Technology

[0003] Tegoprazan, chemical name: (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide. Chemical structural formula:

[0004] This is a novel potassium-competitive acid blocker (P-CAB), the first P-CAB drug in China. Compared to traditional proton pump inhibitors (PPIs), ticoraxen has advantages such as rapid onset of action, long duration of action, stability under acidic conditions, and the ability to simultaneously inhibit both activated and resting proton pumps. Through competitive action with potassium ions, it reversibly inhibits H+ ions. + -K + -ATPase, thereby inhibiting gastric acid secretion. When P-CAB is used in combination with antibiotics, its acid-suppressing effect provides an optimal pH environment for antibiotics to eradicate Helicobacter pylori, showing broad prospects for clinical application.

[0005] There are few existing methods for preparing ticorazine tablets, and the compositions used in tablet preparation are relatively limited, without further optimization of tablet hardness and uniformity. CN120131557A uses a dry granulation process to prepare tablets, which is complex, inefficient, and unsuitable for large-scale production. CN120053384A uses fluidized bed granulation to prepare ticorazine tablets; however, this method easily affects the dissolution rate of the finished product. Summary of the Invention

[0006] The technical problem this invention aims to solve is to overcome the shortcomings of traditional ticoraxen tablet preparation methods, such as complex processes, low efficiency, limited preparation methods, unsuitability for large-scale production, susceptibility to changes in the dissolution rate of the resulting product, and limited crystal form and composition of the ticoraxen raw materials. This invention provides an amorphous solid dispersion of ticoraxen, ticoraxen-containing tablet cores, ticoraxen tablets, and their preparation process. The method of this invention uses wet granulation, which simplifies the preparation process, makes product quality easier to control, improves production efficiency, facilitates large-scale production, and produces ticoraxen tablets with good content uniformity and stability.

[0007] The present invention provides a ticoraxan solid dispersion comprising: ticoraxan and a support; the support comprising copovidone and polyethylene glycol; the mass ratio of the copovidone and polyethylene glycol is 1:(0.5-2).

[0008] In this invention, the mass ratio of the copolyvinylpyrrolidone to polyethylene glycol is preferably 1:(0.8-1.8), more preferably 1:(1-1.5).

[0009] In this invention, the mass ratio of ticoraxan to the carrier is 1:(0.4-3), preferably 1:(0.5-0.7), for example 1:0.6.

[0010] In this invention, the ticoraxan solid dispersion contains ticoraxan derived from one or more of ticoraxan A crystal form, ticoraxan B crystal form, and ticoraxan amorphous form.

[0011] In this invention, the ticoraxen A crystal form is described with reference to the method and characterization in patent application CN111187259A.

[0012] In this invention, the ticoraxen B crystal form is described using the method and characterization described in patent application CN117222643A.

[0013] In this invention, the ticoraxone A crystal form preferably has X-ray powder diffraction patterns with peaks at 2θ values ​​of 8.1±0.2°, 10.0±0.2°, 12.6±0.2°, 14.9±0.2°, 15.6±0.2°, 16.5±0.2°, 17.2±0.2°, 19.6±0.2°, 23.1±0.2°, 24.2±0.2°, 28.1±0.2°, 30.2±0.2°, and 31.6±0.2°.

[0014] In this invention, the ticoraxen A crystal form preferably exhibits an endothermic peak at a temperature of 220°C to 225°C when measured using differential scanning calorimetry.

[0015] In this invention, the ticoraxen B crystal form preferably has X-ray powder diffraction patterns with characteristic peaks at 2θ values ​​of 9.5±0.2° and 14.1±0.2°, and has one or more of the following characteristic peaks: 15.4±0.2°, 16.2±0.2°, 19.1±0.2°, 20.6±0.2°, 21.8±0.2°, 22.8±0.2°, 25.1±0.2°, 28.4±0.2°, and 32.2±0.2°.

[0016] In this invention, the ticoraxanthin B crystal form preferably has an X-ray powder diffraction pattern at 2θ values ​​of 9.5±0.2°, 14.1±0.2°, 15.4±0.2°, 16.2±0.2°, 19.1±0.2°, 20.6±0.2°, 21.8±0.2°, 22.8±0.2°, 25.1±0.2°, 28.4±0.2°, and 32.2±0.2°. It has a characteristic peak at ° and has one or more of the following characteristic peaks: 9.2±0.2°, 12.9±0.2°, 13.7±0.2°, 15.9±0.2°, 19.9±0.2°, 21.0±0.2°, 21.6±0.2°, 23.3±0.2°, 24.9±0.2°, 26.0±0.2°, 27.3±0.2° and 30.1±0.2°.

[0017] In this invention, the ticoraxen B crystal form preferably has an absorption peak at 158.5℃ ± 0.5℃ when measured using differential scanning calorimetry (DSC).

[0018] In this invention, preferably, when the ticoraxan is amorphous ticoraxan, the particle size D90 of the ticoraxan solid dispersion is preferably 20 μm-200 μm; more preferably 28 μm-181 μm; most preferably 50 μm-150 μm; more preferably 80 μm-120 μm; for example 100 μm or 101 μm.

[0019] In this invention, preferably, when the ticoraxan is in the ticoraxan A crystal form, the particle size D90 of the ticoraxan solid dispersion is preferably 20 μm-200 μm; more preferably 28 μm-181 μm; most preferably 50 μm-150 μm; more preferably 80 μm-120 μm; for example 101 μm.

[0020] In this invention, preferably, when the ticoraxan is in the ticoraxan B crystal form, the particle size D90 of the ticoraxan solid dispersion is preferably 20 μm-200 μm; more preferably 28 μm-181 μm; most preferably 50 μm-150 μm; more preferably 80 μm-120 μm; for example 100 μm.

[0021] The present invention also provides a method for preparing the ticoraxen solid dispersion, which includes the following steps: drying a solution of ticoraxen and a carrier to obtain a ticoraxen solid dispersion.

[0022] In this invention, the drying process is spray drying; the inlet air temperature for the spray drying is preferably 40-85℃.

[0023] In this invention, the solvent in the solution is preferably pharmaceutical-grade ethanol. The amount of pharmaceutical-grade ethanol used is preferably sufficient to completely dissolve ticoraxan and the carrier into a homogeneous solution. The pharmaceutical-grade ethanol is ethanol that meets the pharmaceutical standards in the Chinese Pharmacopoeia.

[0024] In this invention, the inlet air temperature for spray drying is preferably 40-85℃.

[0025] In this invention, the method for preparing the ticoraxan solid dispersion further includes: pulverizing the ticoraxan solid dispersion to a predetermined particle size.

[0026] The present invention also provides a tablet core containing ticorazine, comprising: the ticorazine solid dispersion, and fillers, disintegrants, binders, flow aids and lubricants.

[0027] In this invention, the filler is preferably selected from one or more of lactose, corn starch, microcrystalline cellulose, mannitol, and dicalcium phosphate; more preferably, it is a combination of mannitol and microcrystalline cellulose; preferably, it is a combination of mannitol and microcrystalline cellulose in a mass ratio of 1:(0.5-2); for example, a combination of mannitol and microcrystalline cellulose in a mass ratio of 1:1. The filler accounts for 40%-65% of the weight of the tablet core, more preferably 45%-55%, for example, 48%.

[0028] In this invention, the adhesive is preferably one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone; for example, hydroxypropyl cellulose. The adhesive preferably accounts for 2%-6% of the weight of the core, for example, 6%.

[0029] In this invention, the disintegrant is preferably one or more selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; for example, croscarmellose hydroxypropyl cellulose. The disintegrant preferably accounts for 2%-7% of the weight of the tablet core, for example, 7%.

[0030] In this invention, the flow aid is preferably one or both of colloidal silica and silica; for example, colloidal silica. The flow aid preferably accounts for 0.5%-2% of the weight of the wafer core, for example, 1.5%.

[0031] In this invention, the lubricant is preferably one or both of magnesium stearate and talc; for example, magnesium stearate. The lubricant preferably accounts for 0.5%-2.5% of the weight of the core, for example, 2%.

[0032] In this invention, the ticoraxan constitutes a weight percentage of 15%-30% of the tablet core, more preferably 20%-25%, for example 22%; In this invention, the core preferably comprises the following components by weight percentage: 30%-45% ticorazine solid dispersion, 40%-65% filler, 2%-6% binder, 2%-7% disintegrant, 0.5%-2% flow aid, and 0.5%-2.5% lubricant; more preferably, 32%-37% ticorazine solid dispersion, 45%-55% filler, 4%-6% binder, 5%-7% disintegrant, 1%-1.5% flow aid, and 1%-2% lubricant; for example, 35.5% ticorazine solid dispersion, 48% filler, 6% binder, 7% disintegrant, 1.5% flow aid, and 2% lubricant.

[0033] In this invention, the core preferably comprises the following components by weight percentage: 35.5% ticoraxan solid dispersion, 48% microcrystalline cellulose and mannitol, 6% hydroxypropyl cellulose, 7% croscarmellose sodium, 1.5% colloidal silica and 2% magnesium stearate.

[0034] The present invention also provides a method for preparing the ticorazine-containing tablet core, comprising: (1) Premixing: The ticorazine solid dispersion, along with the filler, disintegrant and flow aid, are premixed; (2) Wet granulation: The aqueous solution of the adhesive is sprayed into the mixture obtained in step (1) to start wet granulation and obtain wet granules; (3) Drying and granulation: The wet granules obtained in step (2) are dried and then granulated; (4) Mixing: Mix the particles obtained in step (3) with the lubricant; (5) Tableting: Compress tablets according to the set tablet weight.

[0035] In this invention, the purpose of premixing in step (1) is to fully and uniformly mix the raw materials. The premixing time is preferably 8-15 minutes, for example, 10 minutes. The premixing is preferably carried out in a wet granulation machine.

[0036] In this invention, in step (2), the aqueous solution of the adhesive is preferably a homogeneous solution, wherein the water is generally purified water, and the mass concentration of the aqueous solution of the adhesive is preferably 3-8%; for example, 5%.

[0037] In this invention, in step (2), the stirring speed during wet granulation is preferably 100-500 rpm, more preferably 150-250 rpm; for example, 200 rpm; the cutting speed during wet granulation is preferably 1000-2500 rpm; for example, 1000 rpm; the wet granulation time is preferably 1-5 min; more preferably 1-3 min; for example, 1.5 min.

[0038] In this invention, in step (3), the drying is preferably carried out in a fluidized bed. The drying temperature is preferably 50-80°C, more preferably 55-65°C, for example 60°C.

[0039] In this invention, in step (3), the granulation is preferably carried out using a sieve with a mesh size of 1000μm-1300μm, more preferably 1100μm-1200μm, for example 1143μm.

[0040] In this invention, the purpose of the total mixing in step (4) is to mix the particles obtained in step (3) with the lubricant evenly to ensure the fluidity of the particles. The total mixing time is preferably 3 min to 8 min, more preferably 5 min.

[0041] In this invention, the tablet weight of the core is preferably 150-300mg, more preferably 200-260mg, and even more preferably 220-250mg, for example 225mg.

[0042] The present invention also provides a ticorax tablet comprising the tablet core and a coating.

[0043] In this invention, preferably, the weight percentage of the coating to the core is 1%-5%, more preferably 1.5%-4%, most preferably 2%-3%, for example 2.5-3.0%.

[0044] The present invention also provides a method for preparing the ticoraxol tablets, which includes: coating the tablet core.

[0045] In this invention, the coating process conditions can be conventional process conditions in the art. For example, coating can be carried out in a coating pan.

[0046] The present invention also provides a ticorazine tablet comprising a tablet core and a coating, wherein the tablet core comprises ticorazine B crystal form or ticorazine amorphous form, a filler, a disintegrant, a binder, a flow aid, and a lubricant; the particle size D90 of the ticorazine B crystal form is 5 μm-90 μm; and the particle size D90 of the ticorazine amorphous form is 8 μm-130 μm.

[0047] In this invention, the particle size D90 of the ticoraxen B crystal form is preferably 10μm-120μm; more preferably 20μm-100μm; most preferably 35μm-80μm; more preferably 55μm-60μm; for example 59μm.

[0048] In this invention, the amorphous particle size D90 of the ticoraxan is preferably 40μm-80μm, more preferably 50μm-70μm, most preferably 55μm-60μm, for example 59μm.

[0049] In this invention, the filler is preferably selected from one or more of lactose, corn starch, microcrystalline cellulose, mannitol, and dicalcium phosphate; more preferably, it is a combination of mannitol and microcrystalline cellulose; even more preferably, it is a combination with a mannitol to microcrystalline cellulose mass ratio of 1:(0.5-2); for example, a combination with a mannitol to microcrystalline cellulose mass ratio of 1:1.4. The filler accounts for 40%-65% of the weight percentage of the tablet core, more preferably 55%-65%, for example, 60.5%.

[0050] In this invention, the adhesive is preferably one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone; for example, hydroxypropyl cellulose. The adhesive preferably accounts for 2%-6% of the weight of the core, for example, 6%.

[0051] In this invention, the disintegrant is preferably one or more selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; for example, croscarmellose hydroxypropyl cellulose. The disintegrant preferably accounts for 2%-7% of the weight of the tablet core, for example, 7%.

[0052] In this invention, the flow aid is preferably one or both of colloidal silica and silica; for example, colloidal silica. The flow aid preferably accounts for 0.5%-2% of the weight of the wafer core, for example, 1.5%.

[0053] In this invention, the lubricant is preferably one or both of magnesium stearate and talc; for example, magnesium stearate. The lubricant preferably accounts for 0.5%-2.5% of the weight of the core, for example, 2%.

[0054] In this invention, the ticoraxen B crystal form or ticoraxen amorphous form accounts for 15%-30% of the weight of the wafer core, more preferably 20%-25%, for example 23%; In this invention, the core preferably comprises the following components by weight percentage: 15%-30% ticoraxan B crystalline form or ticoraxan amorphous form, 40%-65% filler, 2%-6% binder, 2%-7% disintegrant, 0.5%-2% flow aid, and 0.5%-2.5% lubricant; more preferably 20%-25% ticoraxan B crystalline form or ticoraxan amorphous form, 57%-65% filler, 4%-6% binder, 5%-7% disintegrant, 1%-1.5% flow aid, and 1%-2% lubricant; for example, 23% ticoraxan B crystalline form or ticoraxan amorphous form, 60.5% filler, 6% binder, 7% disintegrant, 1.5% flow aid, and 2% lubricant.

[0055] In this invention, the core preferably comprises the following components by weight percentage: 23% ticoraxan B crystal form or ticoraxan amorphous form, 60.5% microcrystalline cellulose and mannitol, 6% hydroxypropyl cellulose, 7% croscarmellose sodium, 1.5% colloidal silica and 2% magnesium stearate.

[0056] In this invention, preferably, the weight of the coating is 1%-5% of the core, more preferably 1.5%-4%, most preferably 2%-3%, for example 2.5%.

[0057] The present invention also provides a method for preparing the ticoraxan tablets, comprising: coating a tablet core containing the ticoraxan B crystal form or the ticoraxan amorphous form.

[0058] In this invention, the coating process conditions can be conventional process conditions in the art. For example, coating can be carried out in a coating pan.

[0059] In this invention, the ticoraxan tablets can also be packaged using a bottling line to obtain commercially available bottled ticoraxan products. Typically, the bottled products can be boxed, cartoned, stored, and transported via logistics.

[0060] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0061] The reagents and raw materials used in this invention are all commercially available.

[0062] The positive and progressive effects of this invention are as follows: (1) The present invention specifically selected the type and amount of carrier used in tegoragen solid dispersion. The resulting solid dispersion has stable properties and the tablets are easier to form and more stable when used to prepare tegoragen tablets.

[0063] (2) The wet granulation process ensures that the products can maintain rapid dissolution and good stability during preparation and long-term storage, making them suitable for large-scale industrial production.

[0064] (3) The tegoragen tablets of the present invention have good dissolution behavior, few impurities, and long-term stability. Attached Figure Description

[0065] Figure 1 Comparison of XRD patterns of sample 0 days and accelerated XRD patterns after 6 months in Example 4.

[0066] Figure 2 Comparison of XRD patterns of sample 0 days and accelerated XRD patterns at 6 months in Example 5.

[0067] Figure 3 Comparison of XRD patterns of sample 0 days and accelerated XRD patterns after 6 months in Example 6

[0068] Figure 4 Comparison of XRD patterns of sample 7 at day 0 and accelerated XRD pattern at 6 months.

[0069] Figure 5 Comparison of XRD patterns of sample 0 days and accelerated XRD patterns after 6 months in Example 8.

[0070] Figure 6 This is a comparison of DSC detection of sample 0 days and accelerated DSC at 6 months in Example 4.

[0071] Figure 7 Comparison of DSC spectra of sample 5 at day 0 and accelerated DSC at 6 months (Example 5)

[0072] Figure 8 Comparison of DSC spectra of sample 0 days and accelerated DSC at 6 months in Example 6

[0073] Figure 9 Comparison of DSC spectra of sample 7 at day 0 and accelerated DSC at 6 months (Example 7)

[0074] Figure 10 Comparison of DSC spectra of sample 8 at day 0 and accelerated DSC at 6 months.

[0075] Figure 11 XRD patterns of tigorazine solid dispersions prepared for tigorazine B crystal form

[0076] Figure 12 XRD patterns of ticorazine solid dispersions prepared from amorphous ticorazine.

[0077] Figure 13 XRD patterns of tigorazine solid dispersions prepared for tigorazine A crystal form Detailed Implementation

[0078] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0079] The beneficial effects of the present invention will be further described through the following embodiments. These embodiments are for illustrative purposes only and do not limit the scope of the invention. Obvious changes and modifications made by those skilled in the art based on the present invention are also included within the scope of the invention. Technical contents not described in detail in this invention are all well-known technologies. Experimental methods in the following embodiments without specific conditions are performed according to conventional methods and conditions, or as selected according to the product manual.

[0080] Among them, ticoraxen (amorphous) is prepared with reference to the amorphous form of ticoraxen disclosed in patent CN116715660A.

[0081] In the following examples, the reference formulation used was commercially available tyrosine.

[0082] Example 1

[0083] It was prepared using ticoraxen B crystal form as the active ingredient, according to the following formulation and method.

[0084] Table 1. Composition of Tablet Core Formulas 1-5

[0085] Preparation method: (1) Pretreatment: Tigorgren B crystal form was crushed to obtain tigorgren B crystal form with different particle sizes; (2) Premixing: Add the prescribed amounts of mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, colloidal silica and the ticorazine B crystal form pretreated in step (1) into a wet granulator and premix for 10 min; (3) Granulation: Weigh hydroxypropyl cellulose according to the prescription ratio and add it to purified water. Stir until dissolved. After premixing, spray in 5% hydroxypropyl cellulose aqueous solution to start wet granulation. Control the stirring speed at 200 rpm, the cutter speed at 1000 rpm, and the granulation time at 90 s to obtain wet granules. (4) Drying and granulation: After granulation, the particles are transferred to a fluidized bed for drying at 60°C; the particles granulated in the fluidized bed are then granulated using a 1143μm sieve. (5) Total mixing: Add magnesium stearate and mix for 5 minutes; (6) Tableting: The tablet weight is set according to the total mixed particle content test results, and tableting is performed; (7) Coating: Coating the tablet core increases its weight by 2.5-3.0%; (8) Packaging: Bottled packaging, boxing, and warehousing are carried out using a bottling line.

[0086] Example 2

[0087] It was prepared using ticoraxan amorphous as the active ingredient, according to the following formulation and method.

[0088] Table 2 Composition of Tablet Core Formula 6-10

[0089] Preparation method: (1) Pretreatment: Tegoragen amorphous particles were crushed to obtain tegoragen amorphous particles of different sizes; (2) Premixing: Add the prescribed amounts of mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, colloidal silica crystal form and ticoraxen amorphous pretreated in step (1) into a wet granulator and premix for 10 min; (3) Granulation: Weigh out hydroxypropyl cellulose according to the prescription ratio and add it to purified water. Stir until dissolved. After premixing, spray in 5% hydroxypropyl cellulose aqueous solution to start wet granulation. Control the stirring speed at 200 rpm and the cutter speed at 1000 rpm. Granulate for 90 seconds to obtain wet granules. (4) Drying and granulation: After granulation, the particles are transferred to a fluidized bed for drying at 60°C; the particles granulated in the fluidized bed are then granulated using a 1143μm sieve. (5) Total mixing: Add magnesium stearate and mix for 5 minutes; (6) Tableting: The tablet weight is set according to the total mixed particle content test results, and the hardness is controlled during tableting; (7) Coating: Coating the tablet core increases its weight by 2.5-3.0%; (8) Packaging: Bottled packaging, boxing, and warehousing are carried out using a bottling line.

[0090] Example 3

[0091] It was prepared using ticoraxen solid dispersion as the active ingredient, according to the following formulation and method.

[0092] Table 3 Composition of Tablet Core Formula 11-15

[0093] Preparation method: (1) Preparation and pretreatment of ticoraxen solid dispersion: The ratio of ticoraxan amorphous to carrier is 1:0.6; the mass ratio of copovidone to polyethylene glycol of the carrier is 1:(0.5-2), and the solvent is pharmaceutical grade ethanol; the prescribed amount of ticoraxan and carrier are dissolved in pharmaceutical grade ethanol according to the preset ratio, stirred until completely dissolved, and the solvent is removed by spray drying. The inlet air temperature is controlled at 40-85℃ to obtain ticoraxan solid dispersion. After drying, it is mechanically pulverized to obtain ticoraxan solid dispersions of different particle sizes.

[0094] (2) Premixing: Add the prescribed amounts of mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, colloidal silica and ticorazine solid dispersion to a wet granulator and premix for 10 min; (3) Granulation: Weigh out hydroxypropyl cellulose according to the prescription ratio and add it to purified water. Stir until dissolved. After premixing, spray in 5% hydroxypropyl cellulose aqueous solution to start wet granulation. Control the stirring speed at 200 rpm and the cutter speed at 1000 rpm. Granulate for 90 seconds to obtain wet granules. (4) Drying and granulation: After granulation, the particles are transferred to a fluidized bed for drying at 60°C; the particles granulated in the fluidized bed are then granulated using a 1143μm sieve. (5) Total mixing: Add magnesium stearate and mix for 5 minutes; (6) Tableting: The tablet weight is set according to the total mixed particle content test results, and the hardness is controlled during tableting; (7) Coating: Coating the tablet core increases its weight by 2.5-3.0%; (8) Packaging: Bottled packaging, boxing, and warehousing are carried out using a bottling line.

[0095] Examples 4-5

[0096] The tablet core containing ticorazine is composed of the following raw materials and excipients, and is prepared according to the following formulation and method: Table 4. Composition of the tablet core formulation in Examples 4-5

[0097] Preparation method: (1) Pretreatment: Tegorasen B was pulverized to a particle size of 10μm≤D90≤60μm, and amorphous tegorasen was pulverized to a particle size of 20μm≤D90≤100μm; (2) Premixing: Add the prescribed amounts of mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, colloidal silica, and ticorazine B crystal or ticorazine amorphous into a wet granulator and premix for 10 min. (3) Granulation: Weigh out hydroxypropyl cellulose according to the prescription ratio and add it to purified water. Stir until dissolved. After premixing, spray in 5% hydroxypropyl cellulose aqueous solution to start wet granulation. Control the stirring speed at 200 rpm and the cutter speed at 1000 rpm. Granulate for 90 seconds to obtain wet granules. (4) Drying and granulation: After granulation, the particles are transferred to a fluidized bed for drying at 60°C; the particles granulated in the fluidized bed are then granulated using a 1143μm sieve. (5) Total mixing: Add magnesium stearate and mix for 5 minutes; (6) Tableting: The tablet weight is set according to the total mixed particle content test results, and the hardness is controlled during tableting; (7) Coating: Coating the tablet core increases its weight by 2.5-3.0%; (8) Packaging: Bottled packaging, boxing, and warehousing are carried out using a bottling line.

[0098] Examples 6-8

[0099] The tablet core containing ticorazine is composed of the following raw materials and excipients, and is prepared according to the following formulation and method: Table 5. Composition of tablet core formulations in Examples 6-8

[0100] Preparation method: (1) Preparation and pretreatment of ticoraxen solid dispersion: The prescribed amounts of tigoraxan raw materials (tigoraxan A crystal form, tigoraxan B crystal form, and tigoraxan amorphous form) and a carrier were dissolved in pharmaceutical ethanol at a predetermined ratio of 1:0.6. The solution was stirred until completely dissolved, and the solvent was removed by spray drying. The inlet air temperature was controlled at 40-85℃ to obtain a tigoraxan solid dispersion. After drying, the dispersion was mechanically pulverized to obtain a tigoraxan solid dispersion of the predetermined particle size. All solid dispersions prepared from different tigoraxan raw materials were amorphous. Their crystal forms were characterized by X-ray powder diffraction (XRD), and the results are shown in the figure. Figure 11-13 .

[0101] (2) Premixing: Add the prescribed amounts of mannitol, microcrystalline cellulose, cross-linked carboxymethyl cellulose, colloidal silica, and ticoraxan solid dispersion to a wet granulator and premix for 10 min; (3) Granulation: According to the prescription ratio, weigh 5% hydroxypropyl cellulose and add it to purified water, stir until dissolved; after premixing, spray in the hydroxypropyl cellulose aqueous solution to start wet granulation, control the stirring speed to 200 rpm and the cutter speed to 1000 rpm, granulate for 90s to obtain wet granules. (4) Drying and granulation: After granulation, the particles are transferred to a fluidized bed for drying at 60°C; the particles granulated in the fluidized bed are then granulated using a 1143μm sieve. (5) Total mixing: Add magnesium stearate and mix for 5 minutes; (6) Tableting: The tablet weight is set according to the total mixed particle content test results, and the hardness is controlled during tableting; (7) Coating: Coating the tablet core increases its weight by 2.5-3.0%; (8) Packaging: Bottled packaging, boxing, and warehousing are carried out using a bottling line.

[0102] Effect test

[0103] Example 1

[0104] The coated tablets prepared in Examples 1-3 and the reference formulation (commercially available Tasmin) were tested for dissolution behavior in a standard medium of pH 4.0 acetate buffer (dissolution conditions: slurry method at 50 rpm, medium volume 900 ml) according to the slurry method of General Chapter 0931, Part IV, 2020 edition of the Chinese Pharmacopoeia.

[0105] In this embodiment, dissolution behavior is evaluated using a similarity factor (f2), where f2 is a parameter that measures the similarity between two dissolution curves, and the calculation formula is as follows:

[0106] Where n is the number of sampling time points, R t T represents the dissolution value of the reference formulation at time t. t This represents the dissolution rate of the test batch at time t. An f2 value higher than 50 indicates that the two dissolution curves are similar, and the sample and reference formulation are equivalent.

[0107] The uniformity of the tablet content is measured using the general rule 0941 of the Chinese Pharmacopoeia, with A+2.2S as the index. A larger value indicates poor uniformity.

[0108] The dissolution behavior, content uniformity of the coated tablets, and maximum hardness test results of formulations 1-5 in Example 1 are as follows: Table 6 Test results of samples from prescription 1-5 in Example 1

[0109] In Formulations 1-5 of Example 1, samples prepared by wet granulation with a particle size D90 in the range of 10 μm-60 μm showed satisfactory dissolution, exhibiting a similarity to the reference formulation with an f2 greater than 50. When the particle size D90 < 10 μm, the wet-granulated samples dissolved faster than the reference formulation and were dissimilar in f2 to the reference formulation; when the particle size D90 > 60 μm, the wet-granulated samples dissolved slower than the reference formulation and were also dissimilar in f2 to the reference formulation. Furthermore, samples prepared by wet granulation with a particle size D90 in the range of 10 μm-60 μm showed better content uniformity and better hardness.

[0110] In summary, when the particle size D90 of tegogastric B crystal form is between 10 μm and 60 μm, the dissolution rate is suitable, and the tableting and granulation effects are ideal.

[0111] The dissolution behavior, tablet content uniformity, and maximum hardness test results of formulations 6-10 in Example 2 are as follows: Table 7 Test results of samples 6-10 of Formula 2 in Example 2

[0112] In Formulations 6-10 of Example 2, samples prepared by wet granulation with a particle size D90 in the range of 20 μm-100 μm showed satisfactory dissolution, exhibiting a similarity to the reference formulation with an f2 greater than 50. When the particle size D90 < 20 μm, the samples prepared by wet granulation dissolved faster than the reference formulation and were dissimilar to the reference formulation with an f2 value of f2. When the particle size D90 > 100 μm, the samples prepared by wet granulation dissolved slower than the reference formulation and were also dissimilar to the reference formulation with an f2 value of f2. Furthermore, samples prepared by wet granulation with a particle size D90 in the range of 20 μm-100 μm showed better content uniformity and better hardness.

[0113] In summary, when the amorphous particle size D90 of tegoxagen is in the range of 20μm-100μm, the dissolution rate is suitable and the effect is ideal.

[0114] The dissolution behavior, tablet content uniformity, and maximum hardness test results of formulations 11-15 in Example 3 are as follows: Table 8 Test results of samples 11-15 of Formula 3 in Example 3

[0115] In Formulations 11-15 of Examples 3, the samples prepared by wet granulation with a particle size D90 in the range of 50 μm-150 μm showed satisfactory dissolution. Compared with the dissolution behavior of the reference formulation, f2 was greater than 50, indicating similarity. When the particle size D90 < 50 μm, the samples prepared by wet granulation dissolved faster than the reference formulation and were not similar to the reference formulation in terms of f2. When the particle size D90 > 150 μm, the samples prepared by wet granulation dissolved slower than the reference formulation and were not similar to the reference formulation. Furthermore, the samples prepared by wet granulation with a particle size D90 in the range of 50 μm-150 μm exhibited better content uniformity and better hardness.

[0116] In summary, when the particle size D90 of tegogasonic solid dispersion is between 50 μm and 150 μm, the dissolution rate is suitable and the effect is ideal.

[0117] Example 2

[0118] Stability Study

[0119] The packaged samples prepared in Examples 4 and 5 were stored under accelerated conditions (40°C / 75%) for 6 months, and the dissolution rate, related substances and crystal form of the retained samples were measured at day 0 and 6 months of accelerated storage.

[0120] Dissolution was tested according to the second method of General Chapter 0931, Part IV, 2020 edition of the Pharmacopoeia. The coated tablets prepared in Examples 4-8 were tested for dissolution in a standard medium of pH 4.0 acetate buffer (dissolution conditions: slurry method at 50 rpm, medium volume 900 ml) according to the second method of General Chapter 0931, Part IV, 2020 edition of the Pharmacopoeia.

[0121] For related substances, the detection method shall be in accordance with the General Chapter 0512 of the 2020 edition of the Pharmacopoeia, Part IV, High Performance Liquid Chromatography.

[0122] The measurement results are shown in the table below: Table 9. Results of dissolution and determination of related substances in samples from Examples 4-5.

[0123] Table 10. Results of dissolution and determination of related substances in samples from Examples 6-8.

[0124] The crystal form was determined using X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). A comparison of the XRD and DSC spectra is shown below. Figure 1-10 .

[0125] The results of dissolution, related substances and crystal form determinations showed that the packaged samples prepared in Examples 4-8 had stable product quality.

[0126] Example 3

[0127] The uncoated and coated tablets prepared in Examples 4-8 were tested for dissolution in a standard medium of pH 4.0 acetate buffer (dissolution conditions: slurry method at 50 rpm, medium volume 900 ml) according to the slurry method of General Chapter 0931, Part IV, 2020 Pharmacopoeia.

[0128] For related substances, the detection method shall be in accordance with the General Chapter 0512 of the 2020 edition of the Pharmacopoeia, Part IV, High Performance Liquid Chromatography.

[0129] The disintegration time limit and the detection method shall be in accordance with the General Chapter 0921 of Part IV of the 2020 Pharmacopoeia.

[0130] The test results of the uncoated tablets (tablet cores) and coated tablets obtained in Examples 4-8 are as follows: Table 11 Test results of uncoated tablets (tablet cores) and coated tablets from Examples 4-5

[0131] Table 12 Test results of uncoated tablets (tablet cores) and coated tablets from Examples 6-8

[0132] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A ticoraxen solid dispersion comprising: Tigragen and its carriers; The ticoraxan is one or more of ticoraxan A crystal form, ticoraxan B crystal form, and ticoraxan amorphous form; the carrier comprises copovidone and polyethylene glycol; the mass ratio of copovidone to polyethylene glycol is 1:(0.5-2); The ticoraxan A crystal form exhibits characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 8.1±0.2°, 10.0±0.2°, 12.6±0.2°, 14.9±0.2°, 15.6±0.2°, 16.5±0.2°, 17.2±0.2°, 19.6±0.2°, 23.1±0.2°, 24.2±0.2°, 28.1±0.2°, 30.2±0.2°, and 31.6±0.2°. The ticoraxanthin B crystal form has characteristic peaks at 2θ values ​​of 9.5±0.2° and 14.1±0.2° in its X-ray powder diffraction pattern, and has one or more of the following characteristic peaks: 15.4±0.2°, 16.2±0.2°, 19.1±0.2°, 20.6±0.2°, 21.8±0.2°, 22.8±0.2°, 25.1±0.2°, 28.4±0.2°, and 32.2±0.2°.

2. The ticoraxen solid dispersion according to claim 1, characterized in that, One or more of the following conditions must be met: (1) The mass ratio of the copolyvinylpyrrolidone to polyethylene glycol is 1:(0.8-1.8); preferably 1:(1-1.5). (2) The mass ratio of ticoraxan to the carrier is 1:(0.4-3), preferably 1:(0.5-0.7); for example, 1:0.6; (3) The particle size D90 of the ticoraxen solid dispersion is 5μm-200μm.

3. The ticoraxen solid dispersion according to claim 2, characterized in that, When the ticoraxan is in the form of amorphous ticoraxan, the particle size D90 of the ticoraxan solid dispersion is 20 μm-200 μm; preferably 28 μm-181 μm; more preferably 50 μm-150 μm; and most preferably 80 μm-120 μm; for example, 100 μm or 101 μm. When the ticoraxan is in ticoraxan A crystal form, the particle size D90 of the ticoraxan solid dispersion is 20 μm-200 μm; preferably 28 μm-181 μm; more preferably 50 μm-150 μm; and most preferably 80 μm-120 μm; for example, 101 μm. When the ticoraxan is in the ticoraxan B crystal form, the particle size D90 of the ticoraxan solid dispersion is 20 μm-200 μm; preferably 28 μm-181 μm; more preferably 50 μm-150 μm; more preferably 80 μm-120 μm; for example 100 μm.

4. A method for preparing the ticoraxan solid dispersion as described in any one of claims 1-3, comprising the following steps: The solution of ticoraxan and the carrier was dried to obtain a ticoraxan solid dispersion.

5. The method for preparing ticoraxen solid dispersion according to claim 4, characterized in that, Meets one or more of the following conditions: (1) The drying is spray drying; the inlet air temperature of the spray drying is preferably 40-85℃; (2) The solvent in the solution is pharmaceutical grade ethanol; (3) The solvent completely dissolves ticorazine and the support into a homogeneous solution; (4) The method for preparing the solid dispersion further includes pulverizing the dried solid dispersion to a predetermined particle size.

6. A tablet core containing ticoraxen, comprising: The ticoraxan solid dispersion, filler, disintegrant, binder, flow aid, and lubricant as described in any one of claims 1-3.

7. The ticoraxen-containing tablet core according to claim 6, characterized in that, One or more of the following conditions must be met: (1) The filler is selected from one or more of lactose, corn starch, microcrystalline cellulose, mannitol and dicalcium phosphate; preferably a combination of mannitol and microcrystalline cellulose; more preferably a combination of mannitol and microcrystalline cellulose in a mass ratio of 1:(0.5-2); for example, a combination of mannitol and microcrystalline cellulose in a mass ratio of 1:

1. (2) The filler accounts for 40%-65% of the weight of the core, more preferably 45%-55%, for example 48%; (3) The adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone; (4) The adhesive is preferably 2%-6% of the weight of the core; (5) The disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose and croscarmellose; (6) The disintegrant preferably accounts for 2%-7% of the weight of the tablet core; (7) The flow aid is selected from colloidal silica and one or more types of silica; (8) The flow aid is preferably 0.5%-2% of the weight of the tablet core, for example, 1.5%; (9) The lubricant is selected from one or more of magnesium stearate and talc; (10) The lubricant preferably accounts for 0.5%-2.5% of the weight of the core, for example, 2%; (11) The tegorason accounts for 15%-30% of the weight of the tablet core, more preferably 20%-25%, for example 23%; (12) The core comprises the following components by weight percentage: 30%-45% ticorazine solid dispersion, 40%-65% filler, 2%-6% binder, 2%-7% disintegrant, 0.5%-2% flow aid and 0.5%-2.5% lubricant; preferably 32%-37% ticorazine solid dispersion, 45%-55% filler, 4%-6% binder, 5%-7% disintegrant, 1%-1.5% flow aid and 1%-2% lubricant; for example 35.5% ticorazine solid dispersion, 48% filler, 6% binder, 7% disintegrant, 1.5% flow aid and 2% lubricant; (13) The core comprises the following components by weight percentage: 35.5% ticoraxan solid dispersion, 48% microcrystalline cellulose and mannitol, 6% hydroxypropyl cellulose, 7% croscarmellose sodium, 1.5% colloidal silica and 2% magnesium stearate.

8. A method for preparing a tablet core containing ticoraxen as described in claim 6 or 7, comprising: (1) Premixing: The ticorazine solid dispersion, filler, disintegrant and flow aid are premixed; (2) Wet granulation: The aqueous solution of the adhesive is sprayed into the mixture obtained in step (1) to start wet granulation and obtain wet granules; (3) Drying and granulation: The wet granules obtained in step (2) are dried and then granulated; (4) Mixing: Mix the particles obtained in step (3) with the lubricant; (5) Tableting.

9. The method for preparing a tablet core containing ticoraxen according to claim 8, characterized in that, Meets one or more of the following conditions: (1) The premixing time is 8-15 min, for example 10 min; (2) The premixing is carried out in a wet granulation machine; (3) In the aqueous solution of the adhesive, the water is purified water; (4) The mass concentration of the aqueous solution of the adhesive is 3-8%; for example, 5%; (5) The stirring speed of the wet granulation is 100-500 rpm; preferably 150-250 rpm; for example, 200 rpm; (6) The cutting speed of the wet granulation process is 1000-2500 rpm; for example, 1000 rpm; (7) The wet granulation time is 1-5 min; preferably 1-3 min; for example, 1.5 min; (8) The drying is carried out in a fluidized bed; (9) The drying temperature is 50-80℃; preferably 55-65℃; for example, 60℃; (10) The granulation is carried out using a sieve; the sieve is preferably a sieve with a diameter of 1000μm-1300μm; more preferably a sieve with a diameter of 1100μm-1200μm; for example, a sieve with a diameter of 1143μm; (11) The total mixing time is 3 min-8 min; for example, 5 min; (12) The tablet weight of the core is 150-300mg, more preferably 200-260mg, and even more preferably 220-250mg, for example 225mg.

10. A ticorax tablet comprising a core and a coating as described in claim 6 or 7.

11. The ticorax tablets according to claim 10, characterized in that, The coating accounts for 1%-5% of the weight of the tablet core; preferably 1.5%-4%; more preferably 2%-3%; for example 2.5%-3.0%.

12. A method for preparing ticoraxant tablets as described in claim 10 or 11, comprising: The wafer core is coated.

13. A ticorazine tablet comprising a tablet core and a coating, wherein the tablet core comprises ticorazine B crystal form or ticorazine amorphous form, a filler, a disintegrant, a binder, a flow aid, and a lubricant; the particle size D90 of the ticorazine B crystal form is 5 μm-90 μm; and the particle size D90 of the ticorazine amorphous form is 8 μm-130 μm.

14. The ticorax tablets according to claim 13, characterized in that, Meets one or more of the following conditions: (1) The filler is selected from one or more of lactose, corn starch, microcrystalline cellulose, mannitol and dicalcium phosphate; preferably a combination of mannitol and microcrystalline cellulose; more preferably a combination of mannitol and microcrystalline cellulose in a mass ratio of 1:(0.5-2); for example, a combination of mannitol and microcrystalline cellulose in a mass ratio of 1:1.

4. (2) The filler accounts for 40%-65% of the weight of the core, more preferably 55%-65%, for example 60.5%; (3) The adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone; (4) The adhesive is preferably 2%-6% of the weight of the core; (5) The disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose and croscarmellose; (6) The disintegrant preferably accounts for 2%-7% of the weight of the tablet core; (7) The flow aid is selected from one or both of colloidal silica and silica; (8) The flow aid is preferably 0.5%-2% of the weight of the tablet core, for example, 1.5%; (9) The lubricant is selected from one or both of magnesium stearate and talc; (10) The lubricant preferably accounts for 0.5%-2.5% of the weight of the core, for example, 2%; (11) The tegorasen B crystal form or tegorasen amorphous form accounts for 15%-30% of the weight of the wafer core, more preferably 20%-25%, for example 23%; (12) The core comprises the following components by weight percentage: 15%-30% ticorghan B crystal form or ticorghan amorphous form, 40%-65% filler, 2%-6% binder, 2%-7% disintegrant, 0.5%-2% flow aid and 0.5%-2.5% lubricant; preferably 20%-25% ticorghan B crystal form or ticorghan amorphous form, 55%-65% filler, 4%-6% binder, 5%-7% disintegrant, 1%-1.5% flow aid and 1%-2% lubricant; for example 23% ticorghan B crystal form or ticorghan amorphous form, 60.5% filler, 6% binder, 7% disintegrant, 1.5% flow aid and 2% lubricant; (13) The core comprises the following components in weight percentage: 23% ticoraxan B crystal form or ticoraxan amorphous form, 60.5% microcrystalline cellulose and mannitol, 6% hydroxypropyl cellulose, 7% croscarmellose sodium, 1.5% colloidal silica and 2% magnesium stearate.

15. The ticorax tablets according to claim 13, characterized in that, Meets one or more of the following conditions: (1) The particle size D90 of the ticoraxen B crystal form is 6μm-80μm; preferably 10μm-60μm; more preferably 20μm-45μm; and most preferably 30μm-35μm; for example, 31μm; (2) The amorphous particle size D90 of the ticoraxan is 10μm-120μm; preferably 20μm-100μm; more preferably 35μm-80μm; more preferably 55μm-60μm; for example 59μm; (3) The coating accounts for 1%-5% of the weight of the core; preferably 1.5%-4%; more preferably 2%-3%; for example 2.5-3.0%.

16. A method for preparing ticoraxant tablets as described in any one of claims 13-15, comprising: The wafer core containing the ticoraxen B crystal form or ticoraxen amorphous form is coated.

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