Titanium dioxide-free pharmaceutical composition

Abstract

The invention discloses a pharmaceutical composition free of titanium dioxide. The invention provides a pharmaceutical composition. The pharmaceutical composition comprises a tablet core and a coating, the tablet core comprises a compound as shown in a formula (I); the coating comprises an adhesive, a plasticizer and silicon dioxide; the pharmaceutical composition does not include titanium dioxide. The coating provided by the invention has a good protection effect, and a coating preparation prepared from the coating can keep relatively good illumination stability and accelerated experiment stability. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition free of titanium dioxide. Background Art

[0002] Compound (I) [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate (shown in Formula (I) below) is a gabapentin-like drug developed by Daiichi Sankyo Co., Ltd. of Japan. It is primarily used to treat diabetic and postherpetic neuralgia. This drug binds to and modulates the α2σ-1 subunit of the voltage-gated calcium channel. Compared with gabapentin and pregabalin, it has a faster time to peak blood concentration, better bioavailability, and fewer central nervous system-specific adverse drug reactions.

[0003]

[0004] The compound (I) tablets of the original preparation (CN107427483A) are film-coated tablets containing a sunscreen.

[0005] The sunscreen, rutile titanium dioxide, can effectively control the growth of impurities during high-light irradiation experiments. However, the sunscreen used, titanium dioxide, has been evaluated by the European Food Safety Authority and is currently banned for use in food in the EU. Furthermore, its use in pharmaceuticals is still under review, indicating that titanium dioxide poses a hazard and is not suitable for long-term use in pharmaceuticals. Directly removing the titanium dioxide sunscreen from the coating risks exceeding the limit for impurities in the formulation during stability studies. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the problem of titanium dioxide being present in existing solid coating preparations of Compound (I), thereby providing a pharmaceutical composition that does not contain titanium dioxide. The coating of the pharmaceutical composition of the present invention does not contain titanium dioxide. The coating of the present invention has a good protective effect, and the coated preparation produced therefrom can maintain good light stability and accelerated stability.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a pharmaceutical composition comprising a tablet core and a coating;

[0009] The tablet core comprises a compound as shown in formula (I);

[0010] The coating includes a binder, a plasticizer, and silicon dioxide;

[0011] The pharmaceutical composition does not include titanium dioxide;

[0012]

[0013] In a certain embodiment, the weight gain of the silicon dioxide is 0.01-5%, preferably 0.05-5%, more preferably 0.05-2.1%, such as 0.08%, 0.14%, 1.89% or 2.03% compared to the weight of the core.

[0014] In a certain embodiment, the binder is a conventional binder in the art, preferably hypromellose, polyvinyl alcohol or copovidone. The hypromellose is preferably hypromellose E5 or hypromellose E3.

[0015] In a certain embodiment, the weight gain of the binder compared to the weight of the core is 0.5-5%, preferably 0.5-2%, more preferably 0.7-1.4%, such as 0.79%, 0.95%, 1.02% or 1.32%.

[0016] In one embodiment, the plasticizer is a conventional plasticizer in the art, preferably polyethylene glycol, preferably polyethylene glycol 3350, polyethylene glycol 6000 or polyethylene glycol 4000.

[0017] In a certain embodiment, the weight gain of the plasticizer compared to the weight of the core is 0.5-10%, preferably 1-5%, more preferably 1-3%, such as 1.55%, 1.69% or 2.58%.

[0018] In one embodiment, the compound represented by formula (I) accounts for 3-15% by weight of the tablet core, preferably 6-12%, more preferably 8.5-9.5%, for example 8.96%.

[0019] In a certain embodiment, the tablet core further comprises one or more of a filler, a disintegrant and a lubricant.

[0020] In one embodiment, the filler is a conventional filler in the art, preferably directly compressible mannitol and / or microcrystalline cellulose. The directly compressible mannitol may be directly compressible mannitol M100.

[0021] In a certain embodiment, the filler accounts for 75-90% by weight of the core tablet, preferably 80-90%, for example 85.51%.

[0022] In a certain embodiment, the directly compressible mannitol accounts for 30-80% by weight of the tablet core, preferably 40-70% by weight, such as 42.75% or 68.53%.

[0023] In a certain embodiment, the microcrystalline cellulose accounts for 10-50% by weight of the core tablet, preferably 15-45% by weight, such as 42.75% or 16.98%.

[0024] In a certain embodiment, the disintegrant is a conventional disintegrant in the art, preferably selected from one or more of pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose, such as pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

[0025] In a certain embodiment, the disintegrant accounts for 2-10% by weight of the tablet core, preferably 3-6% by weight, more preferably 4.5-5% by weight, such as 4.75%.

[0026] In a certain embodiment, the lubricant is a conventional lubricant in the art, preferably selected from one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl monostearate, poloxamer, sodium benzoate, sodium lauryl sulfate and talc, such as magnesium stearate.

[0027] In a certain embodiment, the lubricant accounts for 0.1-5% by weight of the tablet core, preferably 0.6-1%, more preferably 0.7-0.95%, for example 0.79%.

[0028] In a preferred embodiment, the pharmaceutical composition comprises a core tablet and a coating;

[0029] The core tablets contain the following components by weight:

[0030] The compound represented by formula (I), the filler, the disintegrant and the lubricant;

[0031] The compound represented by formula (I) accounts for 3-15% by weight of the tablet core;

[0032] The filler accounts for 75-90% of the core tablet by weight;

[0033] The disintegrant is 2-10% by weight of the tablet core;

[0034] The lubricant is 0.1-5% by weight of the tablet core;

[0035] The coating comprises the following components by weight:

[0036] The binder, the plasticizer, and the silica;

[0037] Compared with the weight of the core tablet, the weight gain of the binder is 0.5-5%, the weight gain of the plasticizer is 0.5-10%, and the weight gain of the silicon dioxide is 0.01-5%;

[0038] Preferably, the pharmaceutical composition consists of the above components.

[0039] In a preferred embodiment, the pharmaceutical composition comprises a core tablet and a coating;

[0040] The core tablets contain the following components by weight:

[0041] The compound represented by formula (I), the filler, the disintegrant and the lubricant;

[0042] The compound represented by formula (I) accounts for 8.96% of the tablet core by weight;

[0043] The filler accounts for 85.51% of the core tablet by weight;

[0044] The disintegrant is 4.75% by weight of the tablet core;

[0045] The lubricant is 0.79% by weight of the core;

[0046] The coating comprises the following components by weight:

[0047] The binder, the plasticizer, and the silica;

[0048] Compared with the weight of the core, the weight gain of the binder is 0.79%, 0.95%, 1.02% or 1.32%, the weight gain of the plasticizer is 1.55%, 1.69% or 2.58%, and the weight gain of the silicon dioxide is 0.08%, 0.14%, 1.89% or 2.03%;

[0049] Preferably, the pharmaceutical composition consists of the above components.

[0050] In a preferred embodiment, the pharmaceutical composition comprises a core tablet and a coating;

[0051] The core tablets contain the following components by weight:

[0052] The compound represented by formula (I), the filler, the disintegrant and the lubricant;

[0053] The compound represented by formula (I) accounts for 3-15% by weight of the tablet core;

[0054] The filler accounts for 75-90% of the core tablet by weight;

[0055] The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100;

[0056] The disintegrant is 2-10% by weight of the tablet core;

[0057] The disintegrant is pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose;

[0058] The lubricant is 0.1-5% by weight of the tablet core;

[0059] The lubricant is magnesium stearate;

[0060] The coating comprises the following components by weight:

[0061] The binder, the plasticizer, and the silica;

[0062] Compared with the weight of the core tablet, the weight gain of the binder is 0.5-5%, the weight gain of the plasticizer is 0.5-10%, and the weight gain of the silicon dioxide is 0.01-5%;

[0063] The binder is hypromellose, polyvinyl alcohol or copovidone; the hypromellose is preferably hypromellose E5 or hypromellose E3;

[0064] The plasticizer is polyethylene glycol; the polyethylene glycol is preferably polyethylene glycol 3350, polyethylene glycol 6000 or polyethylene glycol 4000;

[0065] Preferably, the pharmaceutical composition consists of the above components.

[0066] In a preferred embodiment, the pharmaceutical composition comprises a core tablet and a coating;

[0067] The core tablets contain the following components by weight:

[0068] The compound represented by formula (I), the filler, the disintegrant and the lubricant;

[0069] The compound represented by formula (I) accounts for 8.96% of the tablet core by weight;

[0070] The filler accounts for 85.51% of the core tablet by weight;

[0071] The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100;

[0072] The disintegrant is 4.75% by weight of the tablet core;

[0073] The disintegrant is pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose;

[0074] The lubricant is 0.79% by weight of the core;

[0075] The lubricant is magnesium stearate;

[0076] The coating comprises the following components by weight:

[0077] The binder, the plasticizer, and the silica;

[0078] Compared with the weight of the core, the weight gain of the binder is 0.79%, 0.95%, 1.02% or 1.32%, the weight gain of the plasticizer is 1.55%, 1.69% or 2.58%, and the weight gain of the silicon dioxide is 0.08%, 0.14%, 1.89% or 2.03%;

[0079] The binder is hypromellose, polyvinyl alcohol or copovidone; the hypromellose is preferably hypromellose E5 or hypromellose E3;

[0080] The plasticizer is polyethylene glycol; the polyethylene glycol is preferably polyethylene glycol 3350, polyethylene glycol 6000 or polyethylene glycol 4000;

[0081] Preferably, the pharmaceutical composition consists of the above components.

[0082] In a specific embodiment, the pharmaceutical composition comprises any combination of the following components by weight:

[0083] Combination 1:

[0084] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0085] Coating: Hydroxypropyl methylcellulose E5 (0.79% weight gain), polyethylene glycol 3350 (1.55% weight gain), and silicon dioxide (0.08% weight gain) compared to the core weight.

[0086] Combination 2:

[0087] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0088] Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet.

[0089] Combination 3:

[0090] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0091] Coating: Hydroxypropyl methylcellulose E5 (1.32% weight gain), polyethylene glycol 3350 (2.58% weight gain), and silicon dioxide (0.14% weight gain) compared to the core weight.

[0092] Combination 4:

[0093] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0094] Coating: Hydroxypropyl methylcellulose E5 (1.32% weight gain), polyethylene glycol 3350 (2.58% weight gain), and silicon dioxide (0.14% weight gain) compared to the core weight.

[0095] Combination 5:

[0096] Tablet core: 8.96% of the compound of formula (I), 42.75% of directly compressible mannitol M100, 42.75% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0097] Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet.

[0098] Combination 6:

[0099] Tablet core: 8.96% of the compound represented by formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of low-substituted hydroxypropyl cellulose and 0.79% of magnesium stearate;

[0100] Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet.

[0101] Combination 7:

[0102] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of crospovidone and 0.79% of magnesium stearate;

[0103] Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet.

[0104] Combination 8:

[0105] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of croscarmellose sodium and 0.79% of magnesium stearate;

[0106] Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet.

[0107] Combination 9:

[0108] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0109] Coating: Hydroxypropyl methylcellulose E3 (1.02% weight gain), polyethylene glycol 4000 (1.69% weight gain), silicon dioxide (2.03% weight gain) compared to the core weight.

[0110] Combination 10:

[0111] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0112] Coating: Hydroxypropyl methylcellulose E5 (1.02% weight gain), polyethylene glycol 6000 (1.69% weight gain), silicon dioxide (2.03% weight gain) compared to the core weight.

[0113] Combination 11:

[0114] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0115] Coating: Polyvinyl alcohol (1.02% weight gain), polyethylene glycol 4000 (1.69% weight gain), silicon dioxide (2.03% weight gain) compared to core weight.

[0116] Combination 12:

[0117] Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate;

[0118] Coating: Copovidone 1.02% by weight, polyethylene glycol 4000 1.69% by weight, silicon dioxide 2.03% by weight, compared to the core weight.

[0119] Preferably, the pharmaceutical composition consists of the above components.

[0120] The present invention also provides a method for preparing the pharmaceutical composition as described above, comprising the following steps: directly tableting the components of the pharmaceutical composition.

[0121] In one embodiment, the preparation method of the pharmaceutical composition comprises the following steps: screening, mixing, and tableting a compound represented by formula (I), a filler, a disintegrant, and a lubricant to obtain a tablet core, and mixing the tablet core with a coating solution to obtain the pharmaceutical composition; the coating solution is a mixture of a binder, a plasticizer, silicon dioxide, and a solvent;

[0122] The compound represented by formula (I), the filler, the disintegrant, the lubricant, the binder, the plasticizer and the silicon dioxide are as described above.

[0123] In a certain embodiment, the screening is through a 40-mesh sieve.

[0124] In a certain embodiment, the solvent is a conventional solvent in the art, such as water.

[0125] The present invention also provides a use of the pharmaceutical composition described above in the preparation of a medicament for treating pain. The pain may be diabetic pain or postherpetic neuralgia. The pain may be chronic pain, central neuropathic pain, or peripheral neuropathic pain. The central neuropathic pain may be central neuropathic pain after spinal cord injury (SCI).

[0126] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0127] The reagents and raw materials used in the present invention are commercially available.

[0128] The present invention provides a titanium dioxide-free pharmaceutical composition. The coating of the pharmaceutical composition does not contain titanium dioxide, providing excellent protective properties. The resulting coated formulation maintains good light stability and accelerated stability. DETAILED DESCRIPTION

[0129] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0130] The original product was purchased from Daiichi Sankyo Co., Ltd.

[0131] Original tablets are obtained by peeling off the coating film of the original product and sealing it with a composite film.

[0132] Example 1

[0133] Study on the formulation composition of titanium dioxide-free and titanium dioxide-containing coated tablets and the stability of the preparations prepared therefrom

[0134] 1.1 Prescription composition of coated tablets without titanium dioxide and coated tablets containing titanium dioxide

[0135] Table 1 Prescription composition of coated tablets without titanium dioxide and coated tablets containing titanium dioxide

[0136]

[0137] Note: Opadry* is a coating powder containing titanium dioxide (its formula composition is: polyvinyl alcohol 37%, talc 31%, titanium dioxide 25%, caprylic and capric mono- and diglycerides 4%, sodium lauryl sulfate 3%).

[0138] 1.2 Accelerated stability and light stability studies

[0139] The coated tablets with different weight gains were studied and the growth of related substances was compared. It can be seen that the growth of related substances under accelerated conditions for 2 weeks is better than that of the original product and the comparative example at different weight gains; the growth of related substances under the condition of 1.2 million lux is equivalent. The results are shown in Table 2.

[0140] Table 2 Test results of relevant substances

[0141]

[0142] The results showed that Comparative Example 1-1, in which talc was substituted for silicon dioxide, had almost no light-shielding effect. Comparative Example 1-3, in which titanium dioxide was added to the coating of the present application, showed no improvement compared to Examples 1-1 to 1-3. Comparative Example 1-2, in which only Opadry was coated, had significantly more related substances than the original product at day 0.

[0143] Example 2

[0144] Study on the formulation composition of titanium dioxide-free and titanium dioxide-containing coated tablets and the stability of the preparations prepared therefrom

[0145] 2.1 Prescription Composition of Coated Tablets Containing Titanium Dioxide and Coated Tablets Without Titanium Dioxide

[0146] Table 3 Prescription composition of coated tablets without titanium dioxide and coated tablets containing titanium dioxide

[0147]

[0148] Note: Opadry* is a coating powder containing titanium dioxide (composition: HPMC E5: PEG3350: titanium dioxide: talc 50:20:15:15).

[0149] Preparation method:

[0150] (1) Compound (I), directly compressible mannitol M100, microcrystalline cellulose, magnesium stearate, and disintegrants (pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose) were weighed in the mixing ratio shown in Table 3, passed through a 40-mesh sieve, and mixed in a hopper mixer.

[0151] (2) Tablet pressing.

[0152] (3) Weigh one or more of Hydroxypropyl Methylcellulose E5, Polyethylene Glycol 3350, and Silicon Dioxide in the mixing ratio shown in Table 3, add them to water in sequence, and stir the solution while adding; and disperse them using a homogenizer to prepare a coating solution.

[0153] (4) Coating.

[0154] 2.2 Accelerated stability and light stability studies

[0155] Evaluation methods and results:

[0156] Accelerated stability test: The original product, original tablets, comparative example 2-1, comparative example 2-2, and tablets of examples 2-1 to 2-5 were sealed with a composite film and placed under accelerated conditions of 40°C and 75% RH for 30 days. The amount of related substances was measured by HPLC (HPLC conditions are shown in Table 4 below).

[0157] Light stability test: The original product, original tablets, comparative example 2-1, comparative example 2-2, and tablets of examples 2-1 to 2-5 were placed in a strong light stability test box with a light intensity of 4500±500 lux*h and a total luminosity of 1.2 million lux. The amount of related substances was measured by HPLC (HPLC conditions are shown in Table 4 below).

[0158] Table 4 HPLC conditions for detection of related substances

[0159]

[0160] The results are shown in Table 5 below, which shows that in Examples 2-1 to 2-5, the increase in the initial total amount of related substances was significantly reduced compared with the original product; compared with the original product, Comparative Example 2-1, and Comparative Example 2-2, the increase in the related substances under accelerated conditions (40°C 75% RH) for 2 weeks was less; compared with the original product, the results were comparable.

[0161] Table 5 Test results of relevant substances

[0162]

[0163]

[0164] Example 3

[0165] The formulation composition of the titanium dioxide-free coated tablets and the stability of the preparations prepared therefrom were studied. The formulation composition of the core tablets was the same as that of Example 2-1, and the effects of different coating film formulation compositions were compared.

[0166] 3.1 Prescription composition of titanium dioxide-free coated tablets

[0167] Table 6 Prescription composition of coating film without titanium dioxide

[0168]

[0169] 3.2 Accelerated stability and light stability studies

[0170] Table 6 shows the comparison of the growth of related substances in the coated tablets with different weight gains. It can be seen that the growth of related substances under accelerated conditions for 2 weeks is comparable to that of the original product and the comparative example at different weight gains. Under the illumination condition of 1.2 million lux, the growth of related substances in the coating film formulation containing silicon dioxide is lower than that in the comparative example without silicon dioxide. The results are shown in Table 7 below.

[0171] Table 7 Test results of relevant substances

[0172]

Claims

1. A pharmaceutical composition, characterized in that It includes a core tablet and a coating; The tablet core comprises a compound as shown in formula (I); The coating comprises a binder, a plasticizer, and silicon dioxide; The pharmaceutical composition does not include titanium dioxide; 2. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) The weight gain of the silicon dioxide compared to the weight of the core is 0.01-5%, preferably 0.05-5%, more preferably 0.05-2.1%, such as 0.08%, 0.14%, 1.89% or 2.03%; (2) The binder is hypromellose, polyvinyl alcohol or copovidone; the hypromellose is preferably hypromellose E5 or hypromellose E3; (3) the weight gain of the binder compared to the weight of the core is 0.5-5%, preferably 0.5-2%, more preferably 0.7-1.4%, for example 0.79%, 0.95%, 1.02% or 1.32%; (4) The plasticizer is polyethylene glycol; the polyethylene glycol is preferably polyethylene glycol 3350, polyethylene glycol 6000 or polyethylene glycol 4000; (5) The weight gain of the plasticizer compared to the weight of the tablet core is 0.5-10%, preferably 1-5%, more preferably 1-3%, for example 1.55%, 1.69% or 2.58%; The compound of formula (I) as described in (6) is 3-15% by weight of the core tablet, preferably 6-12%, more preferably 8.5-9.5%, for example 8.96% and (7) the tablet core further comprises one or more of a filler, a disintegrant, and a lubricant.

3. The pharmaceutical composition according to claim 2, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol may be directly compressible mannitol M100; (2) the filler accounts for 75-90% by weight of the core tablet, preferably 80-90%, for example 85.51%; (3) the disintegrant is one or more of pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose, such as pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, or cross-linked sodium carboxymethyl cellulose; (4) the disintegrant is 2-10% by weight of the tablet core, preferably 3-6%, more preferably 4.5-5%, for example 4.75%; (5) The lubricant is one or more selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl monostearate, poloxamer, sodium benzoate, sodium lauryl sulfate and talc, such as magnesium stearate; and (6) the lubricant is present in an amount of 0.1-5%, preferably 0.6-1%, more preferably 0.7-0.95%, for example 0.79%, by weight of the tablet core.

4. The pharmaceutical composition according to claim 3, wherein The directly compressible mannitol accounts for 30-80% by weight of the tablet core, preferably 40-70%, for example 42.75% or 68.53%; And / or, the microcrystalline cellulose accounts for 10-50% by weight of the tablet core, preferably 15-45% by weight, such as 42.75% or 16.98%.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein The core tablets contain the following components by weight: The compound represented by formula (I), the filler, the disintegrant and the lubricant; The compound represented by formula (I) accounts for 3-15% by weight of the tablet core; The filler accounts for 75-90% of the core tablet by weight; The disintegrant is 2-10% by weight of the tablet core; The lubricant is 0.1-5% by weight of the tablet core; The coating comprises the following components by weight: The binder, the plasticizer, and the silica; Compared with the weight of the core tablet, the weight gain of the binder is 0.5-5%, the weight gain of the plasticizer is 0.5-10%, and the weight gain of the silicon dioxide is 0.01-5%; Preferably, the pharmaceutical composition comprises a core tablet and a coating; The core tablets contain the following components by weight: The compound represented by formula (I), the filler, the disintegrant and the lubricant; The compound represented by formula (I) accounts for 8.96% of the tablet core by weight; The filler accounts for 85.51% of the core tablet by weight; The disintegrant is 4.75% by weight of the tablet core; The lubricant is 0.79% by weight of the core; The coating comprises the following components by weight: The binder, the plasticizer, and the silica; Compared to the weight of the core, the weight gain of the binder is 0.79%, 0.95%, 1.02% or 1.32%, the weight gain of the plasticizer is 1.55%, 1.69% or 2.58%, and the weight gain of the silica is 0.08%, 0.14%, 1.89% or 2.03%.

6. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises a tablet core and a coating; The core tablets contain the following components by weight: The compound represented by formula (I), the filler, the disintegrant and the lubricant; The compound represented by formula (I) accounts for 3-15% by weight of the tablet core; The filler accounts for 75-90% of the core tablet by weight; The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100; The disintegrant is 2-10% by weight of the tablet core; The disintegrant is pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose; The lubricant is 0.1-5% by weight of the tablet core; The lubricant is magnesium stearate; The coating comprises the following components by weight: The binder, the plasticizer, and the silica; Compared with the weight of the core tablet, the weight gain of the binder is 0.5-5%, the weight gain of the plasticizer is 0.5-10%, and the weight gain of the silicon dioxide is 0.01-5%; The binder is hypromellose, polyvinyl alcohol or copovidone; the hypromellose is preferably hypromellose E5 or hypromellose E3; The plasticizer is polyethylene glycol; the polyethylene glycol is preferably polyethylene glycol 3350, polyethylene glycol 6000 or polyethylene glycol 4000; Preferably, the pharmaceutical composition comprises a core tablet and a coating; The core tablets contain the following components by weight: The compound represented by formula (I), the filler, the disintegrant and the lubricant; The compound represented by formula (I) accounts for 8.96% of the tablet core by weight; The filler accounts for 85.51% of the core tablet by weight; The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100; The disintegrant is 4.75% by weight of the tablet core; The disintegrant is pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose; The lubricant is 0.79% by weight of the core; The lubricant is magnesium stearate; The coating comprises the following components by weight: The binder, the plasticizer, and the silica; Compared with the weight of the core, the weight gain of the binder is 0.79%, 0.95%, 1.02% or 1.32%, the weight gain of the plasticizer is 1.55%, 1.69% or 2.58%, and the weight gain of the silicon dioxide is 0.08%, 0.14%, 1.89% or 2.03%; The binder is hypromellose, polyvinyl alcohol or copovidone; the hypromellose is preferably hypromellose E5 or hypromellose E3; The plasticizer is polyethylene glycol; the polyethylene glycol is preferably polyethylene glycol 3350, polyethylene glycol 6000 or polyethylene glycol 4000; More preferably, the pharmaceutical composition comprises any combination of the following components by weight: Combination 1: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 (0.79% weight gain), polyethylene glycol 3350 (1.55% weight gain), and silicon dioxide (0.08% weight gain) compared to the core weight. Combination 2: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet. Combination 3: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 (1.32% weight gain), polyethylene glycol 3350 (2.58% weight gain), and silicon dioxide (0.14% weight gain) compared to the core weight. Combination 4: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 (1.32% weight gain), polyethylene glycol 3350 (2.58% weight gain), and silicon dioxide (0.14% weight gain) compared to the core weight. Combination 5: Tablet core: 8.96% of the compound of formula (I), 42.75% of directly compressible mannitol M100, 42.75% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet. Combination 6: Tablet core: 8.96% of the compound represented by formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of low-substituted hydroxypropyl cellulose and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet. Combination 7: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of crospovidone and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet. Combination 8: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of croscarmellose sodium and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 with a weight gain of 0.95%, polyethylene glycol 3350 with a weight gain of 2.58%, and silicon dioxide with a weight gain of 1.89% compared to the weight of the core tablet. Combination 9: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E3 (1.02% weight gain), polyethylene glycol 4000 (1.69% weight gain), silicon dioxide (2.03% weight gain) compared to the core weight. Combination 10: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Hydroxypropyl methylcellulose E5 (1.02% weight gain), polyethylene glycol 6000 (1.69% weight gain), silicon dioxide (2.03% weight gain) compared to the core weight. Combination 11: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Polyvinyl alcohol (1.02% weight gain), polyethylene glycol 4000 (1.69% weight gain), silicon dioxide (2.03% weight gain) compared to the core weight. Combination 12: Tablet core: 8.96% of the compound of formula (I), 68.53% of directly compressible mannitol M100, 16.98% of microcrystalline cellulose, 4.75% of pregelatinized starch and 0.79% of magnesium stearate; Coating: Copovidone 1.02% by weight, polyethylene glycol 4000 1.69% by weight, silicon dioxide 2.03% by weight compared to the core weight.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: direct tableting of the powders of the components of the pharmaceutical composition and coating.

8. The method for preparing the pharmaceutical composition according to claim 7, wherein: The preparation method of the pharmaceutical composition comprises the following steps: screening, mixing, and tableting the compound represented by formula (I) according to any one of claims 1 to 6, a filler, a disintegrant, and a lubricant to obtain tablet cores; and mixing the tablet cores with a coating solution to obtain the pharmaceutical composition; the coating solution is a mixture of a binder, a plasticizer, silicon dioxide, and a solvent; Preferably, the sieving is through a 40-mesh sieve; and / or the solvent is water.

9. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for treating pain.

10. The use according to claim 9, characterized in that The pain is diabetic pain or post-herpetic neuralgia; And / or, the pain is chronic pain, which may be central neuropathic pain or peripheral neuropathic pain; the central neuropathic pain may be central neuropathic pain after spinal cord injury (SCI).

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