Tablet containing lutrombopag and preparation method thereof

Abstract

The invention provides a tablet containing lutrombopag and a preparation method thereof, lutrombopag and magnesium oxide are dispersed in hydroxypropyl cellulose and lauryl sodium sulfate, high-pressure homogeneous dispersion is carried out, a uniformly dispersed lutrombopag suspension can be prepared, then the high-pressure homogeneous suspension is used as an adhesive, and the tablet containing lutrombopag and magnesium oxide is prepared. The preparation method comprises the following steps: mixing the raw materials, adding the mixture into a one-step granulator containing a diluent and a disintegrating agent in a top spray granulation manner, adding a lubricant into the prepared granules, uniformly mixing, tabletting, and coating to obtain the tablet containing the lutrombopag. The whole preparation method disclosed by the invention is simple to operate, the production efficiency is improved, the content uniformity of the product is improved, and the problem of slow dissolution of the lutrombopag is solved.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a tablet containing lutrombopag and a preparation method thereof. Background Art

[0002] Lusutrombopag is a small molecule thrombopoietin (TPO) receptor antagonist used to treat patients undergoing elective surgery for thrombocytopenia associated with chronic liver disease. The Chinese chemical name of Lusutrombopag is: (2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylprop-2-enoic acid, and its chemical structure is shown in (Ⅰ):

[0003]

[0004] Lutrombopag tablets are used for adult patients with chronic liver disease and thrombocytopenia who are planning to undergo surgery (including diagnostic procedures). Developed by Shionogi, it was launched in Japan on September 28, 2015, which was the first approval of the drug in the world.

[0005] CN103228277A discloses a solubility-improving preparation for a compound of structural formula (I), and mentions that a poorly soluble drug having an acidic group in the molecule is wet granulated by adding a base and a surfactant to form an alkaline environment near the poorly soluble drug to improve the solubility of the preparation and increase the solubility of the drug. However, it is impossible to ensure that the drug is fully mixed with the base and the surfactant, and the proportion of the raw material drug is relatively small, resulting in large dissolution differences between tablets and poor content uniformity.

[0006] Therefore, for the oral tablets of rutrombopag, how to solve the two major problems of its dissolution rate and content uniformity is a technical problem that urgently needs to be improved. Summary of the invention

[0007] The purpose of the present invention is to provide a tablet containing lutronipopar on the basis of the prior art. Lutronipopar and magnesium oxide are dispersed in hydroxypropyl cellulose and sodium lauryl sulfate, and high-pressure homogenization and dispersion are performed to obtain a uniformly dispersed lutronipopar suspension. The suspension after high-pressure homogenization is used as a binder and sprayed into a one-step granulator containing a diluent and a disintegrant by top spray granulation. A lubricant is added to the obtained granules, and after uniform mixing, tableting and coating are performed to obtain tablets containing lutronipopar. The entire preparation method is simple, improves production efficiency, improves content uniformity, and solves the problem of slow dissolution of lutronipopar.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned tablet containing lutrombopag.

[0009] The technical solution of the present invention is as follows:

[0010] The present invention provides a tablet containing lutrombopag, which comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 0.3-2.0 parts of hydroxypropyl cellulose, 1.0-4.0 parts of sodium lauryl sulfate, 1.0-4.0 parts of magnesium oxide, 30-70 parts of a diluent, 1.0-4.0 parts of a disintegrant, and 0.2-1.5 parts of a lubricant.

[0011] In the present invention, during its preparation process, lutrombopag and magnesium oxide are first dispersed in hydroxypropyl cellulose and sodium lauryl sulfate, and high-pressure homogenization is performed to obtain a uniformly dispersed suspension. The obtained suspension is used as a binder, and a mixture consisting of a diluent and a disintegrant is granulated in one step by top spray granulation. After the obtained granules are dried, they are mixed with a lubricant, and are compressed and coated to obtain tablets containing lutrombopag.

[0012] In the present invention, the diluent is one or more of microcrystalline cellulose, mannitol, lactose or sorbitol, preferably microcrystalline cellulose and mannitol; the disintegrant is one or more of carboxymethyl cellulose calcium, cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose or cross-linked povidone, preferably carboxymethyl cellulose calcium; and the lubricant is magnesium stearate.

[0013] For the present invention, rutrombopag and magnesium oxide are dispersed in hydroxypropyl cellulose and sodium lauryl sulfate, and high-pressure homogenization is performed, and the homogenization pressure is 300-900 Bar, which can be but not limited to 300 Bar, 400 Bar, 450 Bar, 500 Bar, 600 Bar, 800 Bar or 900 Bar. In order to obtain better effects, the homogenization pressure is 400-600 Bar. The homogenization times are 3-6 times, which can be but not limited to 3 times, 4 times, 5 times or 6 times. In order to obtain better effects, the homogenization times are 4-5 times.

[0014] In a preferred embodiment, the tablet containing lutrombopag provided by the present invention includes a tablet core and a coating, and the tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 0.5-1.5 parts of hydroxypropyl cellulose, 1.5-3.0 parts of sodium lauryl sulfate, 2.0-3.0 parts of magnesium oxide, 5-15 parts of microcrystalline cellulose, 30-50 parts of mannitol, 2.0-3.5 parts of carboxymethyl cellulose calcium, and 0.5-0.8 parts of magnesium stearate.

[0015] In a more preferred embodiment, the tablet containing lutrombopag provided by the present invention includes a tablet core and a coating, and the tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 0.7-1.2 parts of hydroxypropyl cellulose, 1.8-2.5 parts of sodium lauryl sulfate, 2.1-2.5 parts of magnesium oxide, 8-12 parts of microcrystalline cellulose, 35-45 parts of mannitol, 2.5-3.2 parts of carboxymethyl cellulose calcium, and 0.6-0.8 parts of magnesium stearate.

[0016] In a particularly preferred embodiment, the tablet containing lutrombopag provided by the present invention includes a tablet core and a coating, and the tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 1.0 part of hydroxypropyl cellulose, 2.0 parts of sodium lauryl sulfate, 2.2 parts of magnesium oxide, 10 parts of microcrystalline cellulose, 40 parts of mannitol, 2.7 parts of carboxymethyl cellulose calcium, and 0.7 parts of magnesium stearate.

[0017] The present invention also provides a method for preparing the above-mentioned tablet containing lutrombopag, comprising the following steps:

[0018] (1) dispersing hydroxypropyl cellulose and sodium lauryl sulfate in purified water, adding rutrombopag and magnesium oxide, and stirring to mix uniformly to obtain suspension A;

[0019] (2) subjecting the suspension A obtained in step (1) to high pressure homogenization dispersion to obtain a suspension B;

[0020] (3) adding the diluent and disintegrant into a one-step granulator, stirring and mixing them evenly, and then using the suspension B obtained in step (2) as a binder, spraying the mixture into the one-step granulator by top spray granulation to granulate and dry;

[0021] (4) The granules dried in step (3) are stirred and mixed with the lubricant to be uniformly mixed, and then tabletted and coated to obtain tablets containing lutrombopag.

[0022] In the present invention, the diluent is one or more of microcrystalline cellulose, mannitol, lactose or sorbitol, preferably microcrystalline cellulose and mannitol; the disintegrant is one or more of carboxymethyl cellulose calcium, cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose or cross-linked povidone, preferably carboxymethyl cellulose calcium; and the lubricant is magnesium stearate.

[0023] In the present invention, in step (1), hydroxypropyl cellulose and sodium lauryl sulfate are dispersed in purified water, and then rutrombopag and magnesium oxide are added and stirred and mixed uniformly to obtain suspension A. In the process of preparing the suspension, if the amount of purified water added is too small, the viscosity of the obtained suspension A is too high, resulting in too many bubbles generated during homogenization, affecting the homogenization effect; if the amount of purified water added is too large, the prepared soft material will be too finely divided and the fluidity will be poor.

[0024] Therefore, in the present invention, the weight ratio of hydroxypropyl cellulose to purified water is controlled to be 1:30-50, which can be but not limited to 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49 or 1:50. In order to obtain better results, the weight ratio of hydroxypropyl cellulose to purified water is 1:35-45, and more preferably, the weight ratio of hydroxypropyl cellulose to purified water is 1:40.

[0025] For the present invention, in step (2), during high pressure homogenization, the homogenization pressure is 300-900 Bar, which may be but not limited to 300 Bar, 400 Bar, 450 Bar, 500 Bar, 600 Bar, 800 Bar or 900 Bar. To obtain better effect, the homogenization pressure is 400-600 Bar. The homogenization times are 3-6 times, which may be but not limited to 3 times, 4 times, 5 times or 6 times. To obtain better effect, the homogenization times are 4-5 times.

[0026] For the present invention, in step (3), the granulation parameters are as follows: the fan frequency is controlled to be 20Hz-30Hz, preferably 25Hz; the inlet air temperature is 50-70°C, preferably 60°C; the spray pressure is 0.15Mpa-0.25Mpa, preferably 0.20Mpa; the peristaltic pump speed is 20rpm-60rpm, preferably 30rpm; during drying, the obtained particles are dried to a particle moisture content of ≤1.0%, the fan frequency is controlled to be 15Hz-25Hz, preferably 20Hz; the inlet air temperature is 50-70°C, preferably 60°C.

[0027] For the present invention, in step (4), during tableting, the tablet hardness is controlled to be 6.00-12.00 kp, preferably 8.00-10.00 kp; during coating, the tablet bed temperature is controlled to be 35-45°C, preferably 42°C; and the coating weight gain is controlled to be 3-5%.

[0028] Adopt the technical scheme of the present invention, the advantages are as follows:

[0029] The invention provides a tablet containing lutrombopag. Lutrombopag and magnesium oxide are dispersed in hydroxypropyl cellulose and sodium lauryl sulfate, and high-pressure homogenization and dispersion are performed to obtain a uniformly dispersed lutrombopag suspension. The suspension after high-pressure homogenization is used as a binder and sprayed into a one-step granulator containing a diluent and a disintegrant in a top spray granulation manner. A lubricant is added to the obtained granules, and the granules are uniformly mixed and then tabletted and coated to obtain a tablet containing lutrombopag. The whole preparation method is simple, the production efficiency is improved, the content uniformity is improved, and the problem of slow dissolution of lutrombopag is solved. DETAILED DESCRIPTION

[0030] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0031] Example 1

[0032] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0033] Name of raw materials weight Luqubopa 1.0 copy Hydroxypropylcellulose 1.0 copy Sodium Lauryl Sulfate 2.0 copies Magnesium oxide 2.2 servings Microcrystalline Cellulose 10.0 copies Mannitol 40.0 copies Calcium Carboxymethyl Cellulose 2.7 servings Magnesium Stearate 0.7 parts

[0034] The preparation method thereof comprises the following steps:

[0035] (1) Dispersing hydroxypropyl cellulose and sodium lauryl sulfate in 40.0 parts of purified water, adding rutrombopag and magnesium oxide, and stirring to mix well to obtain suspension A;

[0036] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 400 Bar, the homogenization times being 4 times, to obtain a suspension B;

[0037] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0038] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0039] Example 2

[0040] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0041] Name of raw materials weight Luqubopa 1.0 copy Hydroxypropylcellulose 1.0 copy Sodium Lauryl Sulfate 2.0 copies Magnesium oxide 2.2 servings Microcrystalline Cellulose 10.0 copies Mannitol 40.0 copies Calcium Carboxymethyl Cellulose 2.7 servings Magnesium Stearate 0.7 parts

[0042] The preparation method thereof comprises the following steps:

[0043] (1) dispersing hydroxypropylcellulose and sodium lauryl sulfate in 40.0 parts of purified water, adding rutrombopag and magnesium oxide to the obtained mixed solution, stirring and mixing to obtain a suspension A;

[0044] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 600 Bar, the homogenization times being 5 times, to obtain a suspension B;

[0045] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0046] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0047] Example 3

[0048] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0049]

[0050]

[0051] The preparation method thereof comprises the following steps:

[0052] (1) Dispersing hydroxypropyl cellulose and sodium lauryl sulfate in 40.0 parts of purified water, adding rutrombopag and magnesium oxide, and stirring to mix well to obtain suspension A;

[0053] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 300 Bar, the homogenization times being 6 times, to obtain a suspension B;

[0054] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0055] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0056] Example 4

[0057] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0058] Name of raw materials weight Luqubopa 1.0 copy Hydroxypropylcellulose 1.0 copy Sodium Lauryl Sulfate 2.0 copies Magnesium oxide 2.2 servings Microcrystalline Cellulose 10.0 copies Mannitol 40.0 copies Calcium Carboxymethyl Cellulose 2.7 servings Magnesium Stearate 0.7 parts

[0059] The preparation method thereof comprises the following steps:

[0060] (1) Dispersing hydroxypropyl cellulose and sodium lauryl sulfate in 40.0 parts of purified water, adding rutrombopag and magnesium oxide, and stirring to mix well to obtain suspension A;

[0061] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 900 Bar, the homogenization times being 3 times, to obtain a suspension B;

[0062] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0063] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0064] Comparative Example 1

[0065] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0066] Name of raw materials weight Luqubopa 1.0 copy Hydroxypropylcellulose 1.0 copy Sodium Lauryl Sulfate 2.0 copies Magnesium oxide 2.2 servings Microcrystalline Cellulose 10.0 copies Mannitol 40.0 copies Calcium Carboxymethyl Cellulose 2.7 servings Magnesium Stearate 0.7 parts

[0067] The preparation method thereof comprises the following steps:

[0068] (1) dispersing hydroxypropylcellulose and sodium lauryl sulfate in 40.0 parts of purified water, adding rutrombopag and magnesium oxide to the obtained mixed solution, stirring and mixing to obtain a suspension A;

[0069] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 100 Bar, the homogenization times being 4 times, to obtain a suspension B;

[0070] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0071] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0072] Comparative Example 2

[0073] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0074] Name of raw materials weight Luqubopa 1.0 copy Hydroxypropylcellulose 1.0 copy Sodium Lauryl Sulfate 2.0 copies Magnesium oxide 2.2 servings Microcrystalline Cellulose 10.0 copies Mannitol 40.0 copies Calcium Carboxymethyl Cellulose 2.7 servings Magnesium Stearate 0.7 parts

[0075] The preparation method thereof comprises the following steps:

[0076] (1) dispersing hydroxypropylcellulose and sodium lauryl sulfate in 40.0 parts of purified water, adding rutrombopag and magnesium oxide to the obtained mixed solution, stirring and mixing to obtain a suspension A;

[0077] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 1200 Bar, the homogenization times being 4 times, to obtain a suspension B;

[0078] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0079] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0080] Comparative Example 3

[0081] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0082]

[0083]

[0084] The preparation method thereof comprises the following steps:

[0085] (1) dispersing hydroxypropylcellulose and sodium lauryl sulfate in 60.0 parts of purified water, adding rutrombopag and magnesium oxide to the obtained mixed solution, stirring and mixing to obtain a suspension A;

[0086] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 400 Bar, the homogenization times being 4 times, to obtain a suspension B;

[0087] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0088] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0089] Comparative Example 4

[0090] A tablet containing lutrombopag, prepared from the following components in parts by weight:

[0091] Name of raw materials weight Luqubopa 1.0 copy Hydroxypropylcellulose 1.0 copy Sodium Lauryl Sulfate 2.0 copies Magnesium oxide 2.2 servings Microcrystalline Cellulose 10.0 copies Mannitol 40.0 copies Calcium Carboxymethyl Cellulose 2.7 servings Magnesium Stearate 0.7 parts

[0092] The preparation method thereof comprises the following steps:

[0093] (1) dispersing hydroxypropyl cellulose and sodium lauryl sulfate in 20.0 parts of purified water, adding rutrombopag and magnesium oxide to the obtained mixed solution, stirring and mixing to obtain a suspension A;

[0094] (2) subjecting the suspension A obtained in step (1) to high-pressure homogenization dispersion, the homogenization pressure being 400 Bar, the homogenization times being 4 times, to obtain a suspension B;

[0095] (3) adding microcrystalline cellulose, mannitol and carboxymethyl cellulose calcium into a one-step granulator, stirring and mixing them evenly, controlling the fan frequency to 25 Hz, and mixing time to 10 min; then using the suspension B obtained in step (2) as a binder, spraying it into the one-step granulator by top spray granulation, and granulating the granulation parameters are as follows: controlling the fan frequency to 25 Hz, the inlet air temperature to 60° C., the spray pressure to 0.20 MPa, and the peristaltic pump speed to 30 rpm; drying the obtained granules until the granule moisture content is ≤1.0%, and during drying, controlling the fan frequency to 20 Hz and the inlet air temperature to 60° C.;

[0096] (4) The dried granules in step (3) are sieved through a 40-mesh sieve, magnesium stearate is added, and the mixture is stirred and mixed evenly. The mixture is used as the total mixed material and compressed on a tablet press to obtain plain tablets, and the tablet hardness is controlled to be 8.00-10.00 kp; the obtained plain tablets are added to a coating pan for coating, and the tablet bed temperature is controlled to be 42° C. The coating weight gain is controlled to be 3-5%, thereby obtaining tablets containing rutrombopag.

[0097] Comparative Example 5

[0098] Tablets obtained by referring to the formula and preparation method in Example 20 of patent CN103228277B.

[0099] Effect comparison between the embodiment and the comparative example

[0100] The content uniformity and dissolution curve of Luqubopa in the tablets obtained in the examples of the present invention were tested to further illustrate and verify the effects of each example of the present invention. Among them, Mulpleta tablets are Luqubopa tablets marketed in Japan, and the comparison results are as follows:

[0101] Table 1 Dissolution results of each example

[0102]

[0103] Table 2 Dissolution results of each comparative example

[0104]

[0105]

[0106] The comparison results of Examples 1-4 and Comparative Examples 1-2 show that when the high-pressure homogenization pressure is low (100 Bar), the dissolution rate decreases, the dissolution endpoint decreases slightly, and the content uniformity is poor. When the high-pressure homogenization pressure is high (1200 Bar), the dissolution rate increases and the dissolution is too fast. It can be seen that in the present invention, the tablets prepared by controlling the high-pressure homogenization pressure to 300-900 Bar and the homogenization times to 3-6 times have the same final dissolution as the reference, have good dissolution effect, and the content uniformity is improved compared to Mulpleta tablets.

[0107] The comparison results of Example 1 and Comparative Examples 3-4 show that when the amount of water added is high, the particles of the prepared product are larger, the dissolution rate decreases, the dissolution endpoint is slightly lowered, and the content uniformity is poor. When the amount of water added is low, the prepared particles are fine powder, the fluidity is poor, the dissolution rate increases, the dissolution is too fast, and the content uniformity is poor.

[0108] The comparison results of Examples 1 to 4 with Comparative Example 5 show that the samples prepared without high-pressure homogenization dissolve significantly slower than Mulpleta tablets; the one-step granulation method can significantly improve the content uniformity of Luqubopa tablets compared to the wet granulation method.

[0109] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A tablet containing lutrombopag, characterized in that: The tablet comprises a tablet core and a coating, wherein the tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 0.3-2.0 parts of hydroxypropyl cellulose, 1.0-4.0 parts of sodium lauryl sulfate, 1.0-4.0 parts of magnesium oxide, 30-70 parts of a diluent, 1.0-4.0 parts of a disintegrant, and 0.2-1.5 parts of a lubricant; in the preparation process, lutrombopag and magnesium oxide are first dispersed in hydroxypropyl cellulose and sodium lauryl sulfate, and then high-pressure homogenization is performed to obtain a uniformly dispersed suspension. The obtained suspension is used as a binder and a top spray granulation method is used to perform one-step granulation on a mixture consisting of a diluent and a disintegrant. After the obtained granules are dried, they are mixed with a lubricant, and tablets containing rutrombopag are obtained by tabletting and coating. The diluent is one or more of microcrystalline cellulose, mannitol, lactose or sorbitol; the disintegrant is one or more of carboxymethylcellulose calcium, cross-linked carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose or cross-linked povidone; and the lubricant is magnesium stearate.

2. The tablet containing lutrombopag according to claim 1, characterized in that: During high-pressure homogenization and dispersion, the homogenization pressure is 300-900 Bar, preferably 400-600 Bar; the homogenization times are 3-6 times, preferably 4-5 times.

3. The tablet containing lutrombopag according to claim 2, characterized in that: The diluents are microcrystalline cellulose and mannitol; the disintegrant is carboxymethyl cellulose calcium.

4. The tablet containing lutrombopag according to claim 3, characterized in that: The tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 0.5-1.5 parts of hydroxypropyl cellulose, 1.5-3.0 parts of sodium lauryl sulfate, 2.0-3.0 parts of magnesium oxide, 5-15 parts of microcrystalline cellulose, 30-50 parts of mannitol, 2.0-3.5 parts of carboxymethyl cellulose calcium, and 0.5-0.8 parts of magnesium stearate.

5. The tablet containing lutrombopag according to claim 4, characterized in that: The tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 0.7-1.2 parts of hydroxypropyl cellulose, 1.8-2.5 parts of sodium lauryl sulfate, 2.1-2.5 parts of magnesium oxide, 8-12 parts of microcrystalline cellulose, 35-45 parts of mannitol, 2.5-3.2 parts of carboxymethyl cellulose calcium, and 0.6-0.8 parts of magnesium stearate.

6. The tablet containing lutrombopag according to claim 5, characterized in that: The tablet core is made of the following components in parts by weight: 1.0 part of lutrombopag, 1.0 part of hydroxypropyl cellulose, 2.0 parts of sodium lauryl sulfate, 2.2 parts of magnesium oxide, 10 parts of microcrystalline cellulose, 40 parts of mannitol, 2.7 parts of carboxymethyl cellulose calcium, and 0.8 parts of magnesium stearate.

7. A method for preparing a tablet containing lutrombopag, characterized in that: The method comprises the following steps: 1.0 part of rutrombopag, 1.0 part of hydroxypropyl cellulose, 2.0 parts of sodium lauryl sulfate, 2.2 parts of magnesium oxide, 10 parts of microcrystalline cellulose, 40 parts of mannitol, 2.7 parts of carboxymethyl cellulose calcium and 0.7 parts of magnesium stearate. (1) dispersing hydroxypropyl cellulose and sodium lauryl sulfate in purified water, adding rutrombopag and magnesium oxide, and stirring to mix uniformly to obtain suspension A; (2) subjecting the suspension A obtained in step (1) to high pressure homogenization dispersion to obtain a suspension B; (3) adding the diluent and disintegrant into a one-step granulator, stirring and mixing them evenly, and then using the suspension B obtained in step (2) as a binder, spraying the mixture into the one-step granulator by top spray granulation to granulate and dry; (4) The granules dried in step (3) are stirred and mixed with the lubricant to be uniformly mixed, and then compressed and coated to obtain tablets containing lutrombopag.

8. The method for preparing a tablet containing lutrombopag according to claim 7, characterized in that: In step (1), the weight ratio of hydroxypropyl cellulose to purified water is 1:30-50, preferably 1:35-45, and more preferably 1:40; in step (2), during high-pressure homogenization dispersion, the homogenization pressure is 300-900 Bar, preferably 400-600 Bar; the homogenization times are 3-6 times, preferably 4-5 times; in step (3), the diluents are microcrystalline cellulose and mannitol; and the disintegrant is carboxymethyl cellulose calcium.

9. The method for preparing a tablet containing lutrombopag according to claim 7, characterized in that: In step (3), the granulation parameters are as follows: the fan frequency is controlled to be 20 Hz-30 Hz, preferably 25 Hz; the air inlet temperature is 50-70°C, preferably 60°C; the spray pressure is 0.15 MPa-0.25 MPa, preferably 0.20 MPa; the peristaltic pump speed is 20 rpm-60 rpm, preferably 30 rpm; during drying, the obtained particles are dried to a particle moisture content of ≤1.0%, the fan frequency is controlled to be 15 Hz-25 Hz, preferably 20 Hz; the air inlet temperature is 50-70°C, preferably 60°C.

10. The method for preparing a tablet containing lutrombopag according to claim 7, characterized in that: In step (4), during tableting, the tableting hardness is controlled to be 6.00-12.00 kp, preferably 8.00-10.00 kp; during coating, the tablet bed temperature is controlled to be 35-45°C, preferably 42°C; and the coating weight gain is controlled to be 3-5%.

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