A darunavir and cobicistat compound tablet and a method of preparing the same

Abstract

The application provides a complex tablet of darunavir and cobicistat and a preparation method thereof, and the preparation method is as follows: darunavir ethanolate, part of a first disintegrant and a first lubricant are put into a dry granulator, granulation and whole granulation are carried out to obtain dry granules; hydroxypropyl methyl cellulose and proper water are mixed to form a binder solution, the dry granules and the rest of the first disintegrant are mixed, the binder solution is sprayed, and wet granulation is carried out, drying and whole granulation are carried out to obtain wet granules; the wet granules, silica loaded with cobicistat, a second disintegrant and a filler are mixed until uniform, then sieved, and a second lubricant is added and mixed again; tabletting is carried out, and then film coating is carried out. The application combines darunavir and cobicistat to prepare a medicine, reduces drug resistance caused by single drug use, and provides more choices for AIDS patients. In addition, the complex tablet can improve the content of darunavir.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular to a compound tablet of darunavir and cobicistat and a preparation method thereof. BACKGROUND

[0002] Darunavir is [(1R, 5S, 6R)-2, 8-dioxabicyclo[3.3.0-decane-6-yl-N-[(2S, 3R)-4-[(4- aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenyl-butane-2-yl] carbamate. Darunavir is a protease inhibitor developed by Tibotec, a subsidiary of Johnson & Johnson, and is a second-generation protease inhibitor for the treatment of human immunodeficiency virus (HIV) infection, which selectively inhibits the cleavage of Gag-Pol polyprotein encoded by HIV in infected cells, thereby preventing the formation of mature infectious virus particles. It has been marketed in the United States, the European Union and other countries and regions, and the trade name is Prezista.

[0003] Cobicistat is 1, 3-thiazol-5-ylmethyl [(2R, 5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1, 3- thiazol-4-yl]methyl}aminoformyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1, 6- diphenylhexan-2-yl] carbamate. Cobicistat is a new CYP3A inhibitor developed by Gilead Sciences, and was approved by the US Food and Drug Administration on September 24, 2014. It is the only approved cocktail therapy AIDS drug enhancer. At present, in addition to single agent, it is also used in combination with other anti-reverse transcriptase drugs for HIV infection.

[0004] The combination of darunavir and cobicistat can provide more choices for the treatment of HIV infection in AIDS patients. However, the amount of darunavir added in the preparation of compound tablets of the two drugs in the prior art is limited, and the content of the compound tablets is not uniform, which will affect the drug efficacy. SUMMARY

[0005] Therefore, the present application aims to provide a compound tablet of darunavir and cobicistat and a preparation method thereof, so as to solve the problems of limited content of darunavir in the preparation of compound tablets of darunavir and cobicistat, and the problems of poor content uniformity and stability of the drugs produced in different batches, thereby providing more drug choices for AIDS patients.

[0006] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0007] In one aspect, the present application provides a complex tablet of darunavir and cobicistat, which comprises the following components by weight: darunavir ethanolate 985-1003 parts, silica loaded with cobicistat 145-160 parts (calculated by the amount of cobicistat), first disintegrant 25-30 parts, second disintegrant 35-40 parts, first lubricant 3-6 parts, second lubricant 1-2 parts, hypromellose 20-30 parts, filler 130-150 parts. The method for loading cobicistat into silica is described in CN102307573B.

[0008] Further, the first disintegrant and the second disintegrant are at least one selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, starch, cross-linked povidone, and hydroxypropyl cellulose.

[0009] Still further, the second disintegrant is hydroxypropyl cellulose.

[0010] Further, the first lubricant and the second lubricant are at least one selected from the group consisting of magnesium stearate, colloidal silicon dioxide, and talc.

[0011] Further, the filler is at least one selected from the group consisting of mannitol, lactose, microcrystalline cellulose, and calcium hydrogen phosphate.

[0012] In another aspect, the present application also provides a preparation method of the complex tablet of darunavir and cobicistat, which is used for preparing the above-mentioned complex tablet, and comprises the following steps:

[0013] S1. Put darunavir ethanolate, part of the first disintegrant, and the first lubricant into a dry granulator, and obtain dry granules after granulation and sizing;

[0014] S2. Mix hypromellose and an appropriate amount of water to form a binder solution, mix the dry granules and the remaining first disintegrant, spray the binder solution thereon, and perform wet granulation, and obtain wet granules after drying and sizing;

[0015] S3. Mix the wet granules, silica loaded with cobicistat, the second disintegrant, and the filler uniformly, sieve, and then add the second lubricant and continue mixing;

[0016] S4. tablet and perform film coating.

[0017] Further, in step S1, the amount of the part of the first disintegrant accounts for 20-30% of the total amount of the first disintegrant.

[0018] Further, in step S3, the wet granules and 0.5-1 parts of stearic acid are mixed and sieved, then the silicon dioxide loaded with cobicistat, the second disintegrant, and the filler are added and mixed until uniform, then the second lubricant is added and mixed.

[0019] Further, in step S1, the dry granulator is operated at a feeding speed of 20-35 rpm, a roller gap of 0.5-2 mm, and a granulating speed of 80-100 rpm, and the dry granules are obtained by sieving with a screen of 1.0-1.2 mm in diameter.

[0020] Further, in step S2, the wet granulator is operated at a speed of 100-200 rpm and a shearing speed of 1000-1500 rpm for 3-5 min, and the wet granules are dried in a fluidized bed until the water content is 2%, and then sieved with a 18-20 mesh swinging granulator to obtain the wet granules.

[0021] Compared with the prior art, the compound tablet of darunavir and cobicistat and the preparation method thereof have the following advantages:

[0022] (1) The combination of darunavir and cobicistat for preparing a medicine reduces the drug resistance caused by single drug use, and provides more options for AIDS patients.

[0023] (2) The compound tablet can improve the content of darunavir and ensure the quality of tablet pressing.

[0024] (3) The compound tablets prepared by the method have uniform content, can ensure the drug efficacy, are conducive to large-scale industrial production, and can maintain high stability after long-term storage. DETAILED DESCRIPTION

[0025] The application will be further described in conjunction with specific embodiments. It should be first noted that the data in the following experimental examples are obtained by the inventors through a large number of experiments, and only a part of them are shown in the specification due to the limited space, and the ordinary skilled in the art can understand and implement the application based on the data. The examples are only used to illustrate the application and not to limit the scope of the application. In addition, it should be understood that after reading the content of the application, those skilled in the art can make various modifications or modifications to the application, and these modifications or modifications also fall within the scope of the application.

[0026] Example 1

[0027] 1003 g of darunavir ethanolate, 9 g of cross-linked sodium carboxymethyl cellulose, and 6 g of magnesium stearate are put into a dry granulator, and dry granules are obtained by granulating and sieving.

[0028] The dry granules and 21 g of croscarmellose sodium are mixed, sprayed with a 25% solution of hypromellose in water, and wet granulated, dried, and sized to obtain wet granules.

[0029] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content 145 g), 35 g of croscarmellose sodium, 130 g of microcrystalline cellulose are mixed until uniform, 1 g of magnesium stearate is added and mixed until uniform; the mixture is tabletted and film-coated.

[0030] Example 2

[0031] 989 g of darunavir ethanolate, 7.5 g of crospovidone and 5.5 g of colloidal silicon dioxide are introduced into a dry granulator, granulated, sized to obtain dry granules.

[0032] The dry granules and 17.5 g of crospovidone are mixed, sprayed with a 20% solution of hypromellose in water, and wet granulated, dried, and sized to obtain wet granules.

[0033] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content 150 g), 38 g of crospovidone, 140 g of mannitol are mixed until uniform, 1.5 g of colloidal silicon dioxide is added and mixed until uniform; the mixture is tabletted and film-coated.

[0034] Example 3

[0035] 989 g of darunavir ethanolate, 7.5 g of crospovidone and 5.5 g of colloidal silicon dioxide are introduced into a dry granulator, granulated, sized to obtain dry granules.

[0036] The dry granules and 17.5 g of crospovidone are mixed, sprayed with a 20% solution of hypromellose in water, and wet granulated, dried, and sized to obtain wet granules.

[0037] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content 150 g), 38 g of crospovidone, 140 g of mannitol are mixed until uniform, 1.5 g of colloidal silicon dioxide is added and mixed until uniform; the mixture is tabletted and film-coated.

[0038] Example 4

[0039] Put 985 g of darunavir ethanolate, 5 g of hydroxypropyl cellulose and 3 g of colloidal silicon dioxide into a dry granulator, and after granulation and sizing, dry granules are obtained.

[0040] Mix 20 g of hypromellose with water to form a 22% hypromellose binder solution, mix the dry granules with 20 g of hydroxypropyl cellulose, spray the binder solution, and wet granulation, dry and size after granulation to obtain wet granules.

[0041] Mix the wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content 160 g), 40 g of hydroxypropyl cellulose, 135 g of calcium hydrogen phosphate to uniformity, then add 2 g of colloidal silicon dioxide and mix uniformly; tablet the mixture and then film coat.

[0042] Example 5

[0043] Put 989 g of darunavir ethanolate, 6 g of sodium carboxymethyl starch and 3 g of talc into a dry granulator, and after granulation and sizing, dry granules are obtained.

[0044] Mix 30 g of hypromellose with water to form a 25% hypromellose binder solution, mix the dry granules with 24 g of sodium carboxymethyl starch, spray the binder solution, and wet granulation, dry and size after granulation to obtain wet granules.

[0045] Mix the wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content 150 g), 35 g of hydroxypropyl cellulose, 134 g of lactose to uniformity, then add 1 g of magnesium stearate and mix uniformly; tablet the mixture and then film coat.

[0046] Example 6

[0047] Put 989 g of darunavir ethanolate, 7.5 g of cross-linked povidone and 5.5 g of colloidal silicon dioxide into a dry granulator, and after granulation and sizing, dry granules are obtained.

[0048] Mix 23 g of hypromellose with water to form a 20% hypromellose binder solution, mix the dry granules with 17.5 g of cross-linked povidone, spray the binder solution, and wet granulation, dry and size after granulation to obtain wet granules.

[0049] Mix the wet granules and 0.5 g of stearic acid, then sieve, then add 288 g of silicon dioxide loaded with cobicistat (cobicistat content 150 g), 38 g of hydroxypropyl cellulose, 140 g of mannitol to uniformity, then add 1.5 g of colloidal silicon dioxide and mix uniformly; tablet the mixture and then film coat.

[0050] Example 7

[0051] 989 g of darunavir ethanolate, 7.5 g of crosslinked polyvidone and 5.5 g of colloidal silicon dioxide were put into a dry granulator, granulated, sized, and dry granules were obtained.

[0052] A 20% solution of hypromellose binder was prepared by mixing 23 g of hypromellose and water, the dry granules were mixed with 17.5 g of crosslinked polyvidone, sprayed with the binder solution, and wet granulated, dried, sized, and wet granules were obtained.

[0053] The wet granules were mixed with 1 g of stearic acid, sieved, 288 g of silicon dioxide loaded with cobicistat (cobicistat content 150 g), 38 g of hypromellose, 140 g of mannitol were added and sieved until homogeneous, 1.5 g of colloidal silicon dioxide was added and mixed until homogeneous; the mixture was tabletted and film-coated.

[0054] Example 8

[0055] Example 8 was prepared according to Example 6, except that the filler mannitol was replaced by dibasic calcium phosphate.

[0056] Example 9

[0057] Example 9 was prepared according to Example 7, except that the filler mannitol was replaced by dibasic calcium phosphate.

[0058] In the above examples, the dry granulation was performed at a feed rate of 20-35 rpm, a roller gap of 0.5-2 mm, a rotation speed of 80-100 rpm, and the dry granules were sized using a screen with a diameter of 1.0-1.2 mm to obtain dry granules. The wet granulation was performed at a rotation speed of 100-200 rpm, a shear rotation speed of 1000-1500 rpm, and a granulation time of 3-5 min, the wet granules were dried in a fluidized bed, and the drying was stopped when the water content of the wet granules was 2%, and the dried granules were sized using a 18-20 mesh oscillating granulator to obtain wet granules.

[0059] Comparative Example 1

[0060] Tablets were prepared according to the method in Example 2 of darunavir GS-9350 co-formulation in CN103826616B.

[0061] Tabletting process research

[0062] The tablets of Examples 1-9 were tabletted at 1000 tablets. The tabletting conditions and tablet hardness of the above tablets were tested under the same tabletting conditions, and the results are shown in Table 1.

[0063] Table 1

[0064] No. Tabletting Tablet hardness (kg) Example 1 Smooth tablet surface, easy tabletting 14.5 Example 2 Smooth tablet surface, easy tabletting 14.8 Example 3 Smooth tablet surface, easy tabletting 15.8 Example 4 Smooth tablet surface, easy tabletting 15.9 Example 5 Smooth tablet surface, easy tabletting 15.9 Example 6 Smooth tablet surface, easy tabletting 15.8 Example 7 Smooth tablet surface, easy tabletting 15.8 Example 8 Smooth tablet surface, easy tabletting 15.8 Example 9 Smooth tablet surface, easy tabletting 15.7 Comparative Example 1 Smooth tablet surface, easy tabletting 14.0

[0065] From Table 1, it can be seen that the complex tablets of Examples 1-9 prepared by using the darunavir and combivir compound tablet and the preparation method thereof of the present application improve the content of darunavir, but do not affect the final tabletting process, and the obtained complex tablets have no splitting on the surface. It is shown that the present application can provide a compound tablet for combination use of darunavir and combivir, and the content of the raw material drug is improved, which can provide more medication options for AIDS patients. Compared with Comparative Example 1, the complex tablets of Examples 1-9 have higher hardness, and do not affect the friability. For Example 2 and Example 3, under the same conditions of other parameters, the difference between them lies in the selection of the second disintegrant. The second disintegrant of Example 3 is hydroxypropyl cellulose, and the second disintegrant of Example 2 is cross-linked polyvinylpyrrolidone. The hardness of the complex tablet of Example 3 is better than that of Example 2. It is speculated that the reason is that hydroxypropyl cellulose has a certain porosity, which is beneficial to its rough structure, and can produce certain inlaying effect with the raw material drug when mixed, which helps to improve the hardness of the complex tablet and improve the yield of the tablet.

[0066] Method for determining the content of darunavir:

[0067] An Agilent 1260 type liquid chromatograph, an Agilent C18 (150x4.6mm) chromatographic column, acetonitrile: water = 1:1 as the mobile phase, injection volume 20μL, flow rate 1mL / min, ultraviolet detection wavelength 267nm. Take a proper amount of darunavir ethanol solvate, accurately weigh, dissolve and quantitatively dilute with the mobile phase to prepare a solution containing about 10μg per 1mL as the control solution, accurately take 20μL, inject into the liquid chromatograph, and record the chromatogram. The sample to be tested is determined by the same method, and the peak area is calculated by the external standard method.

[0068] Method for determining the content of combivir:

[0069] Shimadzu 250mmx4.6mm 5um 0120+pre-column as the chromatographic column, mobile phase A: 0.02M ammonium acetate 500ml + 250ul diethylamine + 200ul TFA (PH6.95) buffer, mobile phase B: acetonitrile, detection wavelength: 239nm, flow rate: 1.0ml / min, diluent: acetonitrile / water (1:1), column temperature: 35℃. The gradient elution program is shown in Table 2:

[0070] Table 2

[0071] 0 min 10 min 20 min 30 min 30.1 min 40 min Mobile phase A (V / V %) 40 40 15 15 40 40 Mobile phase B (V / V %) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 60 60 85 85 60 60

[0072] The content of the composite tablets of Examples 1-9 and Comparative Example 1 was determined for samples taken from different batches, and the results are shown in Table 3. It should be noted that, for the sake of brevity, only some of the experimental data is shown in Table 3, but the general principles are not affected.

[0073] Table 3

[0074]

[0075]

[0076] As can be seen from Table 3, the content of the raw material drug in the composite tablets prepared in Examples 6-9 is not significantly different when samples are taken from different batches, indicating that the composite tablets prepared in the application are uniform in content, which is conducive to ensuring the uniformity of the content and the stability of the quality of the drug produced in different batches, and is helpful to improve the drug efficacy. Compared with Examples 1-5, the method used in Examples 6-9 to mix darunavir and cobicistat is to first mix the wet granules of darunavir and stearic acid, then sieve, and then mix with cobicistat and other excipients. Mixing the wet granules of darunavir and stearic acid and sieving can reduce the adhesion of the wet granules to the sieve and increase the content of darunavir. Moreover, in the process of mixing and sieving, the use of stearic acid reduces the aggregation of the wet granules, which can be fully mixed with cobicistat and other excipients in the subsequent mixing process, thereby improving the uniformity of the composite tablets and ensuring that the content of the main drug in the composite tablets produced in different batches is not significantly different.

[0077] Since the composite tablets include two main drugs, darunavir and cobicistat, and considering that long-term contact between the two main drugs and long-term contact between the main drugs and excipients can affect each other, it is necessary to conduct an accelerated experiment (placed at 40°C and 75% humidity for 6 months) on the composite tablets, and the stability of the composite tablets is determined by measuring the content of the two main drugs. The specific results are shown in Table 4.

[0078] Table 4

[0079]

[0080]

[0081] As can be seen from Table 4, after being placed under accelerated conditions for 6 months, the content of darunavir and cobicistat in the composite tablets prepared in Examples 4, 8 and 9 did not decrease significantly, indicating that the composite tablets have good stability, and the raw material drugs and the raw material drugs, and the raw material drugs and the excipients will not affect each other, and will not cause the degradation of the raw material drugs. This is because, in the preparation process of the composite tablets, calcium hydrogen phosphate is selected as the filler, and a large amount of calcium hydrogen phosphate is filled between the components, which is conducive to reducing the adverse effects between them.

[0082] The above description is only the preferred embodiment of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a darunavir and cobicistat compound tablet, characterized in that, The preparation method includes the following steps: S1. Darunavir ethanol, a portion of the first disintegrant and the first lubricant are fed into a dry granulator, and dry granules are obtained after granulation and sizing. S2. Hydroxypropyl methylcellulose and an appropriate amount of water are mixed to form an adhesive solution. The dry granules are mixed with the remaining first disintegrant, sprayed with the adhesive solution, and wet granulated. After drying and granulation, wet granules are obtained. S3. Mix the wet-processed particles, silica loaded with cobistat, the second disintegrant, and the filler until uniform, then sieve the mixture, and then add the second lubricant and continue mixing. S4. After tableting, perform film coating; Wherein, the first disintegrant and the second disintegrant are selected from at least one of croscarmellose sodium, croscarmellose sodium, starch, croscarmellose, and hydroxypropyl cellulose, the second disintegrant is hydroxypropyl cellulose, the first lubricant and the second lubricant are selected from at least one of magnesium stearate, colloidal silica, and talc, and the filler is selected from at least one of mannitol, lactose, microcrystalline cellulose, and dicalcium phosphate.

2. The method for preparing the composite tablet according to claim 1, characterized in that, In step S1, the amount of the first disintegrant is 20-30% of the total amount of the first disintegrant.

3. The method for preparing the composite tablet according to claim 1, characterized in that, In step S1, the conditions of the dry granulator are: feed speed 20-35 rpm, roller gap 0.5-2 mm, granulation speed 80-100 rpm, and after granulation, a sieve with a diameter of 1.0-1.2 mm is used for granulation to obtain dry granules.

4. The method for preparing the composite tablet according to claim 1, characterized in that, In step S2, the wet granulation conditions are a rotation speed of 100-200 rpm, a shearing speed of 1000-1500 rpm, and a granulation time of 3-5 min. The wet granules are fed into a fluidized bed for drying. When the wet granules are dried to a moisture content of 2%, the drying is stopped. The dried granules are then granulated using an 18-20 mesh oscillating granulator to obtain wet granules.

5. The composite tablet prepared according to the method for preparing composite tablets as described in claim 1, characterized in that, The compound tablet comprises the following components in parts by weight: 985-1003 parts of darunavir ethanol, 145-160 parts of silica loaded with cobistat (based on the amount of cobistat), 25-30 parts of the first disintegrant, 35-40 parts of the second disintegrant, 3-6 parts of the first lubricant, 1-2 parts of the second lubricant, 20-30 parts of hydroxypropyl methylcellulose, and 130-150 parts of filler.

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