Darunavir and cobicistat composite tablet and preparation method thereof

Abstract

The invention provides a darunavir and cobicistat composite tablet and a preparation method thereof, and the preparation method comprises the following steps: putting darunavir ethylate, a part of a first disintegrating agent and a first lubricant into a dry granulator, granulating, and finishing to obtain dry granules; mixing the dry particles with the first disintegrating agent, hydroxypropyl methylcellulose and a proper amount of water to form an adhesive solution, mixing the dry particles with the remaining first disintegrating agent, spraying the adhesive solution, performing wet granulation, and drying and finishing the granules to obtain wet particles; uniformly mixing the wet particles, the silicon dioxide loaded with the copibuxostat, a second disintegrating agent and a filling agent, sieving, adding a second lubricating agent, and continuously and uniformly mixing; and performing film coating after tabletting. According to the invention, darunavir and cobicistat are combined to prepare the medicine, so that the drug resistance generated by single medication is reduced, and more choices are provided for medication of AIDS patients. In addition, the compound tablet provided by the invention can increase the content of darunavir.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a darunavir and cobicistat composite tablet and a preparation method thereof. Background Art

[0003] Darunavir is chemically named [(1R, 5S, 6R)-2,8-dioxobicyclo[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, Ireland. It is a second-generation protease inhibitor for the treatment of human immunodeficiency virus (HIV) infection. It selectively inhibits the cleavage of HIV-encoded Gag-Pol polyprotein in virus-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 under the trade name Prezista.

[0004] Cobicistat is chemically named 1,3-thiazol-5-methylene [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propane-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholinyl-4-yl)butanoyl]amino}-1,6-diphenylhexane-2-yl]carbamate. Cobicistat is a novel CYP3A inhibitor developed by Gilead Sciences, Inc., and was approved by the U.S. Food and Drug Administration on September 24, 2014. It is currently the only approved cocktail therapy AIDS drug enhancer. In addition to single prescriptions, it is also used in combination with other anti-retroviral drugs for HIV infection.

[0005] The combination of darunavir and cobicistat can provide more options for AIDS patients to treat HIV infection. However, in the prior art, the amount of darunavir added when the two drugs are combined to prepare compound tablets is limited, and the content of the compound tablets is uneven, which will affect the efficacy. Summary of the invention

[0006] In view of this, the present invention aims to propose a darunavir and cobicistat composite tablet and a preparation method thereof, so as to solve the problem of limited darunavir content when preparing darunavir and cobicistat composite tablets, as well as the problem of uneven content of composite tablets, and poor content uniformity and stability of drugs produced in different batches, thereby providing more medication options for AIDS patients.

[0007] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0008] On the one hand, the present invention provides a darunavir and cobicistat composite tablet, the composite tablet comprising the following components in parts by weight: 985-1003 parts of darunavir ethanolate, 145-160 parts of silicon dioxide loaded with cobicistat (calculated according to the amount of cobicistat), 25-30 parts of a first disintegrant, 35-40 parts of a second disintegrant, 3-6 parts of a first lubricant, 1-2 parts of a second lubricant, 20-30 parts of hypromellose, and 130-150 parts of a filler. The method of loading cobicistat onto silicon dioxide is referred to CN102307573B.

[0009] Furthermore, the first disintegrant and the second disintegrant are selected from at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, cross-linked polyvinylpyrrolidone, and hydroxypropyl cellulose.

[0010] Furthermore, the second disintegrant is hydroxypropyl cellulose.

[0011] Furthermore, the first lubricant and the second lubricant are selected from at least one of magnesium stearate, colloidal silicon dioxide and talc.

[0012] Furthermore, the filler is selected from at least one of mannitol, lactose, microcrystalline cellulose and calcium hydrogen phosphate.

[0013] On the other hand, the present invention also provides a method for preparing a composite tablet of darunavir and cobicistat, which is used to prepare the composite tablet. The method for preparing the composite tablet comprises the following steps:

[0014] S1. putting the darunavir ethanolate, a portion of the first disintegrant and the first lubricant into a dry granulator, and obtaining dry granules after granulation and granulation;

[0015] S2. Hydroxypropyl methylcellulose and an appropriate amount of water are mixed to form a binder solution, the dry granules and the remaining first disintegrant are mixed, sprayed with the binder solution, and wet granulated, and the wet granules are obtained after drying and granulation;

[0016] S3. The wet granules, the silicon dioxide loaded with cobicistat, the second disintegrant, and the filler are mixed until uniform and then sieved, and then the second lubricant is added and mixed;

[0017] S4. Film coating is performed after tableting.

[0018] Furthermore, in step S1, the amount of the first disintegrant accounts for 20-30% of the total amount of the first disintegrant.

[0019] Furthermore, in step S3, the wet granules and 0.5-1 parts of stearic acid are mixed and sieved, and then silicon dioxide loaded with cobicistat, a second disintegrant, and a filler are added, mixed until uniform, and then sieved, and then a second lubricant is added and mixed continuously.

[0020] Furthermore, in step S1, the conditions of the dry granulator are as follows: a feed rate of 20-35 rpm, a roller gap of 0.5-2 mm, a granulation speed of 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.

[0021] Furthermore, in step S2, the conditions for wet granulation are a rotation speed of 100-200 rpm, a shear speed of 1000-1500 rpm, and a granulation time of 3-5 min. The wet granules are put into a fluidized bed for drying. When the wet granules are dried to a moisture content of 2%, the drying is stopped, and the dried granules are granulated using an 18-20 mesh oscillating granulator to obtain wet granules.

[0022] Compared with the prior art, the darunavir and cobicistat composite tablet and the preparation method thereof of the present invention have the following advantages:

[0023] (1) Darunavir and cobicistat are combined to prepare drugs to reduce drug resistance caused by single drug use, providing more drug options for AIDS patients.

[0024] (2) The composite tablet of the present invention can increase the content of darunavir and ensure the quality of tableting.

[0025] (3) The composite tablets prepared in different batches have uniform content, which can ensure the efficacy, is conducive to industrial large-scale production, and can maintain high stability even after long-term storage. DETAILED DESCRIPTION

[0026] The present invention will be further described below in conjunction with specific embodiments. It should be noted that the data in the following experimental examples are obtained by the inventor through a large number of experiments. Due to space limitations, only a part of them is shown in the specification, and those of ordinary skill in the art can understand and implement the present invention under these data. These embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these changes or modifications also fall within the scope protected by the present application.

[0027] Example 1

[0028] 1003 g of darunavir ethanolate, 9 g of cross-linked carboxymethyl cellulose sodium and 6 g of magnesium stearate were put into a dry granulator, and dry granules were obtained after granulation and granulation.

[0029] 23 g of hypromellose and water are mixed to form a 25% hypromellose binder solution. The dry granules are mixed with 21 g of cross-linked sodium carboxymethyl cellulose, sprayed with the binder solution, and wet granulated. After drying and granulation, wet granules are obtained.

[0030] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content: 145 g), 35 g of cross-linked sodium carboxymethyl cellulose, and 130 g of microcrystalline cellulose were mixed until uniform and sieved, and then 1 g of magnesium stearate was added and continued to mix; the mixture was tableted and film-coated.

[0031] Example 2

[0032] 989 g of darunavir ethanolate, 7.5 g of cross-linked polyvinylpyrrolidone and 5.5 g of colloidal silicon dioxide were put into a dry granulator, and dry granules were obtained after granulation and granulation.

[0033] 23 g of hypromellose and water are mixed to form a 20% hypromellose binder solution. The dry granules are mixed with 17.5 g of cross-linked polyvinylpyrrolidone, sprayed with the binder solution, and wet granulated. After drying and granulation, wet granules are obtained.

[0034] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content: 150 g), 38 g of cross-linked polyvinylpyrrolidone, and 140 g of mannitol were mixed until uniform and sieved, and then 1.5 g of colloidal silicon dioxide was added and continued to mix; the mixture was tableted and film-coated.

[0035] Example 3

[0036] 989 g of darunavir ethanolate, 7.5 g of cross-linked polyvinylpyrrolidone and 5.5 g of colloidal silicon dioxide were put into a dry granulator, and dry granules were obtained after granulation and granulation.

[0037] 23 g of hypromellose and water are mixed to form a 20% hypromellose binder solution. The dry granules are mixed with 17.5 g of cross-linked polyvinylpyrrolidone, sprayed with the binder solution, and wet granulated. After drying and granulation, wet granules are obtained.

[0038] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content 150 g), 38 g of hydroxypropyl cellulose, and 140 g of mannitol were mixed until uniform and sieved, and then 1.5 g of colloidal silicon dioxide was added and continued to mix; the mixture was tableted and film-coated.

[0039] Example 4

[0040] 985 g of darunavir ethanolate, 5 g of hydroxypropylcellulose and 3 g of colloidal silicon dioxide were put into a dry granulator, and dry granules were obtained after granulation and granulation.

[0041] 20 g of hydroxypropyl methylcellulose and water are mixed to form a 22% hydroxypropyl methylcellulose binder solution. The dry granules are mixed with 20 g of hydroxypropyl cellulose, sprayed with the binder solution, and wet granulated. After drying and granulation, wet granules are obtained.

[0042] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content: 160 g), 40 g of hydroxypropylcellulose, and 135 g of calcium hydrogen phosphate were mixed until uniform and sieved, and then 2 g of colloidal silicon dioxide was added and continued to mix; the mixture was tableted and film-coated.

[0043] Example 5

[0044] 989 g of darunavir ethanolate, 6 g of sodium carboxymethyl starch and 3 g of talc were put into a dry granulator, and dry granules were obtained after granulation and granulation.

[0045] 30 g of hypromellose and water are mixed to form a 25% hypromellose binder solution. The dry granules are mixed with 24 g of sodium carboxymethyl starch, sprayed with the binder solution, and wet granulated. After drying and granulation, wet granules are obtained.

[0046] The wet granules, 288 g of silicon dioxide loaded with cobicistat (cobicistat content: 150 g), 35 g of hydroxypropyl cellulose, and 134 g of lactose were mixed until uniform and sieved, and then 1 g of magnesium stearate was added and continued to mix; the mixture was tableted and film-coated.

[0047] Example 6

[0048] 989 g of darunavir ethanolate, 7.5 g of cross-linked polyvinylpyrrolidone and 5.5 g of colloidal silicon dioxide were put into a dry granulator, and dry granules were obtained after granulation and granulation.

[0049] 23 g of hypromellose and water are mixed to form a 20% hypromellose binder solution. The dry granules are mixed with 17.5 g of cross-linked polyvinylpyrrolidone, sprayed with the binder solution, and wet granulated. After drying and granulation, wet granules are obtained.

[0050] The wet granules and 0.5 g of stearic acid were mixed and sieved, and then 288 g of silicon dioxide loaded with cobicistat (cobicistat content was 150 g), 38 g of hydroxypropyl cellulose, and 140 g of mannitol were added, mixed until uniform, and sieved, and then 1.5 g of colloidal silicon dioxide was added and continued to mix; the mixture was tableted and film-coated.

[0051] Example 7

[0052] 989 g of darunavir ethanolate, 7.5 g of cross-linked polyvinylpyrrolidone and 5.5 g of colloidal silicon dioxide were put into a dry granulator, and dry granules were obtained after granulation and granulation.

[0053] 23 g of hypromellose and water are mixed to form a 20% hypromellose binder solution. The dry granules are mixed with 17.5 g of cross-linked polyvinylpyrrolidone, sprayed with the binder solution, and wet granulated. After drying and granulation, wet granules are obtained.

[0054] The wet granules and 1 g of stearic acid were mixed and sieved, and then 288 g of silicon dioxide loaded with cobicistat (cobicistat content was 150 g), 38 g of hydroxypropyl cellulose, and 140 g of mannitol were added, mixed until uniform, and sieved, and then 1.5 g of colloidal silicon dioxide was added and continued to mix; the mixture was tableted and film-coated.

[0055] Example 8

[0056] The preparation method of Example 8 is the same as that of Example 6, except that the filler mannitol is replaced by calcium hydrogen phosphate.

[0057] Example 9

[0058] The preparation method of Example 9 is the same as that of Example 7, except that the filler mannitol is replaced by calcium hydrogen phosphate.

[0059] In the above embodiment, the conditions for dry granulation are feed speed 20-35rpm, roller gap 0.5-2mm, granulation speed 80-100rpm, and granulation is performed with a screen with a diameter of 1.0-1.2mm to obtain dry granules. The conditions for wet granulation are rotation speed 100-200rpm, shear speed 1000-1500rpm, granulation time 3-5min, wet granules are put into a fluidized bed for drying, and drying is stopped when the wet granules are dried to a moisture content of 2%, and the dried granules are then granulated with a 18-20 mesh swing granulator to obtain wet granules.

[0060] Comparative Example 1

[0061] Tablets prepared according to the method of Example 2 of CN103826616B for the co-formulation of darunavir GS-9350.

[0062] Tablet Compression Process Research

[0063] Examples 1 to 9 were compressed into 1000 tablets. The tablet compression and tablet hardness of the above tablets were tested under the same tablet compression conditions. The specific results are shown in Table 1.

[0064] Table 1

[0065] Serial number Tablet pressing Tablet hardness (kg) Example 1 Smooth surface, easy to form tablets 14.5 Example 2 Smooth surface, easy to form tablets 14.8 Example 3 Smooth surface, easy to form tablets 15.8 Example 4 Smooth surface, easy to form tablets 15.9 Example 5 Smooth surface, easy to form tablets 15.9 Example 6 Smooth surface, easy to form tablets 15.8 Example 7 Smooth surface, easy to form tablets 15.8 Example 8 Smooth surface, easy to form tablets 15.8 Example 9 Smooth surface, easy to form tablets 15.7 Comparative Example 1 Smooth surface, easy to form tablets 14.0

[0066] It can be seen from Table 1 that the composite tablets of Examples 1-9 prepared by using the composite tablets of darunavir and cobicistat of the present invention and the preparation method thereof, increase the content of darunavir, but do not affect the final tableting process, and the surface of the composite tablets obtained is free of splitting. It is explained that the present application can provide a composite tablet for the combination of darunavir and cobicistat, which increases the content of the raw material drug and can provide more medication options for AIDS patients. Compared with Comparative Example 1, the composite 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 the two 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 composite tablet of Example 3 is better than that of Example 2. It is speculated that hydroxypropyl cellulose has a certain porosity, which is conducive to its rough structure. When mixed with the raw material drug, it can produce a certain mosaic effect with the raw material drug, which helps to improve the hardness of the composite tablet and improve the yield of tableting.

[0067] Determination method of darunavir content:

[0068] Use Agilent 1260 liquid chromatograph, Agilent C18 (150×4.6mm) column, acetonitrile: water = 1:1 as mobile phase, injection volume 20μL, flow rate 1mL / min, UV detection wavelength 267nm. Take an appropriate amount of Darunavir ethanol solvate, accurately weigh and dissolve in the mobile phase and quantitatively dilute to make a solution containing about 10μg per 1mL, as the reference solution, accurately measure 20μL, inject into the liquid chromatograph, and record the chromatogram. Determine the sample to be tested in the same way, and calculate the peak area according to the external standard method.

[0069] Determination method of cobicistat content:

[0070] Shimadzu 250mm×4.6mm 5um 0120+pre-column was used 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:

[0071] Table 2

[0072] 0min 10min 20min 30min 30.1min 40min Mobile phase A (V / V%) 40 40 15 15 40 40 Mobile phase B (V / V%) 60 60 85 85 60 60

[0073] The composite tablets of Examples 1-9 and Comparative Example 1 were respectively sampled from different batches for content determination, and the specific results are shown in Table 3. It should be noted that, due to space limitations, only part of the experimental data is shown in Table 3, but the overall description is not affected.

[0074] Table 3

[0075]

[0076]

[0077] As shown in Table 3, the content of raw materials is not much different when different batches of composite tablets prepared by Examples 6-9 of the present application are sampled, indicating that the content of composite tablets prepared by the present application is uniform, which is conducive to ensuring the content uniformity and quality stability of the drugs produced under different batches, and is helpful to improve drug efficacy. Compared with Examples 1-5, the method adopted by Examples 6-9 when Darunavir and Cobicistat are mixed is to first sieve the wet granules of Darunavir after mixing with stearic acid, and then mix with Cobicistat and other excipients. The wet granules of Darunavir and stearic acid are mixed and sieved, which can reduce the attachment of the screen to the wet granules and improve the content of Darunavir, and in the process of mixed sieving, stearic acid is used to reduce the aggregation of wet granules, and can be fully mixed when mixed with Cobicistat and other excipients in the follow-up, improve the uniformity of composite tablets, and ensure that the content of the main drug of the composite tablets produced in different batches is not much different.

[0078] Since the composite tablets include two main drugs, darunavir and cobicistat, and considering that the long-term contact between the two main drugs and the long-term contact between the main drugs and the excipients may have mutual effects, it is necessary to conduct an accelerated test on the composite tablets (placed at 40°C and 75% humidity for 6 months) to determine the stability of the composite tablets by measuring the content of the two main drugs. The specific results are shown in Table 4.

[0079] Table 4

[0080]

[0081]

[0082] As shown in Table 4, the composite tablets prepared in Example 4, Example 8 and Example 9, after being placed under accelerated conditions for 6 months, the contents of darunavir and cobicistat did not decrease significantly, indicating that the composite tablets have good stability, and the APIs and APIs, and the APIs and excipients will not affect each other during long-term placement, and will not cause degradation of the APIs. This is because in the preparation process of the composite tablets, calcium hydrogen phosphate is selected as a filler, and a large amount of calcium hydrogen phosphate is filled between the components, which is conducive to reducing the adverse effects between each other.

[0083] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A darunavir and cobicistat composite tablet, characterized in that: The composite tablet comprises the following components in parts by weight: 985-1003 parts of darunavir ethanolate, 145-160 parts of silicon dioxide loaded with cobicistat (calculated according to the amount of cobicistat), 25-30 parts of a first disintegrant, 35-40 parts of a second disintegrant, 3-6 parts of a first lubricant, 1-2 parts of a second lubricant, 20-30 parts of hypromellose, and 130-150 parts of a filler.

2. The composite tablet according to claim 1, characterized in that The first disintegrant and the second disintegrant are selected from at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, cross-linked polyvinylpyrrolidone and hydroxypropyl cellulose.

3. The composite tablet according to claim 2, characterized in that The second disintegrant is hydroxypropylcellulose.

4. The composite tablet according to claim 1, characterized in that The first lubricant and the second lubricant are selected from at least one of magnesium stearate, colloidal silicon dioxide and talc.

5. The composite tablet according to claim 1, characterized in that The filler is selected from at least one of mannitol, lactose, microcrystalline cellulose and calcium hydrogen phosphate.

6. A method for preparing a composite tablet according to any one of claims 1 to 5, characterized in that: The preparation method comprises the following steps: S1. putting the darunavir ethanolate, a portion of the first disintegrant and the first lubricant into a dry granulator, and obtaining dry granules after granulation and granulation; S2. Hydroxypropyl methylcellulose and an appropriate amount of water are mixed to form a binder solution, the dry granules and the remaining first disintegrant are mixed, sprayed with the binder solution, and wet granulated, and the wet granules are obtained after drying and granulation; S3. The wet granules, the silicon dioxide loaded with cobicistat, the second disintegrant, and the filler are mixed until uniform and then sieved, and then the second lubricant is added and mixed; S4. Film coating is performed after tableting.

7. The method for preparing a composite tablet according to claim 6, characterized in that: In step S1, the amount of the first disintegrant is 20-30% of the total amount of the first disintegrant.

8. The method for preparing a composite tablet according to claim 6, characterized in that: In step S1, the conditions of the dry granulator are as follows: a feed rate of 20-35 rpm, a roller gap of 0.5-2 mm, a granulation rotation speed of 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.

9. The method for preparing a composite tablet according to claim 6, characterized in that: In step S2, the conditions for wet granulation are a rotation speed of 100-200 rpm, a shear speed of 1000-1500 rpm, and a granulation time of 3-5 min. The wet granules are put 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.

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