A compound preparation for treating high blood pressure and its preparation method

Abstract

The application discloses an antihypertensive compound preparation, which comprises 4.0% benazepril hydrochloride, 5.0% hydrochlorothiazide, 78-82% diluent, 6-11% disintegrant, 2-3% lubricant and coating material in percentage by weight. The diluent is selected from one or more of lactose and microcrystalline cellulose, the ratio of the amount of lactose to the amount of microcrystalline cellulose is (10-13):(1-2), the disintegrant is crospovidone, the lubricant is hydrogenated castor oil, and the particle size of benazepril hydrochloride and hydrochlorothiazide is D90<70 mu m. The benazepril hydrochloride and hydrochlorothiazide tablet provided by the application has good stability and dissolution performance.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to an anti-hypertensive compound preparation and a preparation method thereof. BACKGROUND

[0002] The anti-hypertensive compound preparation is benazepril hydrochlorothiazide tablets, which is a compound anti-hypertensive drug and is composed of two pharmaceutical ingredients, benazepril and hydrochlorothiazide. Benazepril belongs to angiotensin converting enzyme inhibitors (ACEI), which can inhibit the conversion of angiotensin I to angiotensin II by inhibiting the activity of angiotensin converting enzyme, thereby dilating blood vessels and reducing blood pressure. Hydrochlorothiazide is a thiazide diuretic, which can increase urine output by inhibiting the reabsorption of sodium and water in the renal tubule, thereby reducing blood volume and achieving the effect of reducing blood pressure. Hydrochlorothiazide can further enhance the antihypertensive effect of benazepril by stimulating the activity of the renin-angiotensin system. The benazepril hydrochlorothiazide tablets as a compound preparation are developed to improve the antihypertensive effect and reduce adverse reactions through the synergistic effect of the two components, and have clear antihypertensive effect and certain clinical application value.

[0003] In the prior art, there are few disclosed literatures on the benazepril hydrochlorothiazide tablets. The currently marketed benazepril hydrochlorothiazide tablets are chemically unstable in a high-temperature and high-humidity environment, the content of active ingredients decreases, and impurities increase. Therefore, how to improve the stability of the benazepril hydrochlorothiazide tablets in a high-temperature and high-humidity environment while ensuring good dissolution performance is still a problem to be explored. SUMMARY

[0004] The application provides an anti-hypertensive compound preparation with good stability and dissolution performance.

[0005] The application discloses an anti-hypertensive compound preparation, which comprises, by weight percentage, 4.0% of benazepril hydrochloride, 5.0% of hydrochlorothiazide, 78-82% of a diluent, 6-11% of a disintegrant, 2-3% of a lubricant and a coating material.

[0006] In an embodiment of the application, the diluent can be one or more of lactose and microcrystalline cellulose.

[0007] In an embodiment of the application, the disintegrant is crospovidone.

[0008] In an embodiment of the application, the lactose and the microcrystalline cellulose are used in a ratio of (10-13):(1-2).

[0009] In an embodiment of the application, the benazepril hydrochlorothiazide tablets comprise, by weight percentage, 4.0% of benazepril hydrochloride, 5.0% of hydrochlorothiazide, 80% of a diluent, 8.6% of a disintegrant, 2.4% of a lubricant and a coating material.

[0010] In one embodiment of the present application, the diluent comprises 71.1% lactose and 8.9% microcrystalline cellulose.

[0011] In one embodiment of the present application, the lubricant is hydrogenated castor oil.

[0012] In one embodiment of the present application, the benazepril hydrochloride has a particle size D90 < 70 μm.

[0013] In one embodiment of the present application, the hydrochlorothiazide has a particle size D90 < 70 μm.

[0014] The present application also provides a preparation method of an antihypertensive compound preparation, comprising the following steps:

[0015] 1) Weigh the prescription amount of raw and auxiliary materials and mix them; the stirring speed is set to 120-200 rpm, the cutting speed is 800-1200 rpm, and the mixing time is 200-400 s.

[0016] 2) Add liquid: add water to wet the mixture; the stirring speed is 120-180 rpm, and the shearing speed is 800-1200 rpm.

[0017] 3) Granulation: the stirring speed is 120-180 rpm, the shearing speed is 800-1200 rpm, and the time is 150-200 s.

[0018] 4) Drying: place the prepared soft material in a fluidized bed, and set the drying temperature to 50-80℃, and the moisture content to less than 2%.

[0019] 5) Granulation: use a rapid granulator to perform granulation, and set the frequency to 180-240 Hz and the screen mesh to 1 mm.

[0020] 6) Total mixing: add lubricant.

[0021] 7) Tabletting: tablet according to the theoretical tablet weight, and record the tabletting parameters; the hardness is 70-90 N.

[0022] 8) Coating: the coating liquid concentration is 13%, the coating temperature is 60℃, and the coating weight gain is 2%-4%.

[0023] Beneficial effects:

[0024] The diluent is mainly used to increase the volume and weight of the tablet, so that it is easy to be compressed. The pore structure formed by the disintegrant in the tablet is crucial for the penetration of moisture and the dissolution of the drug. The appropriate proportion of disintegrant can form enough pores, which is conducive to the rapid penetration of moisture and the disintegration of the tablet. However, too much diluent can reduce this pore structure, affecting the disintegration performance of the tablet. The proportion of the two will directly affect the hardness and friability of the tablet, and then affect its disintegration rate and stability. After a large number of experiments, the inventors have explored the appropriate proportion and the appropriate types of diluent and disintegrant, and the dissolution and stability of the prepared benazepril and hydrochlorothiazide tablets are significantly improved. DETAILED DESCRIPTION

[0025] The present application discloses an antihypertensive compound preparation, which comprises, by weight percentage, 4.0% benazepril hydrochloride, 5.0% hydrochlorothiazide, 78-82% diluent, 6-11% disintegrant, 2-3% lubricant and coating material. The amount of diluent added can be 78%, 80%, 82%; the disintegrant can be 6%, 6.6%, 8.6%, 10.6%, 11%; the lubricant can be 2%, 2.4%, 3%.

[0026] Preferably, the diluent can be one or more of lactose and microcrystalline cellulose. It can be a combination of lactose and microcrystalline cellulose, and the ratio of the amount of lactose to microcrystalline cellulose is (10-13) : (1-2). The ratio of the amount of lactose to microcrystalline cellulose can be 10:1.5, 12:1.5, 13:1.5, 12:1, 12:3.

[0027] Preferably, the disintegrant is cross-linked polyvinylpyrrolidone.

[0028] Preferably, the benazepril and hydrochlorothiazide tablet comprises, by weight percentage, 4.0% benazepril hydrochloride, 5.0% hydrochlorothiazide, 80% diluent, 8.6% disintegrant, 2.4% lubricant and coating material. The diluent comprises 71.1% lactose and 8.9% microcrystalline cellulose.

[0029] Preferably, the lubricant is hydrogenated castor oil.

[0030] Preferably, the particle size D90 of benazepril hydrochloride is less than 70 μm.

[0031] Preferably, the particle size D90 of hydrochlorothiazide is less than 70 μm.

[0032] The preparation method of the benazepril and hydrochlorothiazide tablet comprises the following steps:

[0033] 1) Take the prescription amount of raw and auxiliary materials and mix them: the stirring speed is set to 120-200 rpm, the cutting speed is 800-1200 rpm, and the mixing time is 200-400 s. The stirring speed can be set to 120 rpm, 150 rpm, 180 rpm, or 200 rpm; the cutting speed can be 800 rpm, 1000 rpm, or 1200 rpm; and the mixing time can be 200 s, 300 s, or 400 s.

[0034] 2) Add liquid: add water to wet the mixture, the stirring parameter is 120-180 rpm, and the shearing parameter is 800-1200 rpm. The stirring parameter can be 120 rpm, 150 rpm, or 180 rpm; and the shearing parameter can be 800 rpm, 1000 rpm, or 1200 rpm.

[0035] 3) Granulation: the stirring speed is 120-180 rpm, the shearing speed is 800-1200 rpm, and the time is 150-200 s. The stirring speed can be 120 rpm, 150 rpm, or 180 rpm; the shearing speed can be 800 rpm, 1000 rpm, or 1200 rpm; and the time can be 150 s, 180 s, or 200 s.

[0036] 4) Drying: place the prepared soft material in a fluidized bed, set the drying temperature to 50-80℃, and the moisture content is less than 2%. The drying temperature can be 50℃, 65℃, or 80℃.

[0037] 5) Size reduction: use a fast size reduction machine to size the particles, set the frequency to 180-240 Hz, and the screen mesh is 1 mm. The frequency can be 180 Hz, 200 Hz, 220 Hz, or 240 Hz.

[0038] 6) Total mixing: add lubricant.

[0039] 7) Tablet compression: compress the tablets according to the theoretical tablet weight, and record the tablet compression parameters. The hardness is 70-90 N, and the hardness can be 70 N, 80 N, or 90 N.

[0040] 8) Coating: the coating liquid concentration is 13%, the coating temperature is 60℃, and the coating weight gain is 2%-4%.

[0041] The benazepril and hydrochlorothiazide tablets prepared by the method have good stability and dissolution performance.

[0042] Example 1

[0043] Prescription amount: see Table 1.

[0044] Table 1 Prescription amount of Example 1

[0045]

[0046] Preparation process:

[0047] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, cross-linked povidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0048] 2) Liquid addition: The stirring parameters are 150 rpm, the shearing parameters are 1000 rpm, and the wetting agent is water.

[0049] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0050] 4) Drying: Place the prepared soft material in a fluidized bed, set the drying temperature to 60°C, and the moisture content to less than 2%.

[0051] 5) Size reduction: Use a rapid size reduction machine for size reduction (frequency 200.5 Hz, screen 1.0 mm).

[0052] 6) Total mixing: Add hydrogenated castor oil.

[0053] 7) Tablet compression: Perform tablet compression according to the theoretical tablet weight, and record the tablet compression parameters. The hardness is 70-90 N.

[0054] 8) Coating: The coating liquid concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0055] Example 2

[0056] Prescription amount: See Table 2.

[0057] Table 2 Prescription amount of Example 2

[0058]

[0059] Preparation process:

[0060] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, cross-linked povidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0061] 2) Liquid addition: The stirring parameters are 150 rpm, the shearing parameters are 1000 rpm, and the wetting agent is water.

[0062] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0063] 4) Drying: Place the prepared soft material in a fluidized bed, set the drying temperature to 60°C, and the moisture content to less than 2%.

[0064] 5) Granulation: Granulation was performed using a rapid granulator (frequency 200.5 Hz, screen 1.0 mm).

[0065] 6) Total mixing: Hydrogenated castor oil was added.

[0066] 7) Compression: Compression was performed according to the theoretical tablet weight, and the compression parameters were recorded, hardness 70-90 N.

[0067] 8) Coating: The coating liquid concentration was 13%, the coating temperature was 60°C, and the coating weight gain was 2%-4%.

[0068] Example 3

[0069] Prescription amount: see Table 3.

[0070] Table 3 Prescription amount of Example 3

[0071]

[0072] Preparation process:

[0073] 1) Premixing: Lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and cross-linked povidone were sequentially added to a wet granulator. The stirring speed was 150 rpm, the cutting speed was 1000 rpm, and the mixing time was 300 s.

[0074] 2) Liquid addition: The stirring parameters were 150 rpm, the shearing parameters were 1000 rpm, and the wetting agent was water.

[0075] 3) Granulation: The stirring speed was 150 rpm, the cutting speed was 1000 rpm, and the time was 180 s.

[0076] 4) Drying: The prepared soft material was placed in a fluidized bed, and the drying temperature was set to 60°C, with a moisture content of less than 2%.

[0077] 5) Granulation: Granulation was performed using a rapid granulator (frequency 200.5 Hz, screen 1.0 mm).

[0078] 6) Total mixing: Hydrogenated castor oil was added.

[0079] 7) Compression: Compression was performed according to the theoretical tablet weight, and the compression parameters were recorded, hardness 70-90 N.

[0080] 8) Coating: The coating liquid concentration was 13%, the coating temperature was 60°C, and the coating weight gain was 2%-4%.

[0081] Example 4

[0082] Prescription amount: see Table 4.

[0083] Table 4 Prescription amount of Example 4

[0084]

[0085] Preparation process:

[0086] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, crosslinked polyvinylpyrrolidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0087] 2) Liquid addition: The stirring parameter is 150 rpm, the shearing parameter is 1000 rpm, and the wetting agent is water.

[0088] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0089] 4) Drying: Place the prepared soft material in a fluidized bed, set the drying temperature to 60°C, and the moisture content to less than 2%.

[0090] 5) Granulation: Use a rapid granulator for granulation (frequency 200.5 Hz, screen 1.0 mm).

[0091] 6) Total mixing: Add hydrogenated castor oil.

[0092] 7) Tabletting: Tablet according to the theoretical tablet weight, and record the tabletting parameters. The hardness is 70-90 N.

[0093] 8) Coating: The coating liquid concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0094] Example 5

[0095] Prescription amount: see Table 5.

[0096] Table 5 Prescription amount of Example 5

[0097]

[0098] Preparation process:

[0099] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, crosslinked polyvinylpyrrolidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0100] 2) Liquid addition: The stirring parameter is 150 rpm, the shearing parameter is 1000 rpm, and the wetting agent is water.

[0101] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0102] 4) Drying: Place the prepared soft material in a fluidized bed, set the drying temperature to 60°C, and the moisture content to less than 2%.

[0103] 5) Granulation: Granulation was performed using a rapid granulator (frequency 200.5 Hz, screen 1.0 mm).

[0104] 6) Total mixing: Hydrogenated castor oil was added.

[0105] 7) Compression: Compression was performed according to the theoretical tablet weight, and the compression parameters were recorded, with hardness of 70-90 N.

[0106] 8) Coating: The coating liquid concentration was 13%, the coating temperature was 60°C, and the coating weight gain was 2%-4%.

[0107] Example 6

[0108] Prescription amount: see Table 6.

[0109] Table 6 Prescription amount of Example 6

[0110]

[0111] Preparation process:

[0112] 1) Premixing: Lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and cross-linked povidone were sequentially added to a wet granulator. The stirring speed was 150 rpm, the cutting speed was 1000 rpm, and the mixing time was 300 s.

[0113] 2) Liquid addition: The stirring parameters were 150 rpm, the shearing parameters were 1000 rpm, and the wetting agent was water.

[0114] 3) Granulation: The stirring speed was 150 rpm, the cutting speed was 1000 rpm, and the time was 180 s.

[0115] 4) Drying: The prepared soft material was placed in a fluidized bed, and the drying temperature was set to 60°C, with a moisture content of less than 2%.

[0116] 5) Granulation: Granulation was performed using a rapid granulator (frequency 200.5 Hz, screen 1.0 mm).

[0117] 6) Total mixing: Hydrogenated castor oil was added.

[0118] 7) Compression: Compression was performed according to the theoretical tablet weight, and the compression parameters were recorded, with hardness of 70-90 N.

[0119] 8) Coating: The coating liquid concentration was 13%, the coating temperature was 60°C, and the coating weight gain was 2%-4%.

[0120] Example 7

[0121] Prescription amount: see Table 7.

[0122] Table 7 Prescription amount of Example 7

[0123]

[0124]

[0125] Preparation process:

[0126] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, cross-linked povidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0127] 2) Liquid addition: The stirring parameters are 150 rpm, the shearing parameters are 1000 rpm, and the wetting agent is water.

[0128] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0129] 4) Drying: Place the prepared soft material in a fluidized bed, set the drying temperature to 60°C, and the moisture content to less than 2%.

[0130] 5) Granulation: Use a rapid granulator for granulation (frequency 200.5 Hz, screen 1.0 mm).

[0131] 6) Total mixing: Add hydrogenated castor oil.

[0132] 7) Tabletting: Tablet according to the theoretical tablet weight, and record the tabletting parameters. The hardness is 70-90 N.

[0133] 8) Coating: The coating liquid concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0134] Comparative Example 1

[0135] Prescription amount: see Table 8.

[0136] Table 8 Prescription amount of Comparative Example 1

[0137]

[0138]

[0139] Preparation process:

[0140] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, cross-linked povidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0141] 2) Liquid addition: The stirring parameters are 150 rpm, the shearing parameters are 1000 rpm, and the wetting agent is water.

[0142] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0143] 4) Drying: the prepared soft material is placed in a fluidized bed, and the drying temperature is set to 60°C, and the moisture is less than 2%.

[0144] 5) Granulation: the fast granulator is used for granulation (frequency 200.5 Hz, screen 1.0 mm).

[0145] 6) Total mixing: hydrogenated castor oil is added.

[0146] 7) Tabletting: tabletting is performed according to the theoretical tablet weight, and the tabletting parameters are recorded, and the hardness is 70-90 N.

[0147] 8) Coating: the coating liquid concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0148] Comparative Example 2

[0149] Prescription amount: see Table 9.

[0150] Table 9 Prescription amount of Comparative Example 2

[0151]

[0152]

[0153] Preparation process:

[0154] 1) Premixing: lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and cross-linked polyvinylpyrrolidone are sequentially added to a wet granulator. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0155] 2) Liquid addition: stirring parameters 150 rpm, shearing parameters 1000 rpm, and wetting agent is water.

[0156] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0157] 4) Drying: the prepared soft material is placed in a fluidized bed, and the drying temperature is set to 60°C, and the moisture is less than 2%.

[0158] 5) Granulation: the fast granulator is used for granulation (frequency 200.5 Hz, screen 1.0 mm).

[0159] 6) Total mixing: hydrogenated castor oil is added.

[0160] 7) Tabletting: tabletting is performed according to the theoretical tablet weight, and the tabletting parameters are recorded, and the hardness is 70-90 N.

[0161] 8) Coating: Coating liquid concentration is 13%, coating temperature is 60°C, coating weight gain is 2%-4%.

[0162] Comparative Example 3

[0163] Prescription amount: see Table 10.

[0164] Table 10 Prescription amount of Comparative Example 3

[0165]

[0166]

[0167] Preparation process:

[0168] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, cross-linked povidone, and add them into the wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0169] 2) Liquid addition: The stirring parameter is 150 rpm, the shearing parameter is 1000 rpm, and the wetting agent is water.

[0170] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0171] 4) Drying: Place the prepared soft material in the fluidized bed, set the drying temperature to 60°C, and the moisture content is less than 2%.

[0172] 5) Granulation: Use the rapid granulator for granulation (frequency 200.5 Hz, screen 1.0 mm).

[0173] 6) Total mixing: Add hydrogenated castor oil.

[0174] 7) Tabletting: Tablet according to the theoretical tablet weight, and record the tabletting parameters. The hardness is 70-90 N.

[0175] 8) Coating: Coating liquid concentration is 13%, coating temperature is 60°C, coating weight gain is 2%-4%.

[0176] Comparative Example 4

[0177] Prescription amount: see Table 11.

[0178] Table 11 Prescription amount of Comparative Example 4

[0179]

[0180]

[0181] Preparation process:

[0182] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, cross-linked povidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0183] 2) Liquid addition: The stirring parameters are 150 rpm, the shearing parameters are 1000 rpm, and the wetting agent is water.

[0184] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0185] 4) Drying: The prepared soft material is placed in a fluidized bed, and the drying temperature is set to 60°C, with a moisture content of less than 2%.

[0186] 5) Granulation: The granulation is performed using a rapid granulator (frequency 200.5 Hz, screen 1.0 mm).

[0187] 6) Total mixing: Hydrogenated castor oil is added.

[0188] 7) Tabletting: The tablets are pressed according to the theoretical tablet weight, and the tabletting parameters are recorded, with a hardness of 70-90 N.

[0189] 8) Coating: The coating liquid concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0190] Comparative Example 5

[0191] Prescription amount: See Table 12.

[0192] Table 12 Prescription amount of Comparative Example 5

[0193]

[0194] Preparation process:

[0195] 1) Premix: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, cross-linked povidone, and add them into a wet granulator in turn. The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the mixing time is 300 s.

[0196] 2) Liquid addition: The stirring parameters are 150 rpm, the shearing parameters are 1000 rpm, and the wetting agent is water.

[0197] 3) Granulation: The stirring speed is 150 rpm, the cutting speed is 1000 rpm, and the time is 180 s.

[0198] 4) Drying: The prepared soft material is placed in a fluidized bed, and the drying temperature is set to 60°C, with a moisture content of less than 2%.

[0199] 5) Granulation: The granulation is performed using a rapid granulator (frequency 200.5 Hz, screen 1.0 mm).

[0200] 6) Total mixing: Hydrogenated castor oil was added.

[0201] 7) Compression: Compression was performed according to the theoretical tablet weight, and the compression parameters were recorded, with hardness of 70-90 N.

[0202] 8) Coating: The coating liquid concentration was 13%, the coating temperature was 60°C, and the coating weight gain was 2%-4%.

[0203] Comparative Example 6

[0204] Prescription amount: see Table 13.

[0205] Table 13 Prescription amount of Comparative Example 6

[0206]

[0207] Preparation process:

[0208] 1) Premixing: Lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and cross-linked polyvidone were sequentially added to a wet granulator. The stirring speed was 150 rpm, the cutting speed was 1000 rpm, and the mixing time was 300 s.

[0209] 2) Liquid addition: The stirring speed was 150 rpm, the shearing speed was 1000 rpm, and the wetting agent was water.

[0210] 3) Granulation: The stirring speed was 150 rpm, the cutting speed was 1000 rpm, and the time was 180 s.

[0211] 4) Drying: The prepared soft material was placed in a fluidized bed, and the drying temperature was set to 60°C, with a moisture content of less than 2%.

[0212] 5) Granulation: A rapid granulator was used for granulation (frequency 200.5 Hz, screen 1.0 mm).

[0213] 6) Total mixing: Hydrogenated castor oil was added.

[0214] 7) Compression: Compression was performed according to the theoretical tablet weight, and the compression parameters were recorded, with hardness of 70-90 N.

[0215] 8) Coating: The coating liquid concentration was 13%, the coating temperature was 60°C, and the coating weight gain was 2%-4%.

[0216] A list of variable parameters in Examples 1-7 and Comparative Examples 1-6 is shown in Table 14.

[0217] Table 14 List of variable parameters in Examples 1-7 and Comparative Examples 1-6

[0218]

[0219]

[0220] The dissolution performance of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 was investigated.

[0221] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0931 Second Method), water, 0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer were used as the dissolution medium, the rotation speed was 100 rpm, and the sample was taken at 5 min, 10 min, 15 min, 20 min, and 30 min according to the operation. The dissolution data of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 and the reference reagent (trade name: Lotensin Hct) were detected, and the results are shown in Table 15.

[0222] Table 15 Dissolution data of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 and the reference reagent (trade name: Lotensin Hct)

[0223]

[0224]

[0225]

[0226]

[0227] From Table 15, the following conclusions can be drawn:

[0228] Comparing Example 1-3 with Comparative Example 1-2, the dissolution of Example 1-3 in different media is good, and the dissolution at 20 min is ≧95%. The dissolution of Comparative Example 1-2 in different media is still ≦95% at 30 min. It can be seen that the dissolution performance of Example 1-3 in each medium is better than that of Comparative Example 1-2 in the same medium. Therefore, under the condition that other conditions are the same, when the use amount of diluent and disintegrant is 78-82% and 6-11% respectively, the dissolution performance of the prepared benazepril hydrochlorothiazide tablets is better.

[0229] Comparative Example 1, 4, 5 and Comparative Example 3-4, the dissolution of Examples 1, 4, 5 in different media are good, the dissolution at 20 min has been = 95%; Comparative Example 3-4 in different media, the dissolution at 30 min, still = 95%. It can be seen that the dissolution performance of Examples 1, 4, 5 in each medium is better than that of Comparative Example 3-4 in the same medium. Therefore, under the condition that other conditions are the same, the dissolution performance of the prepared benazepril hydrochlorothiazide tablets is better when the amount ratio of lactose and microcrystalline fiber is (10-13): 1.5.

[0230] Comparative Example 1, 6, 7 and Comparative Example 5, 6, Examples 1, 6, 7 in different media are good, the dissolution at 20 min has been = 95%; Comparative Example 5, 6 in different media, the dissolution at 30 min, still = 95%. It can be seen that the dissolution performance of Examples 1, 6, 7 in each medium is better than that of Comparative Example 3-4 in the same medium. Therefore, under the condition that other conditions are the same, the dissolution performance of the prepared benazepril hydrochlorothiazide tablets is better when the amount ratio of lactose and microcrystalline fiber is 12: (1-3).

[0231] The stability of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 was investigated.

[0232] The samples of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 were placed at 30℃±2℃, RH 65%±5% for 3 months and 6 months respectively, and at 40℃±2℃, RH 75%±5% for 3 months and 6 months respectively, and the content of related substances was detected. The related substances include related substances hydrochlorothiazide (impurity B, chlorothiazide, impurity C), related substances benazepril hydrochloride (impurity C, impurity F, impurity B, impurity D, impurity G). The known impurity information is shown in Table 16.

[0233] Table 16 Impurity information

[0234]

[0235]

[0236]

[0237] The detection data is shown in Table 17.

[0238] Table 17 The stability of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 was investigated.

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247] From Comparative Examples 1-3 and Comparative Example 1-2, it can be seen that after 3 months and 6 months of high temperature and high humidity accelerated test, the active ingredient content of Example 1-3 is still stable, and the impurity content changes little; after 3 months and 6 months of high temperature and high humidity accelerated test, the active ingredient content and the impurity content of Comparative Example 1-2 change greatly. Therefore, under the condition that other conditions are the same, when the amount of diluent and disintegrant is 78-82%, 6-11% respectively, the stability of the prepared benazepril hydrochlorothiazide tablets is better.

[0248] From Comparative Examples 1, 4, 5 and Comparative Examples 3-4, it can be seen that after 3 months and 6 months of high temperature and high humidity accelerated test, the active ingredient content of Examples 1, 4, 5 is still stable, and the impurity content changes little; after 3 months and 6 months of high temperature and high humidity accelerated test, the active ingredient content and the impurity content of Comparative Examples 3-4 change greatly. Therefore, under the condition that other conditions are the same, therefore, under the condition that other conditions are the same, when the amount of lactose and microcrystalline cellulose is (10-13): 1.5, the stability of the prepared benazepril hydrochlorothiazide tablets is better.

[0249] From Comparative Examples 1, 6, 7 and Comparative Examples 5, 6, it can be seen that after 3 months and 6 months of high temperature and high humidity accelerated test, the active ingredient content of Examples 1, 6, 7 is still stable, and the impurity content changes little; after 3 months and 6 months of high temperature and high humidity accelerated test, the active ingredient content and the impurity content of Comparative Examples 5, 6 change greatly. Therefore, under the condition that other conditions are the same, therefore, under the condition that other conditions are the same, when the amount of lactose and microcrystalline cellulose is 12: (1-3), the stability of the prepared benazepril hydrochlorothiazide tablets is better.

[0250] It can be understood that the above embodiments are only exemplary embodiments adopted for illustrating the principles of the present application, and the present application is not limited thereto. Various modifications and improvements can be made by those skilled in the art without departing from the spirit and essence of the present application, and these modifications and improvements are also considered as the protection scope of the present application.

Claims

1. A compound preparation for treating hypertension, characterized in that, By weight percentage, it includes: 4.0% benazepril hydrochloride, 5.0% hydrochlorothiazide, 78-82% diluent, 6-11% disintegrant, 2-3% lubricant and coating material; The diluent is lactose and microcrystalline cellulose, and the ratio of lactose to microcrystalline cellulose is (10-13):(1-2). The disintegrant is crospovidone; The lubricant is hydrogenated castor oil.

2. The antihypertensive compound preparation according to claim 1, characterized in that, By weight percentage, it includes: 4.0% benazepril hydrochloride, 5.0% hydrochlorothiazide, 80% diluent, 8.6% disintegrant, 2.4% lubricant and coating material.

3. The antihypertensive compound preparation according to claim 2, characterized in that, The diluent comprises 71.1% lactose and 8.9% microcrystalline cellulose.

4. The antihypertensive compound preparation according to claim 1, characterized in that, Benazepril D hydrochloride 90 <70μm.

5. The antihypertensive compound preparation according to claim 1, characterized in that, The hydrochlorothiazide D 90 <70μm.

6. The method for preparing the antihypertensive compound preparation according to any one of claims 1 to 5, characterized in that, The method includes the following steps: 1) Weigh out the prescribed amount of raw and auxiliary materials and premix; set the stirring speed to 120-200 rpm, the cutting speed to 800-1200 rpm, and mix for 200-400 seconds; 2) Add liquid: Add water to moisten, stirring parameters 120-180 rpm, shearing parameters 800-1200 rpm; 3) Granulation: Stirring speed 120-180 rpm, shearing parameter 800-1200 rpm, time 150-200 s; 4) Drying: Place the prepared soft material in a fluidized bed and set the drying temperature to 50-80℃, with a moisture content of less than 2%; 5) Granulation: Use a high-speed granulator for granulation, setting the frequency to 180-240Hz and the screen size to 1mm; 6) Final mixing: Add lubricant; 7) Tableting: Compress tablets according to the theoretical tablet weight and record the tableting parameters. Hardness: 70~90N; 8) Coating: The coating solution concentration is 13%, the coating temperature is 60℃, and the coating weight gain is 2%-4%.

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