Anti-hypertension compound preparation and preparation method thereof

Abstract

The invention discloses an anti-hypertension compound preparation which comprises the following components in percentage by weight: 4.0% of benazepril hydrochloride, 5.0% of hydrochlorothiazide, 78-82% of a diluent, 6-11% of a disintegrating agent, 2-3% of a lubricant and a coating material. Wherein the diluent is selected from one or more of lactose and microcrystalline cellulose, the dosage ratio of lactose to microcrystalline cellulose is (10-13): (1-2), the disintegrating agent is polyvinylpolypyrrolidone, the lubricant is hydrogenated castor oil, and the particle sizes D90 of benazepril hydrochloride and hydrochlorothiazide are less than 70 microns. The benazepril and hydrochlorothiazide tablet provided by the invention has good stability and dissolution performance.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and specifically relates to an antihypertensive compound preparation and a preparation method thereof. Background Art

[0002] An antihypertensive compound preparation, Benazepril Hydrochlorothiazide Tablets, is a compound antihypertensive drug composed of two active ingredients, benazepril and hydrochlorothiazide. Benazepril is an angiotensin converting enzyme inhibitor (ACEI), which inhibits the activity of angiotensin converting enzyme and prevents the conversion of angiotensin I to angiotensin II, thereby dilating blood vessels and lowering blood pressure. Hydrochlorothiazide is a thiazide diuretic, which mainly inhibits the reabsorption of sodium and water by the renal tubules, increases urine excretion, and thus reduces blood volume to achieve a hypotensive effect. Hydrochlorothiazide further enhances the hypotensive effect of benazepril by stimulating the activity of the renin-angiotensin system. As a compound preparation, the research and development of Benazepril Hydrochlorothiazide Tablets aims to improve the hypotensive effect and reduce adverse reactions through the synergistic effect of the two ingredients. It has a clear hypotensive effect and certain clinical application value.

[0003] In the prior art, there are few public literatures on the research of benazepril hydrochlorothiazide tablets. The benazepril hydrochlorothiazide tablets currently on the market are chemically unstable in high temperature and high humidity environments, with a decreased content of active ingredients and an increased amount of impurities. Therefore, how to improve the stability of benazepril hydrochlorothiazide tablets in high temperature and high humidity environments while ensuring good dissolution performance is still a problem that needs to be explored. Summary of the invention

[0004] The present application provides an antihypertensive compound preparation having good stability and dissolution performance.

[0005] The 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.

[0006] In one embodiment of the present invention, the diluent may be one or more of lactose and microcrystalline cellulose.

[0007] In one embodiment of the present invention, the disintegrant is crospovidone.

[0008] In one embodiment of the present invention, the ratio of lactose to microcrystalline cellulose is (10-13): (1-2).

[0009] In one embodiment of the present invention, the benazepril hydrochlorothiazide tablets include, by weight percentage: 4.0% benazepril hydrochloride, 5.0% hydrochlorothiazide, 80% diluent, 8.6% disintegrant, 2.4% lubricant and coating material.

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

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

[0012] In one embodiment of the present invention, the particle size D90 of benazepril hydrochloride is less than 70 μm.

[0013] In one embodiment of the present invention, hydrochlorothiazide D90 is less than 70 μm.

[0014] The present invention also provides a method for preparing an antihypertensive compound preparation, comprising the following steps:

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

[0016] 2) Add liquid: Add water to moisten, stirring parameter 120-180rpm, shear parameter 800-1200rpm.

[0017] 3) Granulation: stirring speed 120-180 rpm, shear parameter 800-1200 rpm, time 150-200 s.

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

[0019] 5) Granulation: Use a fast granulator for granulation, set the frequency to 180-240 Hz and the screen to 1 mm.

[0020] 6) Total mixing: Add lubricant.

[0021] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0022] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0023] Beneficial effects:

[0024] Diluents are mainly used to increase the volume and weight of tablets to facilitate tableting. The pore structure formed by disintegrants in tablets is crucial for water penetration and drug dissolution. An appropriate disintegrant ratio can form sufficient pores, which is conducive to rapid water penetration and promotes the disintegration of tablets. Too much diluent may reduce this pore structure and affect the disintegration performance of tablets. The ratio of the two will directly affect the hardness and friability of the tablets, and then affect its disintegration speed and stability. After a large number of experiments, the inventors explored the appropriate ratio and the right type of diluent and disintegrant, and the dissolution and stability of the prepared benazepril hydrochlorothiazide tablets were significantly improved. DETAILED DESCRIPTION

[0028] 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 amount of disintegrant can be 6%, 6.6%, 8.6%, 10.6%, 11%; the amount of lubricant can be 2%, 2.4%, 3%.

[0029] Preferably, the diluent may be one or more of lactose and microcrystalline cellulose. It may be a combination of lactose and microcrystalline cellulose, wherein the ratio of lactose to microcrystalline cellulose is (10-13): (1-2). The ratio of lactose to microcrystalline cellulose may be 10:1.5, 12:1.5, 13:1.5, 12:1, or 12:3.

[0030] Preferably, the disintegrant is crospovidone.

[0031] Preferably, the benazepril hydrochlorothiazide tablets include, by weight percentage: 4.0% benazepril hydrochloride, 5.0% hydrochlorothiazide, 80% diluent, 8.6% disintegrant, 2.4% lubricant and coating material. The diluent includes 71.1% lactose and 8.9% microcrystalline cellulose.

[0032] Preferably, the lubricant is hydrogenated castor oil.

[0033] Preferably, the particle size D90 of benazepril hydrochloride is less than 70 μm.

[0034] Preferably, hydrochlorothiazide D90 < 70 μm.

[0035] The preparation method of benazepril hydrochlorothiazide tablets comprises the following steps:

[0036] 1) Weigh the prescribed amount of raw materials and premix: set the stirring speed to 120-200rpm, the cutting speed to 800-1200rpm, and mix for 200-400s. The stirring speed can be set to 120rpm, 150rpm, 180rpm, 200rpm; the cutting speed can be 800rpm, 1000rpm, 1200rpm; the mixing time can be 200s, 300s, 400s.

[0037] 2) Add liquid: add water to moisten, stirring parameter 120-180rpm, shear parameter 800-1200rpm. The stirring parameter can be 120rpm, 150rpm, 180rpm; the shear parameter can be 800rpm, 1000rpm, 1200rpm.

[0038] 3) Granulation: stirring speed 120-180rpm, shearing speed 800-1200rpm, time 150-200s. The stirring speed can be 120rpm, 150rpm, 180rpm; the shearing speed can be 800rpm, 1000rpm, 1200rpm; the time can be 150, 180, 200s.

[0039] 4) Drying: Place the prepared soft material in a fluidized bed, set the drying temperature to 50-80°C, and the moisture content to less than 2%. The drying temperature can be 50°C, 65°C, or 80°C.

[0040] 5) Granulation: Use a fast granulator for granulation, set the frequency to 180-240Hz, and the screen to 1mm. The frequency can be 180Hz, 200Hz, 220Hz, 240Hz.

[0041] 6) Total mixing: Add lubricant.

[0042] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70-90N, hardness 70N, 80N, 90N.

[0043] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0044] The benazepril hydrochlorothiazide tablets prepared by the invention have good stability and dissolution performance.

[0045] Example 1

[0046] Prescription quantity: See Table 1.

[0047] Table 1 Example 1 Prescription

[0048]

[0049] Preparation process:

[0050] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone, and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0051] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0052] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0053] 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%.

[0054] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0055] 6) Total mixing: Add hydrogenated castor oil.

[0056] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0057] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0058] Example 2

[0059] Prescription quantity: See Table 2.

[0060] Table 2 Example 2 Prescription

[0061]

[0062] Preparation process:

[0063] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0064] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0065] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0066] 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%.

[0067] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0068] 6) Total mixing: Add hydrogenated castor oil.

[0069] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0070] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0071] Example 3

[0072] Prescription quantity: See Table 3.

[0073] Table 3 Example 3 Prescription

[0074]

[0075] Preparation process:

[0076] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0077] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0078] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0079] 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%.

[0080] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0081] 6) Total mixing: Add hydrogenated castor oil.

[0082] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0083] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0084] Example 4

[0085] Prescription quantity: See Table 4.

[0086] Table 4 Example 4 Prescription

[0087]

[0088] Preparation process:

[0089] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0090] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0091] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0092] 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%.

[0093] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0094] 6) Total mixing: Add hydrogenated castor oil.

[0095] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0096] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0097] Example 5

[0098] Prescription quantity: See Table 5.

[0099] Table 5 Example 5 Prescription

[0100]

[0101] Preparation process:

[0102] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0103] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0104] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0105] 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%.

[0106] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0107] 6) Total mixing: Add hydrogenated castor oil.

[0108] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0109] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0110] Example 6

[0111] Prescription dosage: See Table 6.

[0112] Table 6 Example 6 Prescription

[0113]

[0114] Preparation process:

[0115] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0116] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0117] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0118] 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%.

[0119] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0120] 6) Total mixing: Add hydrogenated castor oil.

[0121] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0122] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0123] Example 7

[0124] Prescription quantity: See Table 7.

[0125] Table 7 Example 7 Prescription Quantity

[0126]

[0127]

[0128] Preparation process:

[0129] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0130] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0131] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0132] 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%.

[0133] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0134] 6) Total mixing: Add hydrogenated castor oil.

[0135] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0136] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0137] Comparative Example 1

[0138] Prescription dosage: See Table 8.

[0139] Table 8 Prescription amount of comparative example 1

[0140]

[0141]

[0142] Preparation process:

[0143] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0144] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0145] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0146] 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%.

[0147] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0148] 6) Total mixing: Add hydrogenated castor oil.

[0149] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0150] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0151] Comparative Example 2

[0152] Prescription dosage: See Table 9.

[0153] Table 9 Comparative Example 2 Prescription

[0154]

[0155]

[0156] Preparation process:

[0157] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0158] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0159] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0160] 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%.

[0161] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0162] 6) Total mixing: Add hydrogenated castor oil.

[0163] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0164] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0165] Comparative Example 3

[0166] Prescription dosage: See Table 10.

[0167] Table 10 Prescription amount of comparative example 3

[0168]

[0169]

[0170] Preparation process:

[0171] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0172] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0173] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0174] 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%.

[0175] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0176] 6) Total mixing: Add hydrogenated castor oil.

[0177] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0178] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0179] Comparative Example 4

[0180] Prescription quantity: See Table 11.

[0181] Table 11 Comparative Example 4 Prescription Quantity

[0182]

[0183]

[0184] Preparation process:

[0185] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0186] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0187] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0188] 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%.

[0189] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0190] 6) Total mixing: Add hydrogenated castor oil.

[0191] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0192] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0193] Comparative Example 5

[0194] Prescription dosage: See Table 12.

[0195] Table 12 Prescription amount of comparative example 5

[0196]

[0197] Preparation process:

[0198] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0199] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0200] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0201] 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%.

[0202] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0203] 6) Total mixing: Add hydrogenated castor oil.

[0204] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0205] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0206] Comparative Example 6

[0207] Prescription dosage: See Table 13.

[0208] Table 13 Prescription amount of comparative example 6

[0209]

[0210] Preparation process:

[0211] 1) Premixing: Take lactose, microcrystalline cellulose, hydrochlorothiazide, benazepril hydrochloride, and crospovidone and add them into a wet granulator in sequence. Stir at a speed of 150 rpm, a cutting speed of 1000 rpm, and mix for 300 seconds.

[0212] 2) Adding liquid: stirring parameter 150 rpm, shear parameter 1000 rpm, wetting agent is water.

[0213] 3) Granulation: stirring speed 150 rpm, cutting speed 1000 rpm, time 180 s.

[0214] 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%.

[0215] 5) Granulation: Granulation was performed using a fast granulator (frequency 200.5 Hz, screen size 1.0 mm).

[0216] 6) Total mixing: Add hydrogenated castor oil.

[0217] 7) Tablet pressing: Tablet according to theoretical tablet weight and record tablet pressing parameters, hardness 70~90N.

[0218] 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

[0219] See Table 14 for a list of the variable parameters in Examples 1-7 and Comparative Examples 1-6.

[0220] Table 14 List of variable parameters in Examples 1-7 and Comparative Examples 1-6

[0221]

[0222]

[0223] The dissolution properties of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 were investigated.

[0224] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2), water, 0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer were used as dissolution media, respectively, at a speed of 100 rpm. The operation was carried out in accordance with the law, and samples were taken at 5 min, 10 min, 15 min, 20 min, and 30 min, respectively. 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 tested. The results are shown in Table 15.

[0225] Table 15 Dissolution data of benazepril hydrochlorothiazide tablets and reference reagent (trade name: Lotensin Hct) prepared in Examples 1-7 and Comparative Examples 1-6

[0226]

[0227]

[0228]

[0229]

[0230] By observing Table 15, we can draw the following conclusions:

[0231] Comparing Example 1-3 with Comparative Example 1-2, the dissolution of Example 1-3 in different media is good, and the dissolution is ≧95% at 20 minutes, while the dissolution of Comparative Example 1-2 in different media is still ≦95% at 30 minutes. It can be seen that the dissolution performance of Example 1-3 in various media is better than the dissolution performance of Comparative Example 1-2 in the same medium. Therefore, under the same other conditions, when the usage of diluent and disintegrant is 78-82% and 6-11% respectively, the dissolution performance of the prepared benazepril hydrochlorothiazide tablets is better.

[0232] Comparing Examples 1, 4, 5 and Comparative Examples 3-4, the dissolution of Examples 1, 4, 5 in different media is good, and the dissolution is ≧95% at 20 minutes; the dissolution of Comparative Example 3-4 in different media is still ≦95% at 30 minutes. It can be seen that the dissolution performance of Examples 1, 4, 5 in each medium is better than the dissolution performance of Comparative Example 3-4 in the same medium. Therefore, under the same other conditions, when the dosage ratio of lactose and microcrystalline cellulose is (10-13): 1.5, the dissolution performance of the prepared benazepril hydrochlorothiazide tablets is better.

[0233] Comparing Examples 1, 6, 7 with Comparative Examples 5, 6, the dissolution rates of Examples 1, 6, 7 in different media are all good, and the dissolution rates are ≧95% at 20 minutes; the dissolution rates of Comparative Examples 5, 6 in different media are still ≦95% at 30 minutes. It can be seen that the dissolution performance of Examples 1, 6, 7 in various media is better than the dissolution performance of Comparative Examples 3-4 in the same medium. Therefore, under the same other conditions, when the dosage ratio of lactose and microcrystalline cellulose is 12: (1-3), the dissolution performance of the prepared benazepril hydrochlorothiazide tablets is better.

[0234] The stability of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6 was investigated.

[0235] Take samples of benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6, place them at 30°C ± 2°C, RH 65% ± 5% for 3 months and 6 months, and place them at 40°C ± 2°C, RH 75% ± 5% for 3 months and 6 months, respectively, and detect the content of related substances, including related substances hydrochlorothiazide (impurity B, chlorothiazide, impurity C), related substances benazepril hydrochloride (impurity C, impurity F, impurity B, impurity D, impurity G). Known impurity information is shown in Table 16.

[0236] Table 16 Impurity information

[0237]

[0238]

[0239]

[0240] The test data are shown in Table 17.

[0241] Table 17 investigates the stability of the benazepril hydrochlorothiazide tablets prepared in Examples 1-7 and Comparative Examples 1-6.

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] Comparing Examples 1-3 with Comparative Examples 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 Examples 1-3 is still stable and the impurity content does not change much; after 3 months and 6 months of high temperature and high humidity accelerated test, the active ingredient content and impurity content of Comparative Examples 1-2 change greatly. Therefore, under the same other conditions, when the diluent and disintegrant are used in amounts of 78-82% and 6-11%, respectively, the stability of the prepared benazepril hydrochlorothiazide tablets is better.

[0251] Comparing 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 in Examples 1, 4, 5, the active ingredient content is still stable and the impurity content does not change much; after 3 months and 6 months of high temperature and high humidity accelerated test in Comparative Examples 3-4, the active ingredient content and impurity content change greatly. Therefore, under the same conditions, when the dosage ratio of lactose and microcrystalline cellulose is (10-13): 1.5, the stability of the prepared benazepril hydrochlorothiazide tablets is better.

[0252] Comparing Examples 1, 6, and 7 with Comparative Examples 5 and 6, it can be seen that after 3 months and 6 months of high temperature and high humidity accelerated test in Examples 1, 6, and 7, the active ingredient content is still stable and the impurity content does not change much; after 3 months and 6 months of high temperature and high humidity accelerated test in Comparative Examples 5 and 6, the active ingredient content and impurity content change greatly. Therefore, under the same conditions, when the ratio of lactose to microcrystalline cellulose is 12: (1-3), the stability of the prepared benazepril hydrochlorothiazide tablets is better.

[0253] It is to be understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of the present application, but the present application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and essence of the present application, and these modifications and improvements are also considered to be within the scope of protection of the present invention.

Claims

1. An antihypertensive compound preparation, characterized in that: The invention comprises, by weight percentage, 4.0% of benazepril hydrochloride, 5.0% of hydrochlorothiazide, 78-82% of diluent, 6-11% of disintegrant, and 2-3% of lubricant and coating material.

2. An antihypertensive compound preparation according to claim 1, characterized in that: The diluent may be one or more of lactose and microcrystalline cellulose.

3. An antihypertensive compound preparation according to claim 1, characterized in that: The disintegrant is cross-linked polyvinylpyrrolidone.

4. An antihypertensive compound preparation according to claim 2, characterized in that: The dosage ratio of lactose to microcrystalline cellulose is (10-13): (1-2).

5. An antihypertensive compound preparation according to claim 1, characterized in that: The invention comprises, by weight percentage, 4.0% of benazepril hydrochloride, 5.0% of hydrochlorothiazide, 80% of diluent, 8.6% of disintegrant, and 2.4% of lubricant and coating material.

6. An antihypertensive compound preparation according to claim 5, characterized in that: The diluent included 71.1% lactose and 8.9% microcrystalline cellulose.

7. An antihypertensive compound preparation according to claim 5, characterized in that: The lubricant is hydrogenated castor oil.

8. An antihypertensive compound preparation according to claim 1, characterized in that: Benazepril hydrochloride D 90 <70μm.

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

10. The method for preparing the antihypertensive compound preparation according to any one of claims 1 to 9, characterized in that: The method comprises the following steps: 1) Weigh the prescribed amount of raw 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 parameter 120-180rpm, shear parameter 800-1200rpm; 3) Granulation: stirring speed 120-180 rpm, shear parameter 800-1200 rpm, time 150-200 s; 4) Drying: Place the prepared soft material in a fluidized bed, set the drying temperature to 50-80°C, and the moisture content to less than 2%; 5) Granulation: Use a fast granulator for granulation, set the frequency to 180-240Hz and the screen to 1mm; 6) Total mixing: adding lubricant; 7) Tabletting: Tablet according to theoretical tablet weight and record tableting parameters, hardness 70-90N; 8) Coating: The coating solution concentration is 13%, the coating temperature is 60°C, and the coating weight gain is 2%-4%.

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