A medicine for treating hypertension and its preparation method

Abstract

The present invention discloses a drug for treating hypertension and a preparation method thereof. The drug for treating hypertension is made of the following components in parts by mass: 100.00 parts of irbesartan; 25-32 parts of mannitol; 20-25 parts of microcrystalline cellulose; 5-10 parts of disintegrant; 3-5 parts of binder; 6.93-13.86 parts of amlodipine, calculated as amlodipine besylate; 1.5-2.5 parts of lubricant; 5-7.5 parts of Opadry film coating premix. The preparation method of the drug for treating hypertension of the present invention mainly includes the following steps: pretreatment of raw materials and auxiliary materials, premixing, granulation, drying, total mixing, tableting, and coating, that is, obtaining the drug for treating hypertension. The bioavailability of the antihypertensive drug of the present invention is improved; and the stability of the drug is improved to further improve the bioavailability.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and preparation processes, and relates to a medicine for treating hypertension and a preparation method thereof. Background Art

[0002] Irbesartan and Amlodipine Tablets is a compound preparation, including two raw materials, irbesartan and amlodipine, wherein amlodipine is fed in the form of benzenesulfonate. The main physical and chemical parameters of irbesartan are as follows: 25 H 28 N6O, structural formula as shown in formula I, molecular weight 428.53, solubility: easily soluble in acetic acid, slightly soluble in methanol or ethanol, insoluble in water; stability: stable for 60 months in a double-layer polyethylene bag at 25°C and 60% humidity; hygroscopicity: non-hygroscopic. The main physical and chemical parameters of amlodipine besylate are as follows, chemical formula: C 20 H 25 C l N2O5·C6H6O3S, the structural formula is shown in Formula II, the molecular weight is 567.05, and the appearance is white or off-white powder; solubility: easily soluble in methanol, slightly soluble in ethanol and water; stability: stable for 36 months in a polyethylene bag at room temperature (13-29°C); hygroscopicity: non-hygroscopic.

[0003]

[0004] Irbesartan amlodipine tablets were developed by Dainippon Sumitomo Pharma Co., Ltd. and are used as a drug for the treatment of hypertension. They were launched in Japan on September 28, 2012 under the trade name "Aimix" with specifications of "100 mg of irbesartan, 5 mg of amlodipine" and "100 mg of irbesartan, 10 mg of amlodipine". Based on the fact that irbesartan is almost insoluble in water, irbesartan has a parabolic pH solubility distribution in pH buffered saline solution, has a minimum solubility between pH 2.0 and 6.0, and has a maximum solubility in 0.1N hydrochloric acid solution and pH 7.5 phosphate buffer. Irbesartan has a relatively low bulk density and tap density, and also has strong adhesion and is prone to electrostatic agglomeration. These properties of irbesartan make it difficult to prepare an effective dose of the drug into small tablets with uniform weight, hardness and other ideal tablet properties. However, the extremely low water solubility of irbesartan also makes it a challenge to prepare small tablets, because only limited excipients can be added to promote its wetting, disintegration and ultimate rapid release. Therefore, the preparation of tablets containing irbesartan to increase its water solubility and improve bioavailability has brought challenges to the selection of excipients and preparation process of tablets. Summary of the invention

[0005] The purpose of the present invention is to provide a drug for treating hypertension and a preparation method thereof. The present invention can improve the water solubility of irbesartan, thereby improving its bioavailability; and the present invention can improve the stability of the drug, thereby further improving the bioavailability.

[0006] The present invention provides a medicine for treating hypertension, comprising the following components in parts by weight:

[0007] Irbesartan 100.00 parts;

[0008] Mannitol 25-32 parts;

[0009] 20-25 parts of microcrystalline cellulose;

[0010] 5-10 parts of disintegrant;

[0011] 3-5 parts of adhesive;

[0012] Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts;

[0013] 1.5-2.5 parts of lubricant;

[0014] Opadry film coating premix 5-7.5 parts.

[0015] Among the above-mentioned medicines, the medicine for treating hypertension is made of the following components in parts by weight:

[0016] Irbesartan 100.00 parts;

[0017] Mannitol 25-32 parts;

[0018] 22-23 parts of microcrystalline cellulose;

[0019] 5.5-9 parts of disintegrant;

[0020] 3.5-4.5 parts of adhesive;

[0021] Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts;

[0022] 1.5-2.5 parts of lubricant;

[0023] Opadry film coating premix 5-7.5 parts.

[0024] Among the above-mentioned medicines, the medicine for treating hypertension further comprises the following components in parts by weight: 1 to 5 parts of hydroxypropyl-β-cyclodextrin.

[0025] In the above-mentioned medicine, the medicine for treating hypertension further comprises the following components in parts by weight: 0.5 to 2.5 parts of a solubilizer;

[0026] The solubilizing agent is selected from at least one of polyoxyethylene fatty acid esters, dioctyl sodium sulfosuccinate and dioctyl sodium sulfosuccinate.

[0027] In the above-mentioned medicine, the mass ratio of the microcrystalline cellulose added internally to the mass ratio of the microcrystalline cellulose added externally is 3 to 4.5:1;

[0028] The mass ratio of the mannitol added internally to that added externally is 3 to 5:1;

[0029] The ratio of the mass of the disintegrant added internally to that added externally is 1:1.

[0030] In the above-mentioned drug, the disintegrant is selected from cross-linked carboxymethyl cellulose sodium and / or cross-linked povidone XL-10;

[0031] The adhesive is polyvinyl alcohol;

[0032] The lubricant includes magnesium stearate and / or sodium stearyl fumarate;

[0033] The microcrystalline cellulose is MCC PH101 purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd.

[0034] In the above-mentioned medicine, the lubricant is magnesium stearate and sodium stearyl fumarate, and the mass ratio can be 1:0.1-10, specifically 1:1, 1:0.1-1, 1:1-5.

[0035] In the above-mentioned medicine, the mass ratio of the mannitol to the microcrystalline cellulose can be 0.9 to 1.3:1, preferably 1.1:1.

[0036] In the above-mentioned medicine, the medicine for treating hypertension is made of any one of the following components in parts by weight:

[0037] a) 100.00 parts of irbesartan;

[0038] Mannitol 25.07 parts;

[0039] 18.06 parts of microcrystalline cellulose;

[0040] 8.76 parts of disintegrant;

[0041] 3.5 parts of polyvinyl alcohol;

[0042] Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts;

[0043] 1.75 parts of lubricant;

[0044] 6 parts of Opadry film coating premix;

[0045] b) The drug for treating hypertension is made of the following components in parts by weight:

[0046] Irbesartan 100.00 parts;

[0047] Mannitol 32 parts;

[0048] 18.06 parts of microcrystalline cellulose;

[0049] 8.76 parts of disintegrant;

[0050] 3.5 parts of polyvinyl alcohol;

[0051] Amlodipine, calculated as amlodipine besylate, 13.86 parts;

[0052] 1.75 parts of lubricant;

[0053] 6 parts of Opadry film coating premix;

[0054] c) 100.00 parts of irbesartan;

[0055] Mannitol 25.07 parts;

[0056] 18.06 parts of microcrystalline cellulose;

[0057] 8.76 parts of disintegrant;

[0058] 3.5 parts of polyvinyl alcohol;

[0059] 4 parts of hydroxypropyl-β-cyclodextrin;

[0060] Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts;

[0061] 1.75 parts of lubricant; the lubricant may be magnesium stearate and sodium stearyl fumarate in a mass ratio of 1:1;

[0062] 6 parts of Opadry film coating premix;

[0063] d) The drug for treating hypertension is made of the following components in parts by weight:

[0064] Irbesartan 100.00 parts;

[0065] Mannitol 32 parts;

[0066] 18.06 parts of microcrystalline cellulose;

[0067] 8.76 parts of disintegrant;

[0068] 3.5 parts of polyvinyl alcohol;

[0069] 4 parts of hydroxypropyl-β-cyclodextrin;

[0070] Amlodipine, calculated as amlodipine besylate, 13.86 parts;

[0071] 1.75 parts of lubricant; the lubricant may be magnesium stearate and sodium stearyl fumarate in a mass ratio of 1:1;

[0072] 6 parts of Opadry film coating premix;

[0073] e) The drug for treating hypertension is made of the following components in parts by weight:

[0074] Irbesartan 100.00 parts;

[0075] Mannitol 32 parts;

[0076] 18.06 parts of microcrystalline cellulose;

[0077] 8.76 parts of disintegrant;

[0078] 3.5 parts of polyvinyl alcohol;

[0079] 3 parts of hydroxypropyl-β-cyclodextrin;

[0080] 1 part of the solubilizing agent;

[0081] Amlodipine, calculated as amlodipine besylate, 13.86 parts;

[0082] 1.75 parts of lubricant;

[0083] Opadry film coating premix 6 parts.

[0084] The present invention also provides a method for preparing the above-mentioned drug for treating hypertension, comprising the following steps:

[0085] 1) Pretreatment of raw materials and auxiliary materials

[0086] The irbesartan is crushed to a particle size of 17 μm, and the amlodipine is crushed to a particle size of 15 μm;

[0087] preparing an adhesive solution;

[0088] 2) Premix

[0089] Adding the irbesartan, the added microcrystalline cellulose, the mannitol, and the disintegrant into a wet granulator and mixing them to obtain a premix;

[0090] 3) Granulation

[0091] Adding the premix to the binder solution for granulation to obtain a core material;

[0092] 4) Drying

[0093] The core material is dried using a fluidized bed to obtain dry granules;

[0094] 5) Total Mixing

[0095] The amlodipine besylate, the microcrystalline cellulose, the mannitol, and the disintegrant are mixed three times through a 60-mesh sieve and then mixed with the dry granules, and then the lubricant is added and mixed to obtain a total mixed granule;

[0096] 6) Tablet pressing

[0097] Compress the total mixed granules into tablets according to a theoretical tablet weight of 175 mg and a tablet hardness of 130 to 160 N to obtain plain tablets;

[0098] 7) Coating

[0099] The Opadry film coating premix is ​​used to prepare a coating solution, and the plain tablets are coated with the coating solution to obtain the drug for treating hypertension.

[0100] In the above preparation method, in step 1), the mass percentage of the adhesive solution is 8%;

[0101] The ratio of the total mass of the microcrystalline cellulose, the mannitol and the disintegrant added internally to the total mass of the externally added is 1:1;

[0102] In step 2), the premixing time is 5 to 8 minutes, and the mixing rate is 240 to 480 rpm;

[0103] In the premix, the hydroxypropyl-β-cyclodextrin and / or the solubilizer are added and mixed with the irbesartan;

[0104] In step 3), the granulation speed can be 360-1800 rpm, and the time is 2 min-4 min, preferably 3 min;

[0105] In step 4), the drying temperature may be 50-70° C., and the mass percentage of moisture content may be 0-2%; the drying may be performed 1-4 times, preferably 3 times;

[0106] In step 5), the speed of mixing with the dry particles can be 15 rpm, and the mixing time can be 30 min; the speed of mixing with the lubricant can be 15 rpm, and the mixing time can be 5 min;

[0107] In step 7), the mass percentage concentration of the coating solution may be 13%, and the coating is performed by electric stirring for 30 minutes;

[0108] The coating process is as follows:

[0109] The plain tablets are placed in a coating machine and preheated for 4 to 6 minutes to remove floating powder; the coating parameters are: air volume 1000 to 2000 m 3 / h, exhaust air volume 1200~2200m 3 / h, inlet air temperature 60℃, coating weight gain 2.5~3.5%.

[0110] Furthermore, the preparation method comprises the following steps:

[0111] (1) Pretreatment of raw materials and auxiliary materials

[0112] Irbesartan was crushed to a particle size of 17 μm, and amlodipine was crushed to a particle size of 15 μm;

[0113] Prepare an adhesive solution with a mass percentage of 8%;

[0114] (2) Premix

[0115] Add the irbesartan, the added microcrystalline cellulose, the mannitol, and the disintegrant into a wet granulator and mix at 240-480 rpm for 5-10 minutes (preferably 10 minutes);

[0116] (3) Granulation

[0117] Adding the premix to the binder solution and granulating at 360 or 1800 rpm to obtain a core material;

[0118] (4) Drying

[0119] The core material is dried using a fluidized bed with an air inlet temperature of 60° C. to obtain dry particles;

[0120] (5) Total mixing

[0121] The amlodipine besylate and the added microcrystalline cellulose, the mannitol, the disintegrant or the solubilizer are mixed three times through a 60-mesh sieve, and then mixed with the dry granules using a hopper mixer at 15 rpm for 30 minutes, and then the lubricant is added and mixed at 15 rpm for 5 minutes to obtain a total mixed granule;

[0122] (6) Tablet pressing

[0123] Compress the total mixed granules into tablets according to a theoretical tablet weight of 175 mg and a tablet hardness of 130 to 160 N to obtain plain tablets;

[0124] (7) Coating

[0125] The Opadry film coating premix was used to prepare a coating solution with a mass percentage concentration of 13%, and the solution was stirred electrically for 30 minutes for later use;

[0126] The plain tablets were placed in a coating machine and preheated for 5 minutes to remove the floating powder; the coating solution was added for coating. The coating parameters were: air volume 1500m 3 / h, exhaust air volume 1400m 3 / h, the inlet air temperature is 60°C, and the coating weight gain is 3%, thus obtaining the medicine for treating hypertension.

[0127] The present invention has the following advantages:

[0128] 1. In the present invention, the raw material irbesartan is first premixed with part of the auxiliary materials for granulation, and then another raw material amlodipine besylate is mixed with another part of the auxiliary materials to increase the stability of tablet preparation; when the auxiliary materials contain hydroxypropyl-β-cyclodextrin, adding it in the premixing step can increase the water solubility of the finished product irbesartan, so as to increase its bioavailability;

[0129] 2. Adding a solubilizer (polyoxyethylene fatty acid ester, sodium dioctyl sulfosuccinate or sodium dioctyl sulfosuccinate dibutyrate) in the premixing step to further prepare a tablet core material can increase the water solubility of irbesartan in the tablet to increase its bioavailability;

[0130] 3. The present invention uses Opadry film coating premix for coating and adjusts the coating time, so that the coating time in the preparation process is shorter than that of other coating materials for irbesartan and amlodipine tablets in the prior art, and the stability of granulation can be achieved;

[0131] 4. The use of magnesium stearate or magnesium stearate and sodium stearyl fumarate as lubricant is beneficial to the stability of the formulation process.

[0132] 5. The effect of different concentrations and addition forms (solution or powder) of the added binder on the performance of the prepared tablets. The appropriate concentration can be optimized by comparing the cumulative dissolution rate and f2 value.

[0133] 6. In the preparation process, the conditions and parameters can be adjusted, such as different premixing times, to increase the stability of granulation. DETAILED DESCRIPTION

[0134] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0135] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0136] In the following examples, microcrystalline cellulose is MCC PH101 purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd.;

[0137] Film coating premix (white) 03H680001-CN white THL63590 Shanghai Colorcon Coating Technology Co., Ltd.;

[0138] Film coating premix (orange) 03H630001-CN Orange THL65899 Shanghai Colorcon Coating Technology Co., Ltd.

[0139] Example 1: Drug for treating hypertension and its preparation method

[0140] The prescription composition of irbesartan / amlodipine in a large-scale formulation (100 mg / 10 mg) of the drug for treating hypertension is shown in Table 1. According to the prescription quantity in Table 1, 100,000 tablets are prepared.

[0141] Table 1

[0142]

[0143] Note: The amount of purified water in the tablet core is about 500mL / 10,000 tablets, which is eventually removed in the process.

[0144] The preparation method steps are as follows:

[0145] (1) Pretreatment of raw materials and auxiliary materials

[0146] Irbesartan was crushed to a particle size of 17 μm, and amlodipine was crushed to a particle size of 15 μm;

[0147] Prepare an adhesive solution with a mass percentage of 8%;

[0148] (2) Premix

[0149] Irbesartan, additional microcrystalline cellulose, mannitol, and croscarmellose sodium were added to a wet granulator and mixed at 480 rpm for 8 minutes;

[0150] (3) Granulation

[0151] The premix was added to the polyvinyl alcohol solution and granulated at 1800 rpm for 3 min to obtain a core material;

[0152] (4) Drying

[0153] The core material is dried in a fluidized bed with an inlet air temperature of 60°C and dried three times to obtain dry granules;

[0154] (5) Total mixing

[0155] The amlodipine besylate was mixed with the added microcrystalline cellulose, mannitol, and cross-linked sodium carboxymethyl cellulose through a 60-mesh sieve for three times, and then mixed with the dry granules using a laboratory hopper mixer at 15 rpm for 30 minutes, and then a lubricant was added and mixed at 15 rpm for 5 minutes to obtain a total mixed granule;

[0156] (6) Tableting

[0157] The total mixed granules are compressed into tablets according to a theoretical tablet weight of 175 mg and a tablet hardness of 130 to 160 N to obtain plain tablets;

[0158] (7) Coating

[0159] Use Opadry film coating premix to prepare a coating solution with a mass percentage concentration of 13%, stir it electrically for 30 minutes, and set aside;

[0160] Put the plain tablets into the coating machine and preheat for 5 minutes to remove the floating powder; add the coating liquid for coating. The coating parameters are: air volume 1500m 3 / h, exhaust air volume 1400m 3 / h, the inlet air temperature is 60°C, and the coating weight gain is 3%, thus obtaining a medicine for treating hypertension.

[0161] Example 2: Drug for treating hypertension and its preparation method

[0162] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 2. According to the prescription amount in Table 2, 10,000 tablets are prepared.

[0163] Table 2

[0164]

[0165]

[0166] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0167] The preparation was carried out according to the preparation method in Example 1 of the present invention, except that:

[0168] In step (2), the mixture was mixed in a wet granulator at 240 rpm for 5 minutes;

[0169] In step (3), granulation is performed at 360 rpm to obtain a core material.

[0170] Example 3: Drug for treating hypertension and its preparation method

[0171] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 3. According to the prescription amount in Table 3, 10,000 tablets are prepared.

[0172] Table 3

[0173]

[0174] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0175] Prepared according to the preparation method in Example 2 of the present invention.

[0176] Example 4: Drug for treating hypertension and its preparation method

[0177] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 4. According to the prescription amount in Table 4, 10,000 tablets are prepared.

[0178] Table 4

[0179]

[0180]

[0181] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0182] Prepared according to the preparation method in Example 2 of the present invention.

[0183] Example 5: Drug for treating hypertension and its preparation method

[0184] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 5. According to the prescription amount in Table 5, 10,000 tablets are prepared.

[0185] Table 5

[0186]

[0187] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0188] Prepared according to the preparation method in Example 2 of the present invention.

[0189] Example 6: Drug for treating hypertension and its preparation method

[0190] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 6. According to the prescription amount in Table 6, 10,000 tablets are prepared.

[0191] Table 6

[0192]

[0193] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0194] Prepared according to the preparation method in Example 2 of the present invention.

[0195] Example 7: Drug for treating hypertension and its preparation method

[0196] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 7. According to the prescription amount in Table 7, 10,000 tablets are prepared.

[0197] Table 7

[0198]

[0199]

[0200] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0201] The mixture is prepared according to the preparation method in Example 2 of the present invention, and fatty acid polyoxyethylene ester is added during the premixing in step (2).

[0202] Example 8: Drug for treating hypertension and its preparation method

[0203] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 8. According to the prescription amount in Table 8, 10,000 tablets are prepared.

[0204] Table 8

[0205]

[0206] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0207] The mixture is prepared according to the preparation method in Example 2 of the present invention, and dioctyl sodium sulfosuccinate is added during the premixing in step (2).

[0208] Example 9: Drug for treating hypertension and its preparation method

[0209] The prescription composition of irbesartan / amlodipine in a small size (100 mg / 5 mg) of the drug for treating hypertension is shown in Table 9. According to the prescription amount in Table 9, 10,000 tablets are prepared.

[0210] Table 9

[0211]

[0212] Note: The amount of purified water in the tablet core is about 200mL / 10,000 tablets, which is eventually removed in the process.

[0213] The mixture is prepared according to the preparation method in Example 2 of the present invention, and sodium dioctyl sulfonate dibutyrate is added during the premixing in step (2).

[0214] Example 10, effect verification experiment

[0215] The dissolution test of the drug for treating hypertension prepared as above is carried out:

[0216] The dissolution medium of this product was developed by referring to the medium preparation process in the Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations, and pH 6.8 phosphate buffer, pH 4.5 acetate buffer + 0.2% SDS, water + 0.2% SDS, pH 1.2 were selected as the dissolution medium.

[0217] The preparation methods of each dissolution medium are as follows:

[0218] Table 10 Dissolution medium preparation method

[0219]

[0220]

[0221] Specific dissolution methods:

[0222] Method: Paddle method;

[0223] Medium volume: 900ml;

[0224] Medium temperature: 37℃30.5℃;

[0225] Speed: 50 rpm;

[0226] Sampling time points: 5, 10, 15, 20, 30, 45, 60, 90, 120 min;

[0227] Sampling volume: 10ml;

[0228] Rehydration volume: 10ml;

[0229] Test solution: Dissolution at each time point, filter through the membrane into a sampling vial;

[0230] Detection: Liquid phase detection.

[0231] The dissolution curve results of the drugs for treating hypertension prepared in the above Examples 1-9 are shown in Tables 11 to 16. The reference preparation is a commercially available irbesartan amlodipine tablet. The commercially available irbesartan amlodipine tablets used below are batch number 2020C, specification 100 mg / 5 mg (white to light yellow film-coated tablets), batch number 2032C, specification 100 mg / 10 mg (light orange film-coated tablets).

[0232] Table 11 Dissolution curve (I)

[0233]

[0234] Table 12 Dissolution curve (I)

[0235]

[0236] Table 13 Dissolution curve (II)

[0237]

[0238] Table 14 Dissolution curve (II)

[0239]

[0240] Table 15 Dissolution curve (III)

[0241]

[0242]

[0243] Table 16 Dissolution curve (III)

[0244]

[0245] By comparing the data in Tables 11 to 16, it can be seen that the dissolution rate of the present invention is better than that of the commercially available irbesartan amlodipine tablets, and the dissolution stability is good, especially in Examples 6-9, in which hydroxypropyl-β-cyclodextrin and / or sodium dioctyl dibutyrate sulfonate are added during premixing, the overall dissolution rate is improved by one degree compared with the dissolution rate of the commercially available irbesartan amlodipine tablets 2020C and 2032C.

[0246] Embodiment 11,

[0247] The prescription amount and preparation method are the same as those in Example 2 of the present invention, except that the premixing time in the preparation method is 10 minutes.

[0248] Different premixing times were investigated: premixing for 5 minutes (prepared according to the method in Example 2 of the present invention, except that the premixing was for 5 minutes, 8 minutes, and 10 minutes), and the mixing uniformity was tested. The results are shown in Table 17.

[0249] Table 17 Premixed mixing uniformity inspection results (I)

[0250]

[0251]

[0252] As shown in the results in Table 17, the contents of premixing for 5 min, premixing for 8 min and premixing for 10 min all meet the requirements, and the RSD of premixing for 10 min is smaller, so the preferred premixing time of the present invention is 10 min.

[0253] Comparative Example 1

[0254] The prescription amount and preparation method are the same as those in Example 2 of the present invention, except that the mass percentage concentration of the polyvinyl alcohol adhesive used in the preparation method is 10%.

[0255] The concentration of the polyvinyl alcohol adhesive was investigated in Example 2 of the present invention and Comparative Example 1, and the results are shown in Tables 18-19.

[0256] Table 18 Adhesive concentration test results (I)

[0257]

[0258] Table 19 Adhesive concentration test results (II)

[0259]

[0260]

[0261] Conclusion: From the results in Tables 18-19, it can be seen that the 8% binder concentration in Example 2 of the present invention is better than the 10% binder concentration in Comparative Example 1.

[0262] Comparative Example 2

[0263] The prescription amount and preparation method are the same as those in Example 2 of the present invention, except that the polyvinyl alcohol binder is added in powder form in the preparation method.

[0264] The method of adding the adhesive was investigated: the 200923-02 batch prepared in Example 2 of the present invention was added with polyvinyl alcohol in the form of a solution. The 201202-01 batch prepared in Comparative Example 2 was added with polyvinyl alcohol in the form of a powder. The results are shown in Tables 20 and 21.

[0265] Table 20 Test results of different adhesive addition methods (I)

[0266]

[0267] Table 21 Test results

[0268]

[0269]

[0270] From the results in Tables 20 and 21, it can be seen that the dissolution curves of the granulation results of the direct addition of powder and the addition of binder in the form of solution in the present invention are similar, but the fluidity is poor when the powder is directly added to the granulation, so the present invention prefers solution granulation.

Claims

1. A drug for treating hypertension, characterized in that: The composition comprises the following components in parts by weight: Irbesartan 100.00 parts; Mannitol 25-32 parts; 20-25 parts of microcrystalline cellulose; Disintegrant 5-10 parts; 3~5 parts of adhesive; Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts; 1.5~2.5 parts of lubricant; 5-7.5 parts of Opadry film coating premix; The specification of film coating premix is ​​03H680001-CN white THL63590, Shanghai Colorcon Coating Technology Co., Ltd.; or, the specification of film coating premix is ​​03H630001-CN orange THL65899, Shanghai Colorcon Coating Technology Co., Ltd.; Hydroxypropyl-β-cyclodextrin 1-5 parts; 0.5~2.5 parts of solubilizer; The solubilizing agent is selected from at least one of polyoxyethylene fatty acid esters, dioctyl sodium sulfosuccinate and dioctyl sodium sulfosuccinate; The mass ratio of the microcrystalline cellulose added internally to that added externally is 3-4.5:1; The ratio of the mass of mannitol added internally to that of the mass of mannitol added externally is 3-5:1; The mass ratio of the internally added disintegrant to the externally added disintegrant is 1:1; The method for preparing the drug for treating hypertension comprises the following steps: 1) Pretreatment of raw materials and auxiliary materials The irbesartan is crushed to a particle size of 17 µm, and the amlodipine is crushed to a particle size of 15 µm; preparing an adhesive solution; 2) Premix Adding the irbesartan, the added microcrystalline cellulose, the mannitol, and the disintegrant into a wet granulator and mixing them to obtain a premix; In the premix, the hydroxypropyl-β-cyclodextrin and / or the solubilizer are added and mixed with the irbesartan; 3) Granulation Adding the premix to the binder solution for granulation to obtain a core material; 4) Drying The core material is dried using a fluidized bed to obtain dry granules; 5) Total mixing The amlodipine besylate, the microcrystalline cellulose, the mannitol, and the disintegrant are mixed three times through a 60-mesh sieve and then mixed with the dry granules, and then the lubricant is added and mixed to obtain a total mixed granule; 6) Tablet pressing The total mixed granules are compressed into tablets according to a theoretical tablet weight of 175 mg and a tablet hardness of 130-160 N to obtain plain tablets; 7) Coating The Opadry film coating premix is ​​used to prepare a coating solution, and the plain tablets are coated with the coating solution to obtain the drug for treating hypertension.

2. The drug according to claim 1, characterized in that The medicine for treating hypertension is made of the following components in parts by weight: Irbesartan 100.00 parts; Mannitol 25-32 parts; 22-23 parts of microcrystalline cellulose; Disintegrant 5.5-9 parts; 3.5~4.5 parts of adhesive; Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts; 1.5~2.5 parts of lubricant; Opadry film coating premix 5-7.5 parts.

3. The drug according to claim 1 or 2, characterized in that The disintegrant is selected from cross-linked sodium carboxymethylcellulose and / or cross-linked polyvinylpyrrolidone XL-10; The adhesive is polyvinyl alcohol; The lubricant includes magnesium stearate and / or sodium stearyl fumarate; The microcrystalline cellulose is MCC PH101 purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd.

4. The drug according to claim 3, characterized in that The lubricant is magnesium stearate and sodium stearyl fumarate in a mass ratio of 1:0.1 to 10; The mass ratio of the mannitol to the microcrystalline cellulose is 0.9-1.3:

1.

5. The drug according to claim 1 or 2, characterized in that The drug for treating hypertension is prepared from any one of the following components in parts by weight: a) 100.00 parts of irbesartan; Mannitol 25.07 parts; 18.06 parts of microcrystalline cellulose; 8.76 parts of disintegrant; 3.5 parts of polyvinyl alcohol; Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts; 1.75 parts of lubricant; 6 parts of Opadry film coating premix; b) The drug for treating hypertension is made of the following components in parts by weight: Irbesartan 100.00 parts; Mannitol 32 parts; 18.06 parts of microcrystalline cellulose; 8.76 parts of disintegrant; 3.5 parts of polyvinyl alcohol; Amlodipine, calculated as amlodipine besylate, 13.86 parts; 1.75 parts of lubricant; 6 parts of Opadry film coating premix; c) 100.00 parts of irbesartan; Mannitol 25.07 parts; 18.06 parts of microcrystalline cellulose; 8.76 parts of disintegrant; 3.5 parts of polyvinyl alcohol; 4 parts of hydroxypropyl-β-cyclodextrin; Amlodipine, calculated as amlodipine besylate, 6.93 to 13.86 parts; 1.75 parts of lubricant; 6 parts of Opadry film coating premix; d) The drug for treating hypertension is made of the following components in parts by weight: Irbesartan 100.00 parts; Mannitol 32 parts; 18.06 parts of microcrystalline cellulose; 8.76 parts of disintegrant; 3.5 parts of polyvinyl alcohol; 4 parts of hydroxypropyl-β-cyclodextrin; Amlodipine, calculated as amlodipine besylate, 13.86 parts; 1.75 parts of lubricant; 6 parts of Opadry film coating premix; e) The drug for treating hypertension is made of the following components in parts by weight: Irbesartan 100.00 parts; Mannitol 32 parts; 18.06 parts of microcrystalline cellulose; 8.76 parts of disintegrant; 3.5 parts of polyvinyl alcohol; 3 parts of hydroxypropyl-β-cyclodextrin; 1 part of the solubilizing agent; Amlodipine, calculated as amlodipine besylate, 13.86 parts; 1.75 parts of lubricant; Opadry film coating premix 6 parts.

6. A method for preparing a drug for treating hypertension according to any one of claims 1 to 5, comprising the following steps: 1) Pretreatment of raw materials and auxiliary materials The irbesartan is crushed to a particle size of 17 µm, and the amlodipine is crushed to a particle size of 15 µm; preparing an adhesive solution; 2) Premix Adding the irbesartan, the added microcrystalline cellulose, the mannitol, and the disintegrant into a wet granulator and mixing them to obtain a premix; In the premix, the hydroxypropyl-β-cyclodextrin and / or the solubilizer are added and mixed with the irbesartan; 3) Granulation Adding the premix to the binder solution for granulation to obtain a core material; 4) Drying The core material is dried using a fluidized bed to obtain dry granules; 5) Total mixing The amlodipine besylate, the microcrystalline cellulose, the mannitol, and the disintegrant are mixed three times through a 60-mesh sieve and then mixed with the dry granules, and then the lubricant is added and mixed to obtain a total mixed granule; 6) Tablet pressing The total mixed granules are compressed into tablets according to a theoretical tablet weight of 175 mg and a tablet hardness of 130-160 N to obtain plain tablets; 7) Coating The Opadry film coating premix is ​​used to prepare a coating solution, and the plain tablets are coated with the coating solution to obtain the drug for treating hypertension.

7. The preparation method according to claim 6, characterized in that: In step 1), the mass percentage of the adhesive solution is 8%; The mass ratio of the microcrystalline cellulose added internally to that added externally is 3-4.5:1; The ratio of the mass of mannitol added internally to that of the mass of mannitol added externally is 3-5:1; The mass ratio of the internally added disintegrant to the externally added disintegrant is 1:1; In step 2), the premixing time is 5 to 10 minutes, and the mixing rate is 240 to 480 rpm; In step 3), the granulation speed is 360-1800 rpm, and the time is 2 min-4 min, preferably 3 min; In step 4), the drying temperature is 50-70° C., and the drying is performed until the mass percentage of moisture is 0-2%. The drying is performed 1-4 times; In step 5), the speed of mixing with the dry particles is 15 rpm, and the mixing time is 30 min; the speed of mixing with the lubricant is 15 rpm, and the mixing time is 5 min; In step 7), the mass percentage concentration of the coating solution is 13%, and the coating is performed by electric stirring for 30 minutes; The coating process is as follows: The plain tablets are placed in a coating machine and preheated for 4 to 6 minutes to remove floating powder; the coating parameters are: inlet air volume 1000 to 2000 m³ / h, exhaust air volume 1200 to 2200 m³ / h, inlet air temperature 60°C, and coating weight gain 2.5 to 3.5%.

8. The preparation method according to claim 6 or 7, characterized in that: The preparation method comprises the following steps: (1) Pretreatment of raw materials and auxiliary materials Irbesartan was crushed to a particle size of 17 µm, and amlodipine was crushed to a particle size of 15 µm; Prepare an adhesive solution with a mass percentage of 8%; (2) Premix Add the irbesartan and the added microcrystalline cellulose, the mannitol, the disintegrant or the solubilizer into a wet granulator and mix at 240-480 rpm for 10 minutes; (3) Granulation Adding the premix to the binder solution and granulating at 360-1800 rpm to obtain a core material; (4) Drying The core material is dried using a fluidized bed with an air inlet temperature of 60° C. and dried three times to obtain dry particles; (5) Total mixing The amlodipine besylate, the added microcrystalline cellulose, the mannitol, and the disintegrant were mixed three times through a 60-mesh sieve, and then mixed with the dry granules using a laboratory hopper mixer at 15 rpm for 30 minutes, and then the lubricant was added and mixed at 15 rpm for 5 minutes to obtain a total mixed granule; (6) Tableting The total mixed granules are compressed into tablets according to a theoretical tablet weight of 175 mg and a tablet hardness of 130-160 N to obtain plain tablets; (7) Coating The Opadry film coating premix was used to prepare a coating solution with a mass percentage concentration of 13%, and the solution was stirred electrically for 30 minutes for later use; The plain tablets are placed in a coating machine and preheated for 5 minutes to remove floating powder; the coating liquid is added for coating, and the coating parameters are: inlet air volume 1500m³ / h, exhaust air volume 1400m³ / h, inlet air temperature 60°C, and coating weight gain 3%, thereby obtaining the drug for treating hypertension.

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