Perindopril-levamlodipine compound tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a perindopril-levamlodipine compound tablet and a preparation method thereof. The filling agent in the auxiliary materials is sieved, the sieved filling agent is divided into three parts, and the auxiliary materials do not contain lactose; mixing the perindopril arginine, docusate sodium in the auxiliary materials and the first part of filler to obtain a first premix; mixing levamlodipine besylate and a second part of filler to obtain a second premix; and uniformly mixing the first premix, the second premix and the remaining auxiliary materials, and tabletting to obtain the tablet. According to the preparation method provided by the invention, the mixing uniformity can be remarkably improved, the product quality consistency can be improved, and meanwhile, the bioavailability and the stability of the two main drugs can be improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a perindopril-levamlodipine compound tablet and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Amlodipine is a racemic body, containing 50% levoamlodipine and 50% dextroamlodipine. Studies have found that the main hypotensive effect of amlodipine is the levoisomer. The dextroisomer has almost no hypotensive effect, so a dose of 2.5 mg of levoamlodipine can achieve the hypotensive effect of 5 mg of amlodipine. In addition, many patients will find that they will have symptoms of lower limb edema after taking amlodipine. Studies on amlodipine have found that this lower limb edema is related to the dextroisomer in amlodipine. Therefore, levoamlodipine not only has a good hypotensive effect, but also can reduce the adverse effects of lower limb edema.

[0004] The compound preparation of levamlodipine and perindopril can make the mechanisms of perindopril and levamlodipine complementary in terms of efficacy, and has the advantage of synergistic antihypertensive efficacy. However, the inventors have found that the compound preparation of levamlodipine and perindopril is prone to problems such as uneven mixing, low bioavailability, and poor stability. Summary of the invention

[0005] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a perindopril-amlodipine compound tablet and a preparation method thereof. The preparation method provided by the present invention can significantly improve the mixing uniformity, improve the consistency of product quality, and at the same time can improve the bioavailability and the stability of the two main drugs.

[0006] In order to achieve the above object, the technical solution of the present invention is:

[0007] In a first aspect, a method for preparing a perindopril-levoamlodipine compound tablet comprises the following steps:

[0008] Screening the filler in the auxiliary material, and dividing the screened filler into three parts, wherein the auxiliary material does not contain lactose;

[0009] Perindopril arginine, sodium docusate in the auxiliary materials, and the first portion of the filler are mixed to obtain a first premix;

[0010] Mixing levamlodipine besylate and a second portion of filler to obtain a second premix;

[0011] The first premix, the second premix and the remaining auxiliary materials are mixed evenly and compressed into tablets.

[0012] Since levamlodipine besylate replaces amlodipine besylate, the amount of amlodipine besylate raw material is halved, and the specifications of perindopril arginine are smaller, so it is easy to mix unevenly; at the same time, the surface of perindopril arginine raw material is very smooth, similar to corn starch, and it is not easy to integrate with excipients, and it is easy to stratify and cause unevenness.

[0013] Perindopril is an acidic drug that is stable in an alkaline environment, while levamlodipine is a free base that is easy to combine with acid radicals to form salts and is stable in an acidic environment. In addition, both components contain unstable groups, and the interaction between the two components leads to poor stability. Taking into account the poor stability of the two components at the same time is a difficulty that needs to be solved in the formulation process. According to experiments and experience, levamlodipine is more unstable than amlodipine (racemate), and impurities increase faster.

[0014] Arginine perindopril is affected by acidic substances and dissociates into perindopril. Perindopril itself has poor water solubility, which seriously affects the dissolution, dissolution and absorption of the drug, resulting in drug efficacy being affected. At the same time, perindopril has a low melting point, is easy to liquefy, and has unstable properties. In addition, the insolubility and hydrophobicity of the excipients lead to barriers to the dissolution and absorption of the main component, resulting in low bioavailability of the compound preparation.

[0015] The invention first sieves the filler to prevent the large-particle filler from affecting the mixing uniformity of the two main drugs, and then divides the filler into three parts, and mixes two of the parts with arginine perindopril and levamlodipine besylate respectively, so as to improve the mixing uniformity and drug stability; by splitting the third part of the filler, the premixing amount of the filler and the two main drugs can be controlled, so as to make the mixing uniformity better. At the same time, the auxiliary material of the invention does not contain lactose, so as to prevent the amino group of amlodipine from reacting with lactose to generate amlodipine lactose adduct impurities, and the preparation process is simple and suitable for industrial production.

[0016] Secondly, the bioavailability of perindopril decreases after taking it with a meal, but the bioequivalence evaluation requires the consistency of the self-made product and the reference product after a meal, and according to the BE experience related to perindopril, it is known that the bioavailability of the self-made product after a meal is likely to be lower than that of the reference product. In order to ensure the consistency of the bioavailability after a meal, the present invention adds the alkaline solubilizing excipient docusate sodium, while ensuring the equivalence with the reference product and the stability of perindopril.

[0017] However, the addition of docusate sodium will affect the long-term stability of perindopril arginine and levamlodipine besylate. In order to solve this problem, the present invention mixes perindopril arginine, docusate sodium in the auxiliary material, and the first part of the filler, and then performs dry granulation to obtain the first premix.

[0018] There are many fillers that can replace lactose, such as pregelatinized starch, microcrystalline cellulose, etc. Studies have shown that when pregelatinized starch is used as a filler, the friability of the prepared tablets is higher. When microcrystalline cellulose is used as a filler, the friability of the prepared tablets can better meet the relevant requirements. Further studies have shown that when microcrystalline cellulose is used as a filler, disintegrants need to be added to the excipients to better ensure that the dissolution behavior of perindopril in the perindopril levamlodipine tablets is consistent with that of the perindopril arginine tablets.

[0019] In a second aspect, a perindopril-levaline compound tablet is obtained by the above preparation method.

[0020] The beneficial effects of the present invention are:

[0021] The present invention sieves the filler, and then divides it into at least two parts, which are premixed with amlodipine and perindopril respectively. Due to the small amount of active ingredients, the sample uniformity is easy to be large, resulting in a large deviation in the accuracy of the dosage. According to the above-mentioned premixing method, the mixing uniformity can be significantly improved, and the consistency of product quality can be improved; more importantly, the prescription does not contain lactose, which avoids the Maillard reaction between the amino group of amlodipine and lactose to generate amlodipine lactose adduct impurities. In addition, by adding the alkaline solubilizing auxiliary material docusate sodium and dry granulating the perindopril component separately, the stability and bioavailability of perindopril are increased, the influence of the alkaline substance docusate sodium on left amlodipine is avoided, and the mutual influence of two main components with different acidity and alkalinity is avoided, and the preparation process is simple, which is suitable for industrial production. And by comparing the dissolution behavior of the self-made product and the reference preparation in the simulated gastric juice of satiety, it is proved that the dissolution behavior of the product is consistent with the reference preparation, and the bioequivalence of the self-made product is guaranteed to be consistent with the reference preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0023] Figure 1 This is the dissolution curve of the simulated gastric fluid in the embodiment of the present invention. DETAILED DESCRIPTION

[0024] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0025] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0026] In view of the problems of uneven mixing, low bioavailability, poor stability, etc. in composite tablets made of perindopril arginine and levamlodipine besylate, the present invention provides a perindopril levamlodipine composite tablet and a preparation method thereof.

[0027] A typical embodiment of the present invention provides a method for preparing a perindopril-levoamlodipine compound tablet, comprising the following steps:

[0028] Screening the filler in the auxiliary material, and dividing the screened filler into three parts, wherein the auxiliary material does not contain lactose;

[0029] Perindopril arginine, sodium docusate in the auxiliary materials, and the first portion of the filler are mixed to obtain a first premix;

[0030] Mixing levamlodipine besylate and a second portion of filler to obtain a second premix;

[0031] The first premix, the second premix and the remaining auxiliary materials are mixed evenly and compressed into tablets.

[0032] The present invention can solve the problems of uneven mixing, low bioavailability, poor stability, etc. in composite tablets made of perindopril arginine and levamlodipine besylate through the method.

[0033] In some embodiments, the perindopril arginine, the sodium docusate in the auxiliary material, and the first part of the filler are mixed, and then dry granulated to obtain a first premix. Dry granulation can effectively reduce the contact between the perindopril component and levamlodipine, thereby solving the problem of poor long-term stability of the two main drugs.

[0034] In some embodiments, microcrystalline cellulose is used as a filler. Tablets prepared with microcrystalline cellulose as a filler have better friability.

[0035] In one or more embodiments, the excipient includes a disintegrant. Adding a disintegrant can better ensure that the dissolution behavior of perindopril is consistent with that of the reference preparation. Specifically, the disintegrant is sodium carboxymethyl starch. The effect of using this disintegrant is better.

[0036] In some embodiments, the filler in the auxiliary material is sieved through a 40-100 mesh sieve. Studies have shown that under this condition, large particles of filler can be better removed, thereby further ensuring mixing uniformity.

[0037] In some embodiments, the first premix contains, by weight, 50 parts of perindopril arginine, 300-400 parts of the first portion of filler, and 0.25-5 parts of docusate sodium.

[0038] In some embodiments, the second premix contains, by weight, 34.0 to 35.0 parts of levamlodipine besylate and 150 to 200 parts of the second portion of filler.

[0039] In some embodiments, the mass of the third portion of filler is 65-75% of the mass of the total filler.

[0040] In some embodiments, the first premix, the second premix, and the remaining auxiliary materials except the lubricant are uniformly mixed to obtain a third premix, and then the lubricant is added for mixing. The final addition of the lubricant is more conducive to subsequent tableting. Specifically, the lubricant is magnesium stearate.

[0041] In some embodiments, the auxiliary material further comprises silicon dioxide, which acts as a glidant and anti-adhesive agent and is more conducive to mixing.

[0042] Another embodiment of the present invention provides a perindopril-amlodipine compound tablet obtained by the above preparation method.

[0043] In some embodiments, the composition is composed of the following components, measured by mass: 50 parts of perindopril arginine, 34.0-35.0 parts of levamlodipine besylate, 1500-2000 parts of microcrystalline cellulose, 20-40 parts of magnesium stearate, 10-20 parts of silicon dioxide, 95-105 parts of sodium carboxymethyl starch, and 0.25-5 parts of docusate sodium.

[0044] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0045] Unless otherwise stated, the formulations of the following examples and comparative examples are shown in the following table.

[0046]

[0047]

[0048] Embodiment 1:

[0049] S1: Pass the microcrystalline cellulose through a 40-mesh sieve to avoid the presence of large particles that affect the mixing uniformity of the main drug.

[0050] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0051] Dry granulation parameters: screw feeding 30.0rpm, roller oil pressure 30bar, roller speed 14.0rpm, roller gap 0.8mm, granulation speed 120.0rpm, use 1.0mm sieve for dry granulation, and pass through 20 mesh sieve for granulation.

[0052] The main drug cannot be mixed with too much microcrystalline cellulose, which may easily lead to uneven mixing.

[0053] S3: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0054] S4: Add the remaining microcrystalline cellulose into a mixing hopper, then add the first premix and the second premix, then add silicon dioxide and sodium carboxymethyl starch, and mix them in a container mixer at a speed of 15 r / min for 40 minutes to obtain a third premix, add magnesium stearate to the third premix, mix at a speed of 15 r / min for 5 minutes, and take samples to detect uniformity.

[0055] S5: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0056] Embodiment 2:

[0057] S1: Pass microcrystalline cellulose through a 40-mesh sieve.

[0058] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0059] Dry granulation parameters: screw feeding 40.0rpm, roller oil pressure 40bar, roller speed 17.0rpm, roller gap 1.0mm, granulation speed 150.0rpm, 1.0mm sieve was used for dry granulation, and 20-mesh sieve was used for granulation.

[0060] S3: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0061] S4: Add the remaining microcrystalline cellulose into a mixing hopper, then add the first premix and the second premix, then add silicon dioxide and sodium carboxymethyl starch, and mix them in a container mixer at a speed of 15 r / min for 40 minutes to obtain a third premix, add magnesium stearate to the third premix, mix at a speed of 15 r / min for 5 minutes, and take samples to detect uniformity.

[0062] S5: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0063] Embodiment 3:

[0064] S1: Pass microcrystalline cellulose through a 40-mesh sieve.

[0065] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0066] Dry granulation parameters: screw feeding 20.0rpm, roller oil pressure 20bar, roller speed 11.0rpm, roller gap 0.6mm, granulation speed 100.0rpm, 1.0mm sieve was used for dry granulation, and 20-mesh sieve was used for granulation.

[0067] S3: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0068] S4: Add the remaining microcrystalline cellulose into a mixing hopper, then add the first premix and the second premix, then add silicon dioxide and sodium carboxymethyl starch, and mix them in a container mixer at a speed of 15 r / min for 40 minutes to obtain a third premix, add magnesium stearate to the third premix, mix at a speed of 15 r / min for 5 minutes, and take samples to detect uniformity.

[0069] S5: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0070] Comparative Example 1 (not mixed with filler alone):

[0071] After passing the microcrystalline cellulose through a 40-sieve sieve, add it into a mixing hopper together with levamlodipine besylate, perindopril arginine, magnesium stearate, docusate sodium, colloidal silicon dioxide and sodium carboxymethyl starch, mix it in a container mixer at 15 r / min for 40 min, take samples to test the uniformity, and then press it into tablets with the pressure set to 6 KN to obtain perindopril levamlodipine compound tablets.

[0072] Comparative Example 2 (mixed with separate, slightly more filler):

[0073] S1: Pass microcrystalline cellulose through a 40-mesh sieve.

[0074] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0075] Dry granulation parameters: screw feeding 30.0rpm, roller oil pressure 30bar, roller speed 14.0rpm, roller gap 0.8mm, granulation speed 120.0rpm, use 1.0mm sieve for dry granulation, and pass through 20 mesh sieve for granulation.

[0076] S3: Mix levamlodipine besylate with 1 / 5 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0077] S4: adding the remaining microcrystalline cellulose to a mixing hopper, then adding the first premix and the second premix, and then adding silicon dioxide and sodium carboxymethyl starch, and mixing them for 40 minutes at a speed of 15 r / min using a container mixer to obtain a third premix, adding magnesium stearate to the third premix, mixing at a speed of 15 r / min for 5 minutes, and taking samples to detect uniformity;

[0078] S5: After the content uniformity is qualified, tablets are pressed with the pressure set to 6KN to obtain perindopril-amlodipine compound tablets.

[0079] Comparative Example 3 (filler not sieved):

[0080] S1: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0081] Dry granulation parameters: screw feeding 30.0rpm, roller oil pressure 30bar, roller speed 14.0rpm, roller gap 0.8mm, granulation speed 120.0rpm, use 1.0mm sieve for dry granulation, and pass through 20 mesh sieve for granulation.

[0082] S2: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0083] S3: adding the remaining microcrystalline cellulose to a mixing hopper, then adding the first premix and the second premix, and then adding silicon dioxide and sodium carboxymethyl starch, and mixing them for 40 minutes at a speed of 15 r / min using a container mixer to obtain a third premix, adding magnesium stearate to the third premix, mixing at a speed of 15 r / min for 5 minutes, and taking samples to detect uniformity;

[0084] S4: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0085] Comparative Example 4 (without disintegrant - sodium carboxymethyl starch):

[0086] S1: Pass microcrystalline cellulose through a 40-mesh sieve.

[0087] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0088] Dry granulation parameters: screw feeding 30.0rpm, roller oil pressure 30bar, roller speed 14.0rpm, roller gap 0.8mm, granulation speed 120.0rpm, use 1.0mm sieve for dry granulation, and pass through 20 mesh sieve for granulation.

[0089] S3: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0090] S4: Add the remaining microcrystalline cellulose into a mixing hopper, then add the first premix and the second premix, and then add silicon dioxide, and mix them at a speed of 15 r / min for 40 minutes using a container mixer to obtain a third premix, add magnesium stearate to the third premix, mix at a speed of 15 r / min for 5 minutes, and take samples to detect uniformity.

[0091] S5: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0092] Comparative Example 5 (filler-pregelatinized starch):

[0093] The filler was changed from microcrystalline cellulose to pregelatinized starch.

[0094] S1: Pass the pregelatinized starch through a 40-mesh sieve.

[0095] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of pregelatinized starch are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0096] Dry granulation parameters: screw feeding 30.0rpm, roller oil pressure 30bar, roller speed 14.0rpm, roller gap 0.8mm, granulation speed 120.0rpm, use 1.0mm sieve for dry granulation, and pass through 20 mesh sieve for granulation.

[0097] S3: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of pregelatinized starch to obtain a second premix.

[0098] S4: adding the remaining pregelatinized starch to a mixing hopper, then adding the first premix and the second premix, and then adding silicon dioxide and sodium carboxymethyl starch, and mixing them for 40 minutes at a speed of 15 r / min using a container mixer to obtain a third premix, adding magnesium stearate to the third premix, mixing at a speed of 15 r / min for 5 minutes, and taking samples to detect uniformity;

[0099] S5: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0100] Comparative Example 6 (perindopril was not granulated separately):

[0101] S1: Pass microcrystalline cellulose through a 40-mesh sieve.

[0102] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed to obtain a first premix.

[0103] S3: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0104] S4: adding the remaining microcrystalline cellulose to a mixing hopper, then adding the first premix and the second premix, and then adding silicon dioxide and sodium carboxymethyl starch, and mixing them for 40 minutes at a speed of 15 r / min using a container mixer to obtain a third premix, adding magnesium stearate to the third premix, mixing at a speed of 15 r / min for 5 minutes, and taking samples to detect uniformity;

[0105] S5: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0106] Comparative Example 7 (without docusate sodium):

[0107] S1: Pass microcrystalline cellulose through a 40-mesh sieve.

[0108] S2: Perindopril arginine, the prescribed amount of docusate sodium, and 1 / 5 of the prescribed amount of microcrystalline cellulose are mixed, and added to a dry granulator for dry granulation to obtain a first premix.

[0109] Dry granulation parameters: screw feeding 30.0rpm, roller oil pressure 30bar, roller speed 14.0rpm, roller gap 0.8mm, granulation speed 120.0rpm, use 1.0mm sieve for dry granulation, and pass through 20 mesh sieve for granulation.

[0110] S3: Mix levamlodipine besylate with 1 / 10 of the prescribed amount of microcrystalline cellulose to obtain a second premix.

[0111] S4: adding the remaining microcrystalline cellulose to a mixing hopper, then adding the first premix and the second premix, and then adding silicon dioxide and sodium carboxymethyl starch, and mixing them for 40 minutes at a speed of 15 r / min using a container mixer to obtain a third premix, adding magnesium stearate to the third premix, mixing at a speed of 15 r / min for 5 minutes, and taking samples to detect uniformity;

[0112] S5: After the content uniformity is qualified, tablets are pressed, and the average punch pressure is 6KN to obtain perindopril-amlodipine compound tablets.

[0113] Sample quality inspection:

[0114] 1. Content uniformity determination

[0115]

[0116]

[0117] From the content and uniformity results, it can be seen that the microcrystalline cellulose is first sieved, and the two main drugs are first mixed with the sieved microcrystalline cellulose. The uniformity of the content determination is significantly better, and the content determination results are also closer to the theoretical value of the feed.

[0118] 2. Impurity content results

[0119]

[0120]

[0121] From the above stability results, it can be seen that in Comparative Example 1 (each component is not mixed separately), the stability results of amlodipine impurity D, perindopril impurity B, and perindopril impurity F are poor, all greater than the limit of 0.2%. Considering the inconsistency of the acidity and alkalinity of the two components, and the presence of alkaline excipient docusate sodium, the mutual influence leads to serious degradation of impurities; in Comparative Example 6 (perindopril is not granulated separately), the two main components with different acidity and alkalinity influence each other, and there is also the influence of alkaline excipients, resulting in poor stability results. In Comparative Example 7 (without docusate sodium), perindopril has no help of weakly alkaline excipients, and the stability of perindopril is poor.

[0122] 3. Friability test results

[0123] category Friability weight loss limit 1％ Example 1 0.23％ Comparative Example 1 0.36％ Comparative Example 2 0.31％ Comparative Example 3 0.48％ Comparative Example 4 0.29％ Comparative Example 5 0.83％ Comparative Example 6 0.37％ Comparative Example 7 0.27％

[0124] From the above friability results, it can be seen that the friability of the sample using the process of pregelatinized starch (Comparative Example 5) is slightly poor.

[0125] 4. Comparison of dissolution behavior in simulated gastric fluid with full stomach

[0126] Dissolution curve: refer to the dissolution test method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Method 2). Operate in a dark environment and use an inert paddle made of Teflon.

[0127] Dissolution conditions: Use 900 ml of full simulated gastric fluid [buffer (containing 0.25 mol / L sodium chloride, 0.015 mol / L acetic acid, 0.03 mol / L sodium acetate) - milk (50:50)] as the dissolution medium, the rotation speed is 50 revolutions per minute, operate according to the law, and take samples after 5, 10, 15, 20, 30, 45, and 60 minutes.

[0128] Test solution: Take 10 ml of the solution, filter, take 5 ml of the filtrate, put it in a 10 ml volumetric flask, dilute to the scale with mobile phase, and shake well.

[0129] Reference substance solution (5mg / 2.5mg specification): Take appropriate amount of perindopril arginine and amlodipine besylate reference substances respectively, weigh accurately, and add mobile phase to make a solution containing 2.5μg perindopril arginine and 1.25μg amlodipine per 1ml.

[0130] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (C18 50mm×4.6mm, 5μm); 0.01mol / L phosphate buffer (2.72g of potassium dihydrogen phosphate, 1000ml of water, 3ml of triethylamine, and 35% perchloric acid were used to adjust the pH to 2.5)-acetonitrile (65:35) was used as the mobile phase; the flow rate was 1.5ml per minute; the column temperature was 50℃; the detection wavelength was 215nm; the injection volume was 20μl.

[0131] System suitability requirements: In the chromatogram of the reference solution, the separation between the perindopril and levoamlodipine peaks should be greater than 3.

[0132] Determination method: Calculate the dissolution amount of each tablet and multiply the amlodipine determination result by 0.7210.

[0133] The dissolution amount is shown in the following table, and the dissolution curve is shown in Figure 1 shown.

[0134]

[0135]

[0136] From the above dissolution behavior results, it can be seen that the dissolution behavior of Comparative Example 4 (without disintegrant) and Comparative Example 7 (without docusate sodium) is slower than that of the reference preparation.

[0137] 5. Determination of lactose-adducted impurities, dissolution and content of amlodipine

[0138]

[0139] It can be seen from the above test results that the mixing uniformity of Comparative Example 1 (not mixed with the diluent alone), Comparative Example 2 (mixed with a separate, slightly more diluent), and Comparative Example 3 (not sieved) is poor. The preparation of Comparative Example 1 (not mixed with the diluent alone) is mixed with all the excipients, the acidity and alkalinity of the two main drugs are inconsistent, and there is an alkaline excipient, docusate sodium, which affects each other, resulting in serious degradation of impurities; Comparative Example 7 (without docusate sodium) has no solubilizing alkaline excipient, and the dissolution behavior in the full simulated gastric juice is slow, the dissolution similarity factor f2 is less than 50, and the postprandial bioequivalence test results are also unqualified, and perindopril has no help of weak alkaline excipients, and the stability is also poor; Comparative Example 5 (filler-pregelatinized starch) uses pregelatinized starch as a filler, the tablet friability is unqualified, and it is easy to lose powder during transportation, resulting in a low content.

[0140] Comprehensive comparison results show that after the diluent is sieved, the two main components are mixed with a small amount of excipients separately, and the perindopril component is granulated separately. By using disintegrants and solubilizing weak alkaline excipients, the dissolution behavior of perindopril in full simulated gastric fluid of this product is consistent with that of the original research, and the mixing uniformity, impurity content, dissolution behavior, and bioequivalence test all meet the requirements.

[0141] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a perindopril-amlodipine compound tablet, characterized in that: The steps include: Screening the filler in the auxiliary material, and dividing the screened filler into three parts, wherein the auxiliary material does not contain lactose; Perindopril arginine, sodium docusate in the auxiliary materials, and the first portion of the filler are mixed to obtain a first premix; Mixing levamlodipine besylate and a second portion of filler to obtain a second premix; The first premix, the second premix and the remaining auxiliary materials are mixed evenly and compressed into tablets.

2. The method for preparing the perindopril-amlodipine compound tablet according to claim 1, wherein: Perindopril arginine, sodium docusate in the auxiliary materials, and the first part of the filler are mixed, and then dry granulated to obtain a first premix.

3. The method for preparing the perindopril-amlodipine compound tablet according to claim 1, wherein: Microcrystalline cellulose was used as a filler.

4. The method for preparing the perindopril-amlodipine compound tablets as claimed in claim 3, characterized in that: The auxiliary material includes a disintegrant; preferably, the disintegrant is sodium carboxymethyl starch.

5. The method for preparing the perindopril-amlodipine compound tablet according to claim 1, characterized in that: The fillers in the auxiliary materials are sieved through 40-100 mesh.

6. The method for preparing the perindopril-amlodipine compound tablet according to claim 1, characterized in that: In the first premix, by weight, 50 parts of perindopril arginine, 300-400 parts of the first part of filler, and 0.25-5 parts of docusate sodium; Or, in the second premix, by weight, 34.0 to 35.0 parts of levamlodipine besylate and 150 to 200 parts of the second part of filler; Alternatively, the mass of the third portion of filler is 65-75% of the mass of the total filler.

7. The method for preparing the perindopril-amlodipine compound tablet according to claim 1, characterized in that: The first premix, the second premix and the remaining auxiliary materials except the lubricant are uniformly mixed to obtain a third premix, and then the lubricant is added for mixing; preferably, the lubricant is magnesium stearate.

8. The method for preparing the perindopril-amlodipine compound tablet according to claim 1, characterized in that: The auxiliary materials also include silicon dioxide.

9. A perindopril-amlodipine compound tablet, characterized in that: Obtained by the preparation method according to any one of claims 1 to 8.

10. The perindopril-amlodipine compound tablet according to claim 9, characterized in that: The invention is composed of the following components in parts by mass: 50 parts of perindopril arginine, 34.0-35.0 parts of levamlodipine besylate, 1500-2000 parts of microcrystalline cellulose, 20-40 parts of magnesium stearate, 10-20 parts of silicon dioxide, 95-105 parts of sodium carboxymethyl starch and 0.25-5 parts of docusate sodium.

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