Compound lisinopril amlodipine double-layer tablet and preparation method thereof

Abstract

The invention discloses a compound lisinopril amlodipine double-layer tablet and a preparation method thereof, and the compound lisinopril amlodipine double-layer tablet is characterized in that a first layer is an amlodipine besylate layer which contains an active component amlodipine besylate and pharmaceutically acceptable auxiliary materials; the first layer is a lisinopril layer, the second layer is a lisinopril layer, the lisinopril layer contains an active ingredient lisinopril and pharmaceutically acceptable auxiliary materials, and the double-layer tablet is prepared by adopting a powder direct compression process. The tablet is prepared by adopting a method of separately mixing lisinopril and amlodipine and pressing the mixture into a double-layer tablet, and two layers of the double-layer tablet are separately mixed and pressed, so that the proportions of medicines in a single layer can be doubled to 10% and 5%, and the problem of mixing uniformity is avoided; meanwhile, no solvent is introduced in the direct tabletting process, so that new impurities are prevented from being introduced by the solvent, and the stability of the medicine is favorably improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a compound lisinopril and amlodipine double-layer tablet and a preparation method thereof. Background Art

[0002] Amlodipine besylate is a third-generation calcium channel blocker (CCB) that blocks extracellular calcium influx into myocardial and vascular smooth muscle cells, moderates long-term dilation of peripheral and coronary arteries, and reduces vascular resistance. It is used to treat various degrees of hypertension, as well as variant angina and stable angina. It has few adverse reactions and is one of the most clinically effective antihypertensive drugs. Lisinopril is a new-generation angiotensin-converting enzyme inhibitor (ACEI) that primarily lowers blood pressure by inhibiting the renin-angiotensin-aldosterone system.

[0003] Existing studies have shown that amlodipine besylate and lisinopril are two different types of antihypertensive drugs. Their combined use has a certain synergistic effect, can improve clinical efficacy, and has high clinical application value.

[0004] The preparation of amlodipine besylate and lisinopril into a compound preparation can improve patient compliance.

[0005] CN103656608A discloses a lisinopril and amlodipine tablet produced by dry granulation. The specifications of lisinopril and amlodipine are small, and their total proportions in the prescription are relatively low, at 5% and 2.5% respectively. Mixing all the materials together and then granulating and tableting may also lead to uneven mixing.

[0006] CN102423482B discloses a method for preparing compound amlodipine and lisinopril tablets. The method uses a tert-butyl alcohol solution as a binder and wet granulation to produce granules. This method can maintain good drug content uniformity. However, the wet granulation process introduces new solvents, tert-butyl alcohol and ethanol, increasing the risk of impurities, particularly genotoxic impurities. For example, ethanol reacts with the benzenesulfonic acid in amlodipine besylate to form the genotoxic impurity ethyl benzenesulfonate.

[0007] As can be seen, current compound amlodipine and lisinopril tablets are prone to uneven mixing and residual organic solvents. To address these defects and deficiencies, the present invention utilizes a method for preparing tablets by separately mixing lisinopril and amlodipine and then compressing them into bilayer tablets. The two layers of the bilayer tablets are separately mixed and compressed, doubling the drug content in the single layer to 10% and 5%, respectively, thus avoiding mixing uniformity issues. Furthermore, the direct compression process eliminates the introduction of solvents, preventing the introduction of new impurities, and contributing to improved drug stability. Summary of the Invention

[0008] The object of the present invention is to provide a compound lisinopril and amlodipine double-layer tablet and a preparation method thereof, which solves the technical problems of uneven material mixing and residual organic solvent in the prior art.

[0009] To achieve the purpose of the present invention, the following embodiments are provided.

[0010] In one embodiment, a compound lisinopril and amlodipine bilayer tablet of the present invention comprises:

[0011] The first layer is the amlodipine besylate layer, which contains the active ingredient amlodipine besylate and pharmaceutically acceptable excipients; the second layer is the lisinopril layer, which contains the active ingredient lisinopril and pharmaceutically acceptable excipients. The double-layer tablet is made by a powder direct compression process.

[0012] Furthermore, in the above-mentioned bilayer tablet of the present invention, the first layer is composed of 5 parts of amlodipine besylate (calculated as amlodipine), 83-92.5 parts of microcrystalline cellulose, 2-10 parts of sodium starch glycolate and 0.5-2 parts of magnesium stearate, and the second layer is composed of 10 parts of lisinopril, 78-87.5 parts of microcrystalline cellulose, 2-10 parts of sodium starch glycolate and 0.5-2 parts of magnesium stearate, and the parts are calculated by weight.

[0013] Preferably, the weight percentage composition of the components of each layer of the double-layer tablet of the present invention is as follows:

[0014] The components of the amlodipine besylate layer are:

[0015]

[0016] The components of the lisinopril layer are:

[0017]

[0018] Preferably, the composition of each layer of the double-layer tablet of the present invention is as follows:

[0019] Components of the described amlodipine besylate layer:

[0020]

[0021] Components of the Lisinopril layer:

[0022]

[0023]

[0024] In another embodiment, the present invention further provides a method for preparing the above-mentioned compound lisinopril and amlodipine bilayer tablets, wherein both layers are tableted using a powder direct mixing and tableting process, the method comprising:

[0025] (1) Mix the prescribed amount of amlodipine besylate, microcrystalline cellulose, and sodium starch glycolate, and then add magnesium stearate and mix evenly to form the first layer;

[0026] (2) Take the prescribed amount of lisinopril, microcrystalline cellulose, and sodium starch glycolate and mix them evenly, then add magnesium stearate and mix evenly to form the second tablet layer:

[0027] (3) The first layer and the second layer are added to a double-layer tablet press respectively and pressed into double-layer tablets.

[0028] Technical effects:

[0029] Because lisinopril and amlodipine compound preparations contain multiple ingredients, and the proportion of each raw material is relatively low, coupled with different particle sizes and morphologies, they are often prone to uneven mixing. In addition, the use of wet granulation processes often introduces solvents, which may produce new impurities or even genotoxic impurities, resulting in poor stability. To address the technical problems existing in the prior art, the present invention solves the technical problems of the prior art by making the compound lisinopril and amlodipine into double-layer tablets and adopting dry powder direct tableting technology. The present invention prepares the compound preparation by separating amlodipine and lisinopril into two layers, mixing them separately, and then pressing them into double-layer tablets. On the one hand, separate mixing can increase the proportion of the raw material (active ingredient) in each layer, and can double the proportion of the drug in a single layer to 10% and 5%, thereby reducing the risk of uneven mixing. On the other hand, direct pressing of the double-layer tablets after mixing does not introduce solvent residues, greatly improving the stability and safety of the lisinopril and amlodipine compound preparation. DETAILED DESCRIPTION

[0030] The following examples are provided to describe the present invention in more detail. However, the following examples are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art will appreciate that any equivalent substitutions made to the present invention, or corresponding improvements, still fall within the scope of protection of the present invention.

[0031] In the following examples, the weight or weight percentage of amlodipine besylate is based on amlodipine.

[0032] Example 1 Compound Lisinopril Amlodipine Double-layer Tablet

[0033] The double-layer tablet prescription (calculated based on 10,000 tablets) is shown in Tables 1 and 2 below.

[0034] Table 1. Amlodipine layer (wherein, the weight of amlodipine besylate is calculated as amlodipine)

[0035] materials Dosage (g / 10000 tablets) Proportion Amlodipine besylate 50 5％ microcrystalline cellulose 925 92.5％ Sodium starch glycolate 20 2％ magnesium stearate 5 0.5％

[0036] Table 2. Lisinopril Layer

[0037] materials Dosage (g / 10000 tablets) Proportion Lisinopril 100 10％ microcrystalline cellulose 875 87.5％ Sodium starch glycolate 20 2％ magnesium stearate 5 0.5％

[0038] Preparation process:

[0039] (1) Weigh the materials for the amlodipine layer and the lisinopril layer according to the prescribed amount;

[0040] (2) premixing the amlodipine layer material (except magnesium stearate) in a mixing hopper for 15 minutes (10 rpm / min), then adding magnesium stearate and continuing mixing for 5 minutes (10 rpm / min) to obtain a uniformly mixed amlodipine layer material;

[0041] (3) The lisinopril layer material (excluding magnesium stearate) was mixed in a mixing hopper for 15 minutes (10 rpm / min), and magnesium stearate was added and mixed for another 5 minutes (10 rpm / min) to obtain a uniformly mixed lisinopril layer material;

[0042] (4) The two layers of material are placed in the two hoppers of a double-layer tablet press respectively, and pressed to obtain double-layer plain tablets.

[0043] Example 2 Compound Lisinopril Amlodipine Double-layer Tablet

[0044] The double-layer tablet prescription (based on 10,000 tablets) is shown in Tables 3 and 4 below:

[0045] Table 3. Amlodipine layer (wherein, the weight of amlodipine besylate is calculated as amlodipine)

[0046] materials Dosage (g / 10000 tablets) Proportion Amlodipine besylate 50 5％ microcrystalline cellulose 830 83％ Sodium starch glycolate 100 10％ magnesium stearate 20 2％

[0047] Table 4. Lisinopril Layer

[0048] materials Dosage (g / 10000 tablets) Proportion Lisinopril 100 10％ microcrystalline cellulose 780 78％ Sodium starch glycolate 100 10％ magnesium stearate 20 2％

[0049] Preparation process:

[0050] (1) Weigh the materials for the amlodipine layer and the lisinopril layer according to the prescribed amount;

[0051] (2) premixing the amlodipine layer material (excluding magnesium stearate) in a mixing hopper for 15 minutes (10 rpm / min), then adding magnesium stearate and continuing mixing for 5 minutes (10 rpm / min) to obtain the amlodipine layer material;

[0052] (3) The lisinopril layer material (excluding magnesium stearate) was mixed in a mixing hopper for 15 minutes (10 rpm / min), magnesium stearate was added, and mixing was continued for 5 minutes (10 rpm / min) to obtain the lisinopril layer material;

[0053] (4) The two layers of material are placed in the two hoppers of a double-layer tablet press respectively, and pressed to obtain double-layer plain tablets.

[0054] Example 3 Compound Lisinopril Amlodipine Double-layer Tablet

[0055] The double-layer tablet prescription (based on 10,000 tablets) is shown in Tables 5 and 6 below:

[0056] Table 5. Amlodipine layer (wherein, the weight of amlodipine besylate is calculated as amlodipine)

[0057] materials Dosage (g / 10000 tablets) Proportion Amlodipine besylate 50 5％ microcrystalline cellulose 875 87.5％ Sodium starch glycolate 65 6.5％ magnesium stearate 10 1％

[0058] Table 6. Lisinopril Layer

[0059] materials Dosage (g / 10000 tablets) Proportion Lisinopril 100 10％ microcrystalline cellulose 875 83％ Sodium starch glycolate 60 6％ magnesium stearate 10 1％

[0060] Preparation process:

[0061] (1) Weigh the materials for the amlodipine layer and the lisinopril layer according to the prescribed amount;

[0062] (2) premixing the amlodipine layer material (excluding magnesium stearate) in a mixing hopper for 15 minutes (10 rpm / min), then adding magnesium stearate and continuing mixing for 5 minutes (10 rpm / min) to obtain the amlodipine layer material;

[0063] (3) The lisinopril layer material (excluding magnesium stearate) was mixed in a mixing hopper for 15 minutes (10 rpm / min), magnesium stearate was added, and mixing was continued for 5 minutes (10 rpm / min) to obtain the lisinopril layer material;

[0064] (4) The two layers of material are placed in the two hoppers of a double-layer tablet press respectively, and pressed to obtain double-layer plain tablets.

[0065] Comparative Example 1 Compound Lisinopril Amlodipine Double-layer Tablets

[0066] The double-layer tablet prescription (based on 10,000 tablets) is shown in Table 7 and Table 8:

[0067] Table 7. Amlodipine layer (wherein, the weight of amlodipine besylate is calculated as amlodipine)

[0068] materials Dosage (g / 10000 tablets) Proportion Amlodipine besylate 50 5％ microcrystalline cellulose 927.5 92.75％ Sodium starch glycolate 17.5 1.75％ magnesium stearate 5 0.5％

[0069] Table 8. Lisinopril Layer

[0070] materials Dosage (g / 10000 tablets) Proportion Lisinopril 100 10％ microcrystalline cellulose 877.5 87.75％ Sodium starch glycolate 17.5 1.75％ magnesium stearate 5 0.5％

[0071] Preparation process:

[0072] (1) Weigh the materials for the amlodipine layer and the lisinopril layer according to the prescribed amount;

[0073] (2) premixing the amlodipine layer material (excluding magnesium stearate) in a mixing hopper for 15 minutes (10 rpm / min), then adding magnesium stearate and continuing mixing for 5 minutes (10 rpm / min) to obtain the amlodipine layer material;

[0074] (3) The lisinopril layer material (excluding magnesium stearate) was mixed in a mixing hopper for 15 minutes (10 rpm / min), magnesium stearate was added, and mixing was continued for 5 minutes (10 rpm / min) to obtain the lisinopril layer material;

[0075] (4) The two layers of material are placed in the two hoppers of a double-layer tablet press respectively, and pressed to obtain double-layer plain tablets.

[0076] Comparative Example 2: Lisinopril-Amlodipine Single-Layer Tablet

[0077] The single-layer tablet prescription (based on 10,000 tablets) is shown in Table 9:

[0078] Table 9. Single-layer tablet formulation (weight of amlodipine besylate calculated as amlodipine)

[0079] materials Dosage (g / 10000 tablets) Proportion Amlodipine besylate 50 2.5％ microcrystalline cellulose 1800 90％ Sodium starch glycolate 40 2％ Lisinopril 100 5％ magnesium stearate 10 0.5％

[0080] Preparation process:

[0081] (1) Weigh all materials according to the prescribed amount;

[0082] (2) All materials (except magnesium stearate) were premixed in a mixing hopper for 15 min (10 rpm / min), magnesium stearate was added, and mixing was continued for 5 min (10 rpm / min) to obtain a total mixed material;

[0083] (3) The total mixed material is placed in the hopper of a tablet press and pressed to obtain a single-layer plain tablet.

[0084] Comparative Example 3: Lisinopril-Amlodipine Single-Layer Tablet

[0085] The single-layer tablet formulation for wet granulation (based on 10,000 tablets) is shown in Table 10:

[0086] Table 10. Single-layer tablet formulation (weight of amlodipine besylate calculated as amlodipine)

[0087] materials Dosage (g / 10000 tablets) Proportion Amlodipine besylate 50 2.5％ microcrystalline cellulose 1800 90％ Sodium starch glycolate 40 2％ Lisinopril 100 5％ magnesium stearate 10 0.5％ ethanol appropriate amount As granulation solvent

[0088] Preparation process:

[0089] (1) Weigh all materials according to the prescribed amount;

[0090] (2) All materials (except magnesium stearate) were mixed in a wet granulator for 15 minutes (10 rpm / min), and then ethanol was sprayed into the wet granulation pot at an appropriate speed as the formulation solvent. After spraying, granulation was continued for 5 minutes. After granulation, further wet granulation, drying, and dry granulation were performed to obtain dry granules; magnesium stearate was then added and mixing was continued for 5 minutes (10 rpm / min) to obtain the total mixed granules;

[0091] (3) The mixed granules are placed in the hopper of a tablet press and compressed to obtain a single-layer plain tablet.

[0092] Example 4 Dissolution Experiment

[0093] The plain tablets of Example 1, Example 2, Example 3, and Comparative Example 1 were subjected to dissolution curve testing (0.1 mol / L hydrochloric acid, 500 mL, 50 rpm) to compare the dissolution rates of amlodipine besylate and lisinopril. The results are shown in Table 11 below:

[0094] Table 11. Dissolution test results

[0095]

[0096] The results in Table 11 show that when the amount of disintegrant is within the range of 2%-10% (Example 1, Example 2, Example 3), the homemade samples of amlodipine and lisinopril can achieve rapid dissolution (greater than 85% in 15 minutes), while when the amount of disintegrant is less than 2% (Comparative Example 1), the dissolution rate of amlodipine slows down significantly and cannot achieve rapid dissolution. In addition, the difference in solubility before 20 minutes is more than 10%, reflecting a significant difference in dissolution characteristics.

[0097] Example 5 Mixing uniformity test

[0098] The mixing uniformity of the total mixed powders of Example 1, Example 2, Example 3, Comparative Example 2, and Comparative Example 3 was sampled and tested to compare the mixing uniformity of amlodipine besylate and lisinopril. The results are shown in Table 12 below:

[0099] Table 12. Mixing uniformity test results

[0100]

[0101] The mixing uniformity results show that under the same mixing conditions (premixing for 15 minutes + total mixing for 5 minutes) in Example 1 and Comparative Example 2, the amlodipine and lisinopril contents were within the target range. However, in the direct mixing process of Comparative Example 2, a single point of amlodipine content exceeded the mean by 10%, and the mean RSD of the content was >5.0%. This indicates that in the layered mixing process of Example 1, the amlodipine content in the single layer (5%) was higher than in the direct mixing of all materials (2.5%), indicating that the mixing uniformity was better under the same mixing parameters.

[0102] Example 6 Stability Test

[0103] The samples of Example 1, Example 2, Example 3 and Comparative Example 2, Comparative Example 3 were subjected to an accelerated stability test and a light stability test to compare the stability of the samples.

[0104] Accelerated stability test: Place the product at a temperature of 40±2°C and a relative humidity of 75±5% for 6 months. Take samples once in the 1st, 2nd, 3rd and 6th month of the experiment, and determine the relevant substances by high performance liquid chromatography. The results are compared with those in 0 month. See the table below.

[0105] Light stability test: The samples were placed under natural light, ultraviolet light and light (5000±500lx) conditions, and the photodegradation impurities B and D were determined by high performance liquid chromatography. The results are shown in Tables 13-14 below.

[0106] Table 13. Accelerated stability test results

[0107]

[0108]

[0109] Table 14. Light stability test results

[0110]

[0111] Note: ND means not detected.

[0112] The accelerated stability test and light irradiation test showed that, compared with the sample of Comparative Example 2 (direct mixing and tableting) and the sample of Comparative Example 3 (wet granulation process), the samples prepared by the method of the present invention (Example 1, Example 2, Example 3) had a significantly slower increase in lisinopril degradation impurity A (lisinopril EP impurity A) and total impurities, and were more stable to light.

Claims

1. A compound lisinopril and amlodipine double-layer tablet comprising: The first layer is an amlodipine besylate layer, which contains the active ingredient amlodipine besylate and pharmaceutically acceptable excipients; the second layer is a lisinopril layer, which contains the active ingredient lisinopril and pharmaceutically acceptable excipients. It is characterized in that the double-layer tablet is made by a powder direct compression tableting process.

2. The compound lisinopril and amlodipine bilayer tablet according to claim 1, wherein the first layer is composed of 5 parts of amlodipine besylate (calculated as amlodipine), 83-92.5 parts of microcrystalline cellulose, 2-10 parts of sodium starch glycolate, and 0.5-2 parts of magnesium stearate, and the second layer is composed of 10 parts of lisinopril, 78-87.5 parts of microcrystalline cellulose, 2-10 parts of sodium starch glycolate, and 0.5-2 parts of magnesium stearate, wherein the parts are calculated by weight.

3. The compound lisinopril-amlodipine double-layer tablet according to claim 1, wherein the weight percentage of each layer is as follows, and the component composition of the amlodipine besylate layer is: The components of the lisinopril layer are:

4. The compound lisinopril and amlodipine double-layer tablet according to claim 3, The component of described amlodipine besylate layer is: The components of the lisinopril layer are:

5. A method for preparing the compound lisinopril and amlodipine double-layer tablets according to any one of claims 1 to 4, characterized in that: Both layers are made by direct powder mixing and tableting, which includes: (1) Mix the prescribed amount of amlodipine besylate, microcrystalline cellulose, and sodium starch glycolate, and then add magnesium stearate and mix evenly to form the first layer; (2) Take the prescribed amount of lisinopril, microcrystalline cellulose, and sodium starch glycolate and mix them evenly, then add magnesium stearate and mix evenly to form the second tablet layer: (3) The first layer and the second layer are added to a double-layer tablet press respectively and pressed into double-layer tablets.

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