Preparation method of pharmaceutical preparation containing amlodipine and bisoprolol

Abstract

The invention provides a preparation process of a pharmaceutical preparation containing amlodipine and bisoprolol. The preparation process comprises the following steps: respectively granulating a bisoprolol fumarate part and an amlodipine besylate part by a dry method, then mixing bisoprolol fumarate particles, a lubricant and amlodipine besylate particles, and tabletting. According to the method, the bisoprolol fumarate and amlodipine besylate bulk drugs can be blocked to a greater extent, and the stability of the tablet is improved.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a method for preparing a pharmaceutical preparation containing amlodipine and bisoprolol. Background Art

[0002] In recent years, both international and domestic hypertension guidelines have consistently recommended starting SPC (new single-tablet combination preparation) treatment because it can simply and efficiently solve the two key issues faced by hypertension management: combined treatment and compliance.

[0003] There are currently several fixed combinations on the market containing a calcium channel blocker ("calcium antagonist") and a beta-blocker, preferably for the treatment of hypertension and angina pectoris, such as tablets containing felodipine and metoprolol or nifedipine and atenolol.

[0004] International Patent Application No. WO2005 / 099699 discloses a combination of S-amlodipine and a beta blocker, including a combination with bisoprolol. However, this application does not address the main problem of practical application, which is the chemical incompatibility of the two active ingredients.

[0005] Chinese patent application CN102164585B granulates and tablets amlodipine besylate and bisoprolol fumarate together, and then packages the composition in a moisture-proof package. In this production process, since amlodipine besylate and bisoprolol fumarate come into contact and react to produce degradation products after feeding, it is necessary to strictly control the environmental humidity during the entire production process and shorten the production process as much as possible to ensure that the preparation produced by this process has good quality and good stability.

[0006] Indian Patent Application IN845MUM2004 found that amlodipine besylate and bisoprolol fumarate reacted with each other to produce a new impurity, N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridin-2-yl]methoxy}ethyl)aspartic acid (amlodipine and bisoprolol addition impurity). Currently, the import drug registration standard for bisoprolol amlodipine tablets (Standard No.: JX20210038) requires that the limit of this impurity (impurity AML-2) in the composition be ≤1.0%. According to Patent IN845MUM2004, a composition of amlodipine besylate and bisoprolol fumarate can be prepared only when the active ingredients are separated in different granules, and the granules are further mixed with excipients and filled into capsules or sachets, or pressed into bilayer tablets. This patent discloses wet granulating amlodipine besylate and bisoprolol fumarate granules separately, and then mixing the bisoprolol fumarate granules and amlodipine besylate granules together, further lubricating and pressing them into tablets. This patent method has several disadvantages, such as granulating the active ingredients separately and preparing bilayer tablets, but there is still a large contact surface between the two active ingredients, and the chemical reaction between amlodipine base and fumaric acid to form impurity products cannot be completely avoided, resulting in risks to stability and safety.

[0007] Chinese Patent Application CN114668760A discloses dry granulating and tabletting to obtain amlodipine tablets, mixing bisoprolol fumarate and excipients, pressing a bisoprolol layer on the amlodipine tablets, and coating the shell layer to obtain bisoprolol amlodipine preparations.

[0008] Although the above bisoprolol amlodipine preparations can block the contact between bisoprolol and amlodipine to a certain extent and improve stability, there is still room for improvement. Summary of the Invention

[0009] In order to improve the stability of pharmaceutical preparations containing amlodipine besylate and bisoprolol fumarate, the present invention provides a preparation process for a pharmaceutical preparation containing amlodipine besylate and bisoprolol fumarate with improved stability.

[0010] A preparation process for a pharmaceutical preparation containing amlodipine besylate and bisoprolol fumarate, comprising:

[0011] (a) Premixing,

[0012] For the bisoprolol fumarate part: mixing bisoprolol fumarate and excipients;

[0013] For the amlodipine besylate part: mixing amlodipine besylate and excipients;

[0014] (b) Dry granulating,

[0015] The bisoprolol fumarate portion after premixing in the dry granulation step (a) is granulated to obtain bisoprolol fumarate granules;

[0016] The amlodipine besylate portion after premixing in the dry granulation step (a) is granulated to obtain amlodipine besylate granules;

[0017] (c) Total mixing,

[0018] The bisoprolol fumarate granules, lubricant, and amlodipine besylate granules described in step (b) are sequentially added and mixed;

[0019] (d) Tabletting,

[0020] The product obtained in step (c) is tabletted.

[0021] In one embodiment, before premixing, there is also a step of sieving and removing lumps of bisoprolol fumarate, amlodipine besylate, and excipients.

[0022] In one embodiment, the excipients for the bisoprolol fumarate portion in step (a) include a filler, a disintegrant, and a glidant, and the excipients for the amlodipine besylate portion in step (a) include a filler, a disintegrant, and a glidant.

[0023] In one embodiment, the filler for the bisoprolol fumarate portion in step (a) is selected from microcrystalline cellulose, lactose, starch, or pregelatinized starch; the disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, or low-substituted hydroxypropyl cellulose; the glidant is selected from colloidal silicon dioxide, stearic acid, or sodium stearyl fumarate.

[0024] In one embodiment, the filler for the amlodipine besylate portion in step (a) is selected from microcrystalline cellulose, lactose, starch, or pregelatinized starch; the disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, or low-substituted hydroxypropyl cellulose; the glidant is selected from colloidal silicon dioxide, stearic acid, or sodium stearyl fumarate.

[0025] In one embodiment, the lubricant in step (c) is selected from magnesium stearate, stearic acid, or sodium stearyl fumarate.

[0026] Advantages of the present invention: In the preparation process of the present invention, the bisoprolol fumarate portion and the amlodipine besylate portion are dry granulated separately, and then the bisoprolol fumarate granules, lubricant, and amlodipine besylate granules are mixed and then tabletted. This method can block the bisoprolol fumarate and amlodipine besylate raw materials to a greater extent and improve the stability of the tablets. Detailed implementation mode

[0027] Comparative example 1 (original research prescription):

[0028] Prescription composition:

[0029] Name Prescription Quantity (g) Function Amlodipine Besylate 13.9 Active Ingredient 1 Bisoprolol Fumarate 10.0 Active Ingredient 2 Microcrystalline Cellulose 265.1 Filler Sodium Starch Glycolate 10.0 Disintegrant Colloidal Silicon Dioxide 2.0 Glidant Magnesium Stearate 4.0 Lubricant

[0030] The process is as follows:

[0031] Sieve the two active ingredients (amlodipine besylate and bisoprolol fumarate) through a 25-μm sieve, then homogenize them with microcrystalline cellulose, sodium carboxymethyl starch, and colloidal silicon dioxide in a drum mixer for 10 minutes. Then add magnesium stearate into the mixer and homogenize the resulting mixture for 2 minutes;

[0032] Press the mixture into tablets with a tablet weight of 305 mg using a tableting machine;

[0033] Load the tablets into blisters made of cold-formed OPA / AL / PVC composite foil with a thickness of 130 μm and cover them with 20-μm aluminum foil.

[0034] Example 1: Amlodipine Besylate and Bisoprolol Fumarate Tablets

[0035] The specific prescription ratios are as follows:

[0036]

[0037] (1) Weigh each raw and auxiliary material according to the prescription and set aside;

[0038] (2) Mixing

[0039] For the bisoprolol fumarate part: Sieve and mix the microcrystalline cellulose, sodium carboxymethyl starch, and colloidal silicon dioxide in the prescribed amounts;

[0040] For the amlodipine besylate part: Sieve and mix the microcrystalline cellulose, sodium carboxymethyl starch, and colloidal silicon dioxide in the prescribed amounts;

[0041] (3) Dry granulation

[0042] For the bisoprolol fumarate combination: Use a dry granulator to granulate the bisoprolol fumarate combination;

[0043] For the amlodipine besylate combination: Use a dry granulator to granulate the amlodipine besylate combination;

[0044] (4) Total mixing

[0045] Mix the above two combined granules, and then mix them with the glidant magnesium stearate;

[0046] (5) Tableting

[0047] Press the above total-mixed granules into tablets; obtain the compound tablets.

[0048] Example 2: Dissolution Examination in Different Media

[0049] Using 0.005 mol / L hydrochloric acid solution, pH 4.5 acetate buffer solution, pH 6.8 phosphate buffer solution and water as dissolution media respectively, the dissolution curves of the self-made and reference products were determined.

[0050] Dissolution media: 900 ml of water, 0.005 mol / L hydrochloric acid solution, pH 4.5 acetate buffer solution and pH 6.8 phosphate buffer solution were used as dissolution media respectively.

[0051] Dissolution method: The second paddle method in Appendix XC of Part II of Chinese Pharmacopoeia 2020 edition.

[0052] Rotation speed: 50 rpm

[0053] Sampling points: At 5, 10, 15, 20, 30, 45, and 60 min respectively, 10 ml of the dissolution solution was taken, filtered through a 0.45 μm polyethersulfone filter membrane, and an equal volume of the dissolution medium at the same temperature was added simultaneously.

[0054] Determination method: The filtered dissolution solution was taken as the test solution; an appropriate amount of the reference substance was taken, dissolved and diluted with the corresponding dissolution medium to obtain the reference solution. The test solution and the reference solution were taken respectively, and the dissolution was calculated and the cumulative dissolution curve was plotted according to the high performance liquid chromatography method (Appendix VD of Part II of Chinese Pharmacopoeia 2020 edition).

[0055] Table 1: Dissolution in pH 6.8 medium

[0056]

[0057]

[0058] Table 2: Dissolution in pH 4.5 medium

[0059]

[0060] Table 3: Dissolution in pure water medium is as follows:

[0061]

[0062]

[0063] Table 4: Dissolution in 0.005 mol / L hydrochloric acid medium is as follows:

[0064]

[0065] The results showed that: in the dissolution of bisoprolol fumarate, the cumulative dissolution of the two groups of samples was greater than 85% at 15 min, both were rapid dissolution, and there was no significant difference in the dissolution trend. The dissolution results of amlodipine besylate showed that there was basically no difference in the dissolution trend between the two groups of samples.

[0066] Example 3: Stability study

[0067] The self-made tablets and the control preparation tablets (without packaging) were respectively placed under accelerated conditions (40 °C / 75% RH), and samples were taken in January to detect their related substances. The results are as follows:

[0068] Table 5 Results of stability investigation of different batches of preparations

[0069]

[0070] The above results show that: the total impurities on the 0th day of Example 1 are slightly higher than those of Comparative Example 1, but after 28 days of accelerated test, the impurities BIS-1, impurity AML-1, impurity AML-2, impurity BIS-2 and total impurities of the sample in Comparative Example 1 are all higher than those in Example 1. In summary, the stability of the tablets prepared by the dry granulation process is better than that of Comparative Example 1.

[0071] Example 4: Investigation on the stability and dissolution of tablet preparations with different proportions of microcrystalline cellulose

[0072] The prescriptions of R1, R2, and R3 are shown in Table 6, and the process is the same as that of Example 1.

[0073] Stability test:

[0074] The three batches of self-made tablets were respectively placed under accelerated conditions (40 °C / 75% RH) after being packaged with double aluminum foil, and samples were taken in January to detect their related substances;

[0075] Dissolution test:

[0076] Using pH 6.8 phosphate buffer as the dissolution medium, the dissolution curve of the self-made preparation was measured.

[0077] Dissolution medium: pH 6.8 phosphate buffer was used as the dissolution medium

[0078] Dissolution method: The second paddle method in Appendix XC of Part II of the Chinese Pharmacopoeia 2020 edition

[0079] Rotation speed: 50 rpm

[0080] Sampling points: At 5, 10, 15, 20, 30, 45, and 60 minutes respectively, 10 ml of the dissolution solution was taken, filtered through a 0.45 μm polyethersulfone membrane, and an equal amount of the dissolution medium at the same temperature was added at the same time.

[0081] Determination method: The filtered dissolution solution was taken as the test solution; an appropriate amount of the reference substance was taken, dissolved and diluted with the corresponding dissolution medium to obtain the reference solution. The test solution and the reference solution were respectively taken, and the dissolution was calculated and the cumulative dissolution curve was plotted according to the high performance liquid chromatography method (Appendix VD of Part II of the Chinese Pharmacopoeia 2020 edition).

[0082] Table 6-1 Prescriptions of microcrystalline cellulose with different proportions

[0083]

[0084]

[0085] Table 6-2 Microcrystalline Cellulose Prescriptions with Different Proportions

[0086]

[0087] Table 6-3 Microcrystalline Cellulose Prescriptions with Different Proportions

[0088]

[0089] Table 7

[0090]

[0091]

[0092] Table 8

[0093]

[0094] As can be seen from Tables 7-8, the R1-3 prescriptions all have good dissolution and stability.

Claims

1. Preparation process of a pharmaceutical preparation containing amlodipine besylate and bisoprolol fumarate, comprising: (a) Premixing, For the bisoprolol fumarate part: Mix bisoprolol fumarate and excipients; For the amlodipine besylate part: Mix amlodipine besylate and excipients; (b) Dry granulation, Perform dry granulation on the premixed bisoprolol fumarate part in step (a) to obtain bisoprolol fumarate granules; Perform dry granulation on the premixed amlodipine besylate part in step (a) to obtain amlodipine besylate granules; (c) Total mixing, Sequentially add the bisoprolol fumarate granules, lubricant, and amlodipine besylate granules described in step (b) and mix; (d) Tabletting, Tablet the product obtained in step (c).

2. The preparation method according to claim 1, characterized in that One step before premixing further includes the step of sieving and removing lumps of bisoprolol fumarate, amlodipine besylate, and excipients.

3. The preparation method according to claim 2, wherein The excipients for the bisoprolol fumarate part in step (a) include filler, disintegrant, and glidant, and the excipients for the amlodipine besylate part in step (a) include filler, disintegrant, and glidant.

4. The preparation method according to claim 3, characterized in that The filler for the bisoprolol fumarate part in step (a) is selected from microcrystalline cellulose, lactose, starch, or pregelatinized starch; the disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, or low-substituted hydroxypropyl cellulose; the glidant is selected from colloidal silicon dioxide, stearic acid, or sodium stearyl fumarate.

5. The preparation method according to claim 3, characterized in that The filler for the amlodipine besylate part in step (a) is selected from microcrystalline cellulose, lactose, starch, or pregelatinized starch; the disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, or low-substituted hydroxypropyl cellulose; the glidant is selected from colloidal silicon dioxide, stearic acid, or sodium stearyl fumarate.

6. The preparation method according to claim 1, characterized in that The lubricant in step (c) is selected from magnesium stearate, stearic acid, or sodium stearyl fumarate.

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