Bisoprolol amlodipine solid composition

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a bisoprolol amlodipine solid composition and a preparation method thereof. According to the bisoprolol amlodipine solid composition disclosed by the invention, the generation of an amlodipine impurity II is avoided from the source by changing the salt type of bisoprolol; meanwhile, auxiliary materials are screened, and microcrystalline cellulose is replaced by mannitol and hydroxypropyl methylcellulose, so that the tablet is more stable in hardness, friability, dissolution rate and other properties in stability investigation.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a bisoprolol amlodipine solid composition and a preparation method thereof. Background Art

[0002] Bisoprolol amlodipine tablets are the only long-acting single-tablet compound preparation (SPC) of β-blocker (BB) + calcium channel blocker (CCB) currently on the market in China. The active ingredients are bisoprolol fumarate and amlodipine besylate, which are suitable for patients with hypertension combined with high sympathetic activity and hypertension combined with coronary heart disease, bringing dual control of blood pressure and heart rate, and are one of the combination regimens recommended by the guidelines.

[0003] According to Indian Patent No. 845 / MUM / 2004, amlodipine besylate and bisoprolol fumarate react with each other. Specifically, amlodipine reacts with fumaric acid through a chemical reaction to produce the impurity N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]-methoxy}-ethyl)-aspartic acid, that is, the amlodipine impurity shown in formula (II):

[0004]

[0005] The original research patent CN102164585B discloses a method for effectively controlling the above-mentioned impurity II. By using a special moisture-proof packaging and selecting microcrystalline cellulose with a low humidity level in production, it is necessary to prevent the product from getting wet during production and the storage environment needs to be dry, so as to control the addition impurity of bisoprolol fumarate and amlodipine within 0.5%. However, these drying and moisture-proof measures cause certain difficulties in industrial production and storage, increasing the industrial cost.

[0006] The inventors found during the research of this product that using microcrystalline cellulose with a low humidity level significantly helps to solve the impurity II of bisoprolol amlodipine tablets, but problems such as a decrease in the hardness of the plain tablets and a significant decrease in the dissolution of amlodipine during the dissolution curve investigation will occur during the stability investigation. Through continuous exploration, it is found that these problems are firstly due to the adsorption of amlodipine by microcrystalline cellulose, resulting in delayed dissolution; secondly, during the stability investigation, microcrystalline cellulose with low moisture is more likely to absorb moisture, leading to a decrease in the hardness of the tablets and faster disintegration. In the dissolution medium, the plain tablets with low hardness will disintegrate quickly, and the accumulated microcrystalline cellulose hinders the dissolution of amlodipine raw materials. However, replacing microcrystalline cellulose with other excipients will result in a high level of impurity II.

[0007] In view of the problems existing in the prior art, a stable bisoprolol amlodipine composition is needed to ensure that impurity II always remains at a low level; at the same time, during the stability study, the tablet hardness remains stable, there is no tablet crumbling, the friability is appropriate, and there is no tablet chipping during transportation; and it can improve the dissolution rate of amlodipine. Summary of the Invention

[0008] First, regarding the problem of impurity II, the inventors considered screening different acid radicals to replace fumaric acid. Without affecting the bioavailability of the drug, the generation problem of impurity II was fundamentally solved. Through a large number of experimental investigations and screening from numerous acid radicals, it was finally found that using benzoic acid or succinic acid to replace fumaric acid to form a salt with bisoprolol can not only solve the addition reaction problem between fumaric acid and amlodipine, but also benzoic acid bisoprolol or succinic acid bisoprolol has good formulation stability and dissolution effect in the compound preparation.

[0009] After solving the problem of impurity II, the inventors further screened various excipients. For different types of microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, etc., due to the problem of high density of the excipients, there was a stacking problem during the dissolution test, and the dissolution of amlodipine was low. Then, attempts were made to add excipients with low density or soluble excipients to the formulation. Through continuous screening, it was surprisingly found that using mannitol and hypromellose to replace microcrystalline cellulose can not only solve the problem that amlodipine is stacked at the bottom and the dissolution becomes slower, but also the tablets prepared can maintain a relatively appropriate hardness, and there will be no tablet crumbling, increased friability, or tablet chipping during transportation.

[0010] Specifically, the present invention provides the following technical solutions:

[0011] In a first aspect, the present invention provides a bisoprolol amlodipine solid composition, and the solid composition comprises the following components: bisoprolol salt, amlodipine besylate, mannitol, and hypromellose.

[0012] The bisoprolol salt is benzoic acid bisoprolol or succinic acid bisoprolol.

[0013] Preferably, the weight ratio of bisoprolol salt to amlodipine besylate in the composition is 1:1, both calculated as the free base.

[0014] Preferably, the weight ratio of mannitol to hypromellose in the composition is 1:1.

[0015] Preferably, the weight ratio of the active ingredient (calculated as the sum of the free bases of the two compounds) to mannitol in the composition is 1:1 to 7.5; preferably 1:2.5 to 5.

[0016] The composition may further contain pharmaceutically acceptable excipients, such as disintegrants, lubricants, etc. For example, the disintegrant may be selected from one or two of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, etc. For example, the lubricant may be selected from one or more of magnesium stearate, calcium stearate, talc, sodium stearyl fumarate. The dosage of the excipient is a conventional dosage in the art. For example, the weight ratio of the active ingredient to the lubricant may be 1:0.02 - 0.8, preferably 1:0.05 - 0.5; the weight ratio of the active ingredient to the disintegrant is 1:0.05 - 1.5, preferably 1:0.1 - 1; or a reasonable adjustment is made on this basis.

[0017] Preferably, the solid composition may be further made into bisoprolol amlodipine tablets, and the tablets contain bisoprolol salt, amlodipine besylate, mannitol, hypromellose, disintegrant, lubricant; it may also further contain flavoring agent, coating agent.

[0018] Preferably, the bisoprolol amlodipine tablets are prepared from the following raw materials in parts by weight: 2 - 10 parts of bisoprolol salt, 2 - 10 parts of amlodipine besylate, 8 - 300 parts of mannitol / hypromellose in total, 0.2 - 30 parts of disintegrant, 0.08 - 16 parts of lubricant; wherein the active ingredients are all calculated as free bases; the raw materials may further contain flavoring agent and coating agent in conventional dosages in the art.

[0019] More preferably, the bisoprolol amlodipine tablets are prepared from the following raw materials in parts by weight: 5 parts of bisoprolol salt, 5 parts of amlodipine besylate, 20 - 150 parts of mannitol / hypromellose in total, 1 - 10 parts of disintegrant, 0.5 - 5 parts of lubricant; wherein the active ingredients are all calculated as free bases; the raw materials may further contain flavoring agent and coating agent in conventional dosages in the art.

[0020] Preferably, the solid composition may be further made into bisoprolol amlodipine capsules, and the capsules contain bisoprolol salt, amlodipine besylate, mannitol, hypromellose, lubricant; it may also further contain disintegrant.

[0021] Preferably, the granules in the bisoprolol amlodipine capsules are prepared from the following raw materials in parts by weight: 2 - 10 parts of bisoprolol salt, 2 - 10 parts of amlodipine besylate, 8 - 300 parts of mannitol / hypromellose in total, 0.08 - 16 parts of lubricant; wherein the active ingredients are all calculated as free bases; the raw materials may further contain disintegrant in conventional dosage. More preferably, the granules in the bisoprolol amlodipine capsules are prepared from the following raw materials in parts by weight: 5 parts of bisoprolol salt, 5 parts of amlodipine besylate, 20 - 150 parts of mannitol / hypromellose in total, 0.5 - 5 parts of lubricant; wherein the active ingredients are all calculated as free bases; the raw materials may further contain disintegrant in conventional dosage in the art.

[0022] In a second aspect, the present invention also provides a method for preparing a bisoprolol amlodipine solid composition into tablets or capsules, comprising the following steps: uniformly mixing a bisoprolol salt, amlodipine besylate, mannitol, hypromellose, and a disintegrant; adding a lubricant and mixing uniformly; tabletting or filling capsules.

[0023] When the dosage form of the bisoprolol amlodipine solid composition is a capsule, the preparation method may also be: uniformly mixing a bisoprolol salt, amlodipine besylate, mannitol, and hypromellose; adding a lubricant and mixing uniformly; filling capsules.

[0024] Advantages of the present invention:

[0025] The present invention provides a new bisoprolol amlodipine solid composition. During the research process, the inventors found that using bisoprolol benzoate or bisoprolol succinate instead of bisoprolol fumarate can completely avoid the generation of amlodipine impurity II, and fundamentally solve the compatibility problem between bisoprolol fumarate and amlodipine besylate. At the same time, using mannitol and hypromellose instead of microcrystalline cellulose effectively avoids problems such as decreased hardness, tablet capping, increased friability, and tablet chipping caused by moisture absorption during the stability study of tablets; it solves the problem that during the accelerated conditions, the rapid disintegration of tablets causes accumulation, resulting in slower dissolution. The present invention also provides a preparation method for a bisoprolol amlodipine solid composition preparation, which is simple in operation and easy to be industrially applied. Detailed implementation manners

[0026] The present invention will be further described below through examples. It should be understood that the following examples are only for illustrative purposes and are not used to limit the protection scope of the present invention. At the same time, obvious changes and modifications made by those of ordinary skill in the art according to the present invention are also included in the protection scope of the present invention. The weight parts of the active ingredients in the formulation prescriptions of the examples are all calculated as the free base.

[0027] Example 1

[0028] Prescription:

[0029]

[0030] Preparation process: Mix the prescribed amounts of bisoprolol benzoate, amlodipine besylate, mannitol / hypromellose, and sodium carboxymethyl starch in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 min, add talc powder and mix for 5 min; tablet.

[0031] Example 2

[0032] Prescription:

[0033]

[0034] Preparation process: Mix the prescribed amounts of bisoprolol succinate, amlodipine besylate, mannitol / hydroxypropyl methylcellulose, and sodium carboxymethyl starch in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add talc and mix for 5 minutes; then press tablets.

[0035] Example 3

[0036] Prescription:

[0037]

[0038] Preparation process: Mix the prescribed amounts of bisoprolol benzoate, amlodipine besylate, mannitol / hydroxypropyl methylcellulose, and croscarmellose sodium in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add talc and mix for 5 minutes; then press tablets.

[0039] Example 4

[0040] Prescription:

[0041]

[0042] Preparation process: Mix the prescribed amounts of bisoprolol benzoate, amlodipine besylate, mannitol / hydroxypropyl methylcellulose, and crospovidone in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add magnesium stearate and mix for 5 minutes; then press tablets.

[0043] Example 5

[0044] Prescription:

[0045]

[0046] Preparation process: Mix the prescribed amounts of bisoprolol benzoate, amlodipine besylate, mannitol / hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add sodium stearyl fumarate and mix for 5 minutes; then press tablets.

[0047] Example 6

[0048] Prescription:

[0049]

[0050] Preparation process: Mix the prescribed amounts of bisoprolol benzoate, amlodipine besylate, mannitol / hydroxypropyl methylcellulose, and sodium carboxymethyl starch in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add talc and mix for 5 minutes; then fill into capsules.

[0051] Example 7

[0052] Prescription:

[0053]

[0054]

[0055] Preparation process: Mix the prescribed amounts of bisoprolol succinate, amlodipine besylate, mannitol, hypromellose, and sodium carboxymethyl starch in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add talc powder and mix for 5 minutes; then press tablets.

[0056] Example 8

[0057] Prescription:

[0058]

[0059] Preparation process: Mix the prescribed amounts of bisoprolol succinate, amlodipine besylate, mannitol / hypromellose, and sodium carboxymethyl starch in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add talc powder and mix for 5 minutes; then press tablets.

[0060] Comparative Example 1

[0061]

[0062] Preparation process: Mix the prescribed amounts of bisoprolol benzoate, amlodipine besylate, microcrystalline cellulose, and sodium carboxymethyl starch in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add talc powder and mix for 5 minutes; then press tablets.

[0063] Comparative Example 2

[0064]

[0065] Preparation process: Mix the prescribed amounts of bisoprolol fumarate, amlodipine besylate, mannitol / hypromellose, and sodium carboxymethyl starch in a mixer for 10 minutes, pass through a 1.0 mm sieve, mix for another 10 minutes, add talc powder and mix for 5 minutes; then press tablets.

[0066] Verification Example

[0067] 1. Related Substances Detection

[0068] Determined by high performance liquid chromatography (General Chapter 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition). Using octadecylsilane chemically bonded silica gel as the filler (Thermo Acclaim C18, 4.6×250mm, 5μm or a chromatographic column with equivalent efficiency); using 0.05mol / L ammonium dihydrogen phosphate solution (adjust the pH value to 4.5 with phosphoric acid)-acetonitrile (90:10) as the mobile phase; the detection wavelength is 220nm; the flow rate is 1ml per minute; the column temperature is 30°C; the injection volume is 10μl. Operate under light protection. The specific results are shown in Table 1.

[0069] Table 1 Results of the determination of related substances in examples and comparative examples

[0070]

[0071]

[0072] As can be seen from Table 1, after 3 months of the test at 40°C / 75% RH for Examples 1-8, impurity II was never detected, and the content of total impurities was controlled within a relatively low range. Comparative Example 1 was a control test in which mannitol / hydroxypropyl methylcellulose was changed to microcrystalline cellulose on the basis of Example 1. Impurity II was not detected either when the sample was prepared (0 days) or after 3 months of the test at 40°C / 75% RH; Comparative Example 2 was a control test in which bisoprolol benzoate was changed to bisoprolol fumarate on the basis of Example 1. Impurity II was detected both when the sample was prepared (0 days) and after 3 months of the test at 40°C / 75% RH, and there was an obvious increasing trend.

[0073] 2. Investigation of dissolution curve

[0074] Determined according to the method for the determination of dissolution and release (Method 2, General Chapter 0931, Volume IV, Chinese Pharmacopoeia 2020 Edition). Operate under light protection. Dissolution conditions: Using 900ml of pH6.8 phosphate buffer solution as the dissolution medium, the rotation speed is 50 revolutions per minute. Operate according to the law, and sample sequentially at 5min, 10min, 15min, and 30min. The results are shown in Table 2 and Table 3.

[0075] Table 2 Investigation of dissolution curve (0 days)

[0076]

[0077]

[0078] Table 3 Investigation of dissolution curve after 3 months of acceleration (40°C / 75% RH)

[0079]

[0080]

[0081] As can be seen from Tables 2 to 3, after 3 months of testing at 40°C / 75% RH, the dissolution of amlodipine did not decrease in Examples 1-6. Comparative Example 1 was a control test in which mannitol / hydroxypropyl methylcellulose was changed to microcrystalline cellulose based on Example 1. After 3 months of testing at 40°C / 75% RH, the dissolution of amlodipine became significantly slower.

[0082] 3. Investigation of hardness and friability

[0083] Hardness detection: detected with a tablet hardness tester, 10 tablets were detected each time, and the average value was taken. Friability: determined by the friability test method for tablets (General Chapter 0923, Volume IV, Chinese Pharmacopoeia 2020 Edition). The results are shown in Table 4.

[0084] Table 4. Results of the investigation of hardness and friability

[0085]

[0086] As can be seen from Table 4, after 3 months of testing at 40°C / 75% RH, neither the hardness nor the friability of Examples 1-6 changed significantly. Comparative Example 1 was a control test in which mannitol / hydroxypropyl methylcellulose was changed to microcrystalline cellulose based on Example 1. After 3 months of testing at 40°C / 75% RH, there was a tendency for the hardness to decrease and the friability to increase.

Claims

1. A bisoprolol amlodipine solid composition, the solid composition comprising the following components: bisoprolol salt, amlodipine besylate, mannitol, hypromellose.

2. The solid composition according to claim 1, wherein, the bisoprolol salt is bisoprolol benzoate or bisoprolol succinate.

3. The solid composition according to claim 1, wherein, the weight ratio of the bisoprolol salt to amlodipine besylate is 1:1, both calculated as the free base.

4. The solid composition according to claim 1, wherein, the weight ratio of mannitol to hypromellose is 1:

1.

5. The solid composition according to claim 1, wherein, the weight ratio of the active ingredient to mannitol in the composition is 1:1 to 7.5, wherein the active ingredient is calculated as the free base.

6. The solid composition according to claim 1, wherein, the dosage form of the solid composition is a tablet, comprising the following components: bisoprolol salt, amlodipine besylate, mannitol, hypromellose, disintegrant, lubricant.

7. The solid composition according to claim 6, wherein, the tablet is prepared from the following raw materials in parts by weight: 2 - 10 parts of bisoprolol salt, 2 - 10 parts of amlodipine besylate, 8 - 300 parts of mannitol / hypromellose in total, 0.2 - 30 parts of disintegrant, 0.08 - 16 parts of lubricant; wherein the active ingredient is calculated as the free base.

8. The solid composition according to claim 6, wherein, the tablet is prepared from the following raw materials in parts by weight: 5 parts of bisoprolol salt, 5 parts of amlodipine besylate, 20 - 150 parts of mannitol / hypromellose in total, 1 - 10 parts of disintegrant, 0.5 - 5 parts of lubricant; wherein the active ingredient is calculated as the free base.

9. The solid composition according to claim 1, wherein, the dosage form of the solid composition is a capsule, comprising the following components: bisoprolol salt, amlodipine besylate, mannitol, hypromellose, lubricant.

10. A preparation method of a bisoprolol amlodipine solid composition into a tablet, comprising the following steps: mixing bisoprolol salt, amlodipine besylate, mannitol, hypromellose, and disintegrant evenly; adding a lubricant and mixing evenly; tabletting.

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