Bisoprolol amlodipine solid preparation

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a bisoprolol amlodipine solid preparation and a preparation method thereof. According to the bisoprolol and amlodipine solid preparation disclosed by the invention, bisoprolol fumarate is replaced by bisoprolol, so that the problem that raw materials of bisoprolol fumarate and amlodipine are incompatible is solved; the bisoprolol is dissolved in acetone, and the amlodipine besylate and common auxiliary materials are granulated, so that the problem of content uniformity of the oily bisoprolol and amlodipine mixed preparation is solved. Meanwhile, the preparation method of the solid preparation is simple, easy to operate and suitable for industrial application.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a bisoprolol amlodipine solid preparation and a preparation method thereof. Background Art

[0002] The situation of hypertension prevention and control in my country is grim, with the number of patients reaching 245 million, but the control rate is only 16.8%.

[0003] Bisoprolol fumarate is a beta-receptor blocker that inhibits the beta-receptor activity of bronchial and vascular smooth muscle. 1 -Receptors have high affinity, which dilates blood vessels and lowers blood pressure. It is suitable for hypertension, coronary heart disease, and moderate to severe chronic stable heart failure.

[0004] Amlodipine besylate is a long-acting calcium channel inhibitor clinically used to treat cardiovascular diseases such as hypertension.

[0005] Bisoprolol amlodipine tablets are the only long-acting single-tablet compound preparation (SPC) of beta-blocker (BB) + calcium channel blocker (CCB) currently available in China. Through the triple action mechanism of inhibiting sympathetic nerve overexcitation, inhibiting overactivation of renin-angiotensin-aldosterone system (RAAS), and relaxing peripheral arterial blood vessels, it can effectively control heart rate while exerting a synergistic antihypertensive effect, thus achieving dual control of blood pressure and heart rate. Moreover, the combination of the two types of drugs helps to reduce adverse drug reactions, among which BB can offset the increased heart rate caused by reflex sympathetic nerve excitation in CCB treatment to a certain extent, while CCB can reduce the peripheral vasoconstriction effect that may occur in BB treatment.

[0006] Patent WO 2005 / 099699 discloses a pharmaceutical composition comprising optically pure (S) amlodipine and a beta-receptor blocker, wherein the beta-receptor blocker is selected from atenolol or bisoprolol. However, the invention does not study the drug compatibility of amlodipine and bisoprolol.

[0007] According to Indian Patent No. 845 / MUM / 2004, amlodipine besylate and bisoprolol fumarate react with each other to produce an impurity N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridyl]-methoxy}-ethyl)-aspartic acid, i.e., an amlodipine impurity shown in formula (II):

[0008]

[0009] The impurity is formed by the chemical reaction of amlodipine and fumaric acid, and the composition of amlodipine besylate and bisoprolol fumarate can only be prepared when the active ingredients are separated in different particles. The particles are further mixed with excipients and filled into capsules or medicine bags, or pressed into so-called double-layer tablets. That is, the key to solving the problem of the Indian patent is to separate the two components from each other. This basically prevents physical contact between the active ingredients, and helps to form added impurities during the process of mixing particles, especially in the compression process with dense contact on a large surface area. However, the invention is prepared into double-layer tablets, which requires complex and special equipment, and there is a problem of low yield in the tableting process.

[0010] Patent CN102164585B discloses a composition containing amlodipine and bisoprolol. In the preparation process, it is not necessary to separate amlodipine and bisoprolol fumarate, but the added impurities (i.e., formula II) of bisoprolol fumarate and amlodipine are controlled within 0.5% by moisture-proof packaging. The intensity of the reaction of amlodipine and fumaric acid depends on the temperature. At 40°C for one month, the content of amlodipine drops to 59%, and that of bisoprolol drops to 85%. In production, it is necessary to select microcrystalline cellulose of low humidity level, the production process needs to prevent the product from being affected by moisture, and the storage process needs to be dry. All of these cause great difficulties to industrial production.

[0011] CN101766611B discloses a pharmaceutical composition of levamlodipine or its pharmaceutically acceptable salt and beta-receptor blocker. The invention mainly investigates the synergistic effect of levamlodipine and beta-receptor blocker, and does not conduct in-depth research on the specific prescription and stability of the preparation.

[0012] In view of the problems existing in the prior art, a stable amlodipine-bisoprolol compound solid preparation is needed to ensure that the impurity II generated by the incompatibility of the two active ingredients is always kept at a low level, and the preparation process is simple and suitable for industrial production. Summary of the invention

[0013] Based on the problems existing in the prior art, the inventors considered that fully isolating the contact between bisoprolol fumarate and amlodipine is the key to product stability. Unexpectedly, the inventors came up with the following solution: the fumaric acid in bisoprolol fumarate can react with amlodipine. If bisoprolol base is used instead of bisoprolol fumarate and amlodipine to prepare a compound preparation, the problem is naturally fundamentally solved.

[0014] However, bisoprolol is a yellow oily chemical and is difficult to mix evenly with pharmaceutically acceptable solid excipients. Further, the inventors considered dissolving bisoprolol in ethanol and granulating it on amlodipine besylate and common excipients, resulting in granules with a uniform drug content.

[0015] Surprisingly, a new toxic impurity, ethyl benzenesulfonate, appeared during the stability study. Analysis showed that it was caused by the reaction of residual ethanol and benzenesulfonic acid. After continuous testing, the inventors finally chose acetone as an alternative solvent and obtained a bisoprolol amlodipine compound preparation with uniform content and good stability.

[0016] Specifically, the present invention provides the following technical solutions:

[0017] In one aspect, the present invention provides a bisoprolol amlodipine solid preparation, which comprises the following components: bisoprolol, amlodipine, and excipients.

[0018] The bisoprolol amlodipine solid preparation is prepared from the following raw materials: bisoprolol, amlodipine, acetone and excipients.

[0019] Preferably, the amlodipine is amlodipine besylate or levoamlodipine besylate.

[0020] Preferably, the weight ratio of bisoprolol to amlodipine besylate in the solid preparation is 1:1; when levamlodipine besylate is used, the weight ratio of bisoprolol to levamlodipine besylate is 1:0.5; all are calculated as free base.

[0021] Preferably, the weight of acetone is 10% to 50% of the weight of other raw materials.

[0022] More preferably, the weight of acetone is 15% to 45% of the weight of other raw materials.

[0023] Furthermore, the weight of acetone is 18% to 42% of the weight of other raw materials.

[0024] The excipients include fillers and lubricants; further, they may also include disintegrants and binders.

[0025] The filler can be selected from one or more of microcrystalline cellulose, starch, calcium hydrogen phosphate, and mannitol; the disintegrant is selected from one or two of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose; the binder is selected from one or more of pregelatinized starch, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, and sucrose; the lubricant can be selected from one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate.

[0026] The amount of the excipient is conventional in the art, such as the weight ratio of the active ingredient to the filler is 1:0.2-25; the weight ratio of the active ingredient to the lubricant is 1:0.02-1; the weight ratio of the active ingredient to the binder or disintegrant is 1:0.2-5.

[0027] The solid preparation can be a plain tablet, a coated tablet or a capsule.

[0028] On the other hand, the present invention also provides a method for preparing a bisoprolol amlodipine solid preparation, comprising the following steps:

[0029] (1) dissolving bisoprolol in acetone;

[0030] (2) mixing amlodipine and excipients except lubricant;

[0031] (3) adding the bisoprolol solution in step 1 to the mixture in step 2; drying at a temperature not exceeding 30° C. to remove acetone;

[0032] (4) Add lubricant, mix well and then compress into tablets or pack into capsules.

[0033] Beneficial effects of the present invention:

[0034] The present invention provides a new bisoprolol amlodipine solid preparation. The inventor found in the research process that the use of bisoprolol instead of bisoprolol fumarate can completely avoid the impurity II of amlodipine, and fundamentally solves the compatibility problem of bisoprolol and amlodipine. At the same time, the solvent acetone is used to solve the problem of uneven content mixing caused by the oily state of bisoprolol, and the genotoxic impurity ethyl benzenesulfonate generated by the use of ethanol is avoided. The present invention also provides a preparation method of the bisoprolol amlodipine solid preparation. The method is simple, easy to operate, and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 . HPLC chart of ethyl benzenesulfonate in comparative example 4 tablets (0 days)

[0036] Figure 2 .HPLC chart of ethyl benzenesulfonate, methyl benzenesulfonate and isopropyl benzenesulfonate DETAILED DESCRIPTION

[0037] The present invention is further described below by way of examples. It should be understood that the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. At the same time, obvious changes and modifications made by a person of ordinary skill in the art according to the present invention are also included in the scope of the present invention. The weight portions of the active ingredients in the formulations of the examples are all based on free base.

[0038] Example 1

[0039] prescription:

[0040]

[0041] Preparation process: Add the prescribed amount of bisoprolol to acetone, stir mechanically until dissolved and dispersed, add amlodipine besylate, mannitol, microcrystalline cellulose, povidone, sodium carboxymethyl starch to a wet granulator, stir and shear, and mix; add the bisoprolol solution to the wet granulator, stir and shear, granulate, wet granulate through a 2mm sieve; dry at a temperature not exceeding 30°C to remove acetone; dry granulate through a 1.0mm sieve. Add the dried granules to a mixer, add talcum powder, mix until uniform; and compress into tablets.

[0042] Supplementary Example 1:

[0043] The prescription and method of reference example 1 are different in that the amount of acetone is changed according to the following table:

[0044]

[0045] Take 10 tablets of each of batches I to XI and Example 1, and measure them according to the content uniformity test method of Part IV 0941 of the 2020 edition of the Chinese Pharmacopoeia. The A+2.2S values ​​of batches IV to VII and Example 1 are in the range of 3.3 to 6.0, the A+2.2S values ​​of batches III and VIII are 8.5 and 11.0 respectively, the A+2.2S values ​​of batches II and IX to XI are in the range of 11.6 to 14.3, and the A+2.2S value of batch I is greater than 15.0, and the A+S value is 15.4, which does not meet the requirements. Batches IX to XI have certain solvent residue problems, and excessive use of acetone will prolong the drying and solvent removal time, so the acetone range is selected to be 10% to 50% of the weight of the composition.

[0046] Example 2

[0047] prescription:

[0048]

[0049] Preparation process: Add the prescribed amount of bisoprolol to acetone, stir mechanically until dissolved and dispersed, add amlodipine besylate, microcrystalline cellulose, hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose to a wet granulator, stir and shear, and mix; add the bisoprolol solution to the wet granulator; stir and shear, granulate, wet granulate through a 2.0 mm sieve, dry at a temperature not exceeding 30°C, remove acetone; dry granulate through a 1.0 mm sieve. Add the dried granules to a mixer, add magnesium stearate, mix evenly, and compress into tablets.

[0050] Example 3

[0051] prescription:

[0052]

[0053] Preparation process:

[0054] Add the prescribed amount of bisoprolol to acetone, stir mechanically until dissolved and dispersed, add amlodipine besylate, starch, microcrystalline cellulose, hydroxypropyl methylcellulose, and low-substituted hydroxypropyl cellulose to a wet granulator, stir and shear, and mix; add the bisoprolol solution to the wet granulator, stir and shear, granulate, and pass the wet granules through a 2.0 mm sieve; dry at a temperature not exceeding 30° C., remove acetone, and pass the dry granules through a 1.0 mm sieve; add the dried granules to a mixer, add sodium stearyl fumarate, and mix evenly; and compress into tablets.

[0055] Example 4

[0056] prescription:

[0057]

[0058]

[0059] Preparation process: ① Add the prescribed amount of bisoprolol to acetone, and stir mechanically until it is dissolved and dispersed; ② Add levamlodipine besylate, calcium hydrogen phosphate, and microcrystalline cellulose to a wet granulation mixer, stir and shear, and mix evenly; ③ Add the bisoprolol solution in step ① to step ②, stir and shear, granulate, and wet granulate through a 2.0 mm sieve; dry at a temperature not exceeding 30° C., remove acetone, and dry granulate through a 1.0 mm sieve; ④ Add talcum powder, mix evenly, and then pack into capsules to obtain the product.

[0060] Comparative Example 1

[0061] prescription:

[0062]

[0063] Preparation process:

[0064] Add the prescribed amount of bisoprolol fumarate to acetone, stir mechanically until dissolved and dispersed, add amlodipine besylate, mannitol, microcrystalline cellulose, povidone, sodium starch glycolate in a wet granulator, stir and shear, and mix; add the bisoprolol fumarate solution to the wet granulator, stir and shear, granulate, and pass the wet granules through a 2.0 mm sieve; dry at a temperature not exceeding 30° C., remove acetone, and pass the dry granules through a 1.0 mm sieve; add the dried granules to a mixer, add talcum powder, mix evenly, and press into tablets.

[0065] Comparative Example 2

[0066] prescription:

[0067]

[0068]

[0069] Preparation process: Put levamlodipine besylate, bisoprolol, microcrystalline cellulose, pregelatinized starch, lactose and sodium hydroxymethyl starch into a mortar and grind and mix evenly, pass through a 20-mesh sieve, add an appropriate amount of 95% ethanol to make a soft material, pass through a 20-mesh sieve to granulate, dry under ventilation at 40°C, sieve the dry granules through a 16-mesh sieve, add magnesium stearate, mix evenly and press into tablets.

[0070] Comparative Example 3

[0071] prescription:

[0072]

[0073] Preparation process: Put levamlodipine besylate, bisoprolol and microcrystalline cellulose into a mortar and grind them evenly, pass through a 20-mesh sieve, add an appropriate amount of 0.5% PVP-k30 ethanol solution to make a soft material, pass through a 20-mesh sieve to granulate, dry under ventilation at 40°C, sieve the dry granules with a 16-mesh sieve, add talcum powder, mix evenly and then pack into capsules.

[0074] Comparative Example 4

[0075] prescription:

[0076]

[0077] Preparation process: add the prescribed amount of bisoprolol to ethanol, stir mechanically until dissolved and dispersed, add amlodipine besylate, microcrystalline cellulose, hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose to a wet granulator, stir and shear, and mix; add the bisoprolol solution to the wet granulator, stir and shear, granulate, and wet granulate through a 2.0 mm sieve; dry at a temperature not exceeding 30°C, remove ethanol, and dry granulate through a 1.0 mm sieve; add the dried granules to a mixer, add magnesium stearate, and mix evenly; and compress into tablets.

[0078] Verification Example

[0079] 1. Related substance detection

[0080] Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). Use octadecylsilane bonded silica gel as filler (Thermo Acclaim C18, 4.6×250mm, 5μm or equivalent chromatographic column); 0.05mol / L diammonium phosphate solution (adjust pH to 4.5 with phosphoric acid)-acetonitrile (90:10) as mobile phase; detection wavelength is 220nm; flow rate is 1ml per minute; column temperature is 30℃; injection volume is 10μl. Operate in dark. Specific results are shown in Table 1.

[0081] Table 1 Determination results of related substances in Examples and Comparative Examples

[0082]

[0083] As shown in Table 1, after the 40°C / 75%RH test for 3 months, impurity II and ethyl benzenesulfonate were not detected in Examples 1-4, and the total impurity content was controlled at a lower range. Comparative Example 4 is a control test set by changing acetone to ethanol on the basis of Example 2. After the sample preparation was completed (0 day) and after the 40°C / 75%RH test for 3 months, the gene impurity ethyl benzenesulfonate was detected, and the retention time in HPLC was about 12.014min.

Claims

1. A bisoprolol amlodipine solid preparation, characterized in that: The solid preparation comprises the following components: bisoprolol, amlodipine and excipients; and the solid preparation is prepared from the following raw materials: bisoprolol, amlodipine, acetone and excipients.

2. The bisoprolol amlodipine solid preparation according to claim 1, characterized in that Amlodipine is amlodipine besylate or levoamlodipine besylate.

3. The bisoprolol amlodipine solid preparation according to claim 1, characterized in that The weight of acetone is 10% to 50% of the weight of other raw materials.

4. The bisoprolol amlodipine solid preparation according to claim 3, characterized in that: The weight of acetone is 15% to 45% of the weight of other raw materials.

5. The bisoprolol amlodipine solid preparation according to claim 4, characterized in that: The weight of acetone is 18% to 42% of the weight of other raw materials.

6. The bisoprolol amlodipine solid preparation according to claim 2, characterized in that: The weight ratio of bisoprolol to amlodipine besylate in the solid preparation is 1:1; when levamlodipine besylate is used, the weight ratio of bisoprolol to levamlodipine besylate is 1:0.5; all are calculated based on free base.

7. The bisoprolol amlodipine solid preparation according to claim 1, characterized in that: The excipients include fillers and lubricants.

8. The bisoprolol amlodipine solid preparation according to claim 1, characterized in that: The excipients include fillers, lubricants, disintegrants, and binders.

9. A method for preparing the bisoprolol amlodipine solid preparation according to any one of claims 1 to 8, characterized in that: The steps include: (1) dissolving bisoprolol in acetone; (2) mixing amlodipine and excipients except lubricant; (3) adding the bisoprolol solution in step 1 to the mixture in step 2; Dry at no more than 30°C to remove acetone; (4) Add lubricant, mix well and then compress into tablets or pack into capsules.

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