Bisoprolol amlodipine tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to bisoprolol amlodipine tablets and a preparation method thereof. The bisoprolol amlodipine tablet is composed of a bisoprolol fumarate solid dispersion, amlodipine besylate / levamlodipine besylate, a filler, a disintegrating agent and a lubricant, the bisoprolol fumarate solid dispersion takes HPMCP as a carrier material, and triethyl citrate is added. The obtained bisoprolol and amlodipine tablet blocks the contact opportunity of bisoprolol fumarate and amlodipine, the problem of compatibility of bisoprolol fumarate and amlodipine is fundamentally solved, the storage requirement can be met without special packaging, the preparation process is simple, and the industrialization requirement is met.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a bisoprolol amlodipine tablet. BACKGROUND

[0002] The situation of hypertension prevention and control in China is grim, with a high prevalence of 245 million, but the control rate is only 16.8%. Fumarate bisoprolol is a beta receptor blocker, which has high affinity for beta1-receptors of bronchial and vascular smooth muscle, thereby causing vasodilation and reducing blood pressure. It is suitable for hypertension, coronary heart disease, and moderate to severe chronic stable heart failure, etc. Amlodipine besylate is a long-acting calcium channel blocker, which is clinically used for the treatment of cardiovascular diseases such as hypertension.

[0003] Bisoprolol amlodipine tablet is the only long-acting single tablet compound preparation (SPC) of beta receptor blocker (BB) + calcium channel blocker (CCB) currently listed in China. Through the triple mechanism of inhibiting excessive excitement of sympathetic nerve, inhibiting excessive activation of renin-angiotensin-aldosterone system (RAAS), and dilating peripheral arterial blood vessels, it can effectively control heart rate while exerting synergistic antihypertensive effect, and achieve dual control of blood pressure and heart rate. Moreover, the combination of the two types of drugs helps to reduce adverse drug reactions. The BB can offset the increase in heart rate caused by reflex sympathetic nervousness to some extent, and the CCB can reduce the peripheral vasoconstriction effect that may occur during BB treatment. Moreover, both components are long-acting and safe antihypertensive drugs with proven clinical treatment effect, and once-a-day administration can achieve stable and standard antihypertensive effect.

[0004] Compared with free combination, bisoprolol amlodipine tablet has better compliance, and the blood pressure control of patients is better and the compliance rate is higher. However, amlodipine and fumarate in the preparation react with each other to generate compound N-(2-{[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridyl]-methoxy}-ethyl)-aspartic acid (AML-2 impurity for short), which needs to be controlled within a very low limit.

[0005]

[0006] CN101766611A discloses a pharmaceutical composition of levorotatory amlodipine or a pharmaceutically acceptable salt thereof and a beta receptor blocker and its application. The present application only relates to the efficacy of the compound preparation, and does not study the stability of the preparation; WO2005 / 099699 discloses a pharmaceutical composition comprising optically pure (S) amlodipine and a beta receptor blocker. The beta blocker is atenolol or bisoprolol, and the compatibility of amlodipine and bisoprolol is not studied.

[0007] Indian Patent No. 845 / MUM / 2004 provides a stable pharmaceutical composition of bisoprolol fumarate and amlodipine besylate, which is critical to separate the two components in different granules, preventing physical contact between the active ingredients, and the granules are further mixed with excipients and filled into capsules or sachets, or compressed into so-called bilayer tablets. However, the separate granulation and homogenization of the active ingredients increase the number of required technical steps, and the preparation of bilayer tablets requires complex and special equipment, in addition to the problem of low yield in the tabletting process.

[0008] CN114668760A uses the equal increment method to prepare amlodipine layer and bisoprolol fumarate layer by multiple sieving, and then combines the two to form a single tablet with a core-shell layer. In order to further isolate the interaction of the active ingredients, a partition is provided between the two separate drugs, but its stability needs to be improved in long-term tests. CN102949391A discloses a pharmaceutical composition with S(-)-bisoprolol and S(-)-amlodipine as active ingredients, which is prepared by crushing the active ingredients and adding excipients. It needs to be packaged in a high-humidity-resistant bottle, and the stability is poor.

[0009] CN102164585A discloses a composition containing amlodipine and bisoprolol, which does not need to separate amlodipine and bisoprolol fumarate, but uses moisture-proof packaging to control the AML-2 impurity within 0.5%. However, low-humidity-grade microcrystalline cellulose needs to be selected in production, and the production process needs to prevent the product from being damp, otherwise the moisture in the internal air will be difficult to escape, which will accelerate the instability of the product, and the storage process also requires a dry environment, which causes great difficulty in industrial production.

[0010] CN116687926A discloses a composition containing amlodipine and bisoprolol, which uniformly and stably adsorbs colloidal silicon dioxide on the surface of amlodipine, reduces the contact between amlodipine and bisoprolol during mixing, and absorbs moisture, avoiding the contact of amlodipine with moisture, further improving the stability of the preparation. However, the active ingredients and disintegrants, glidants in the composition need to be sieved and premixed multiple times, and the filler also needs to be added in several times, and the mixing time is longer.

[0011] Therefore, a bisoprolol amlodipine preparation with simple preparation process and excellent stability is essential. SUMMARY

[0012] In view of the shortcomings of the prior art, the inventors consider preparing a bisoprolol amlodipine preparation product with good stability and no special requirements for environmental humidity and packaging, which not only can reduce the cost of preparation and the burden of patients, but also can fundamentally solve the problem of the generation of impurities of two raw materials.

[0013] The present application is achieved by the following solutions:

[0014] A bisoprolol amlodipine tablet, comprising a fumarate bisoprolol solid dispersion, a benzenesulfonic acid amlodipine / benzenesulfonic acid levamlodipine, a filler, a disintegrant and a lubricant.

[0015] The fumarate bisoprolol solid dispersion is composed of fumarate bisoprolol, hydroxypropyl methyl cellulose phthalate and a plasticizer.

[0016] Preferably, the weight ratio of fumarate bisoprolol, hydroxypropyl methyl cellulose phthalate HPMCP and the plasticizer in the solid dispersion is 5:5-10:1-4.

[0017] Further preferably, the weight ratio of fumarate bisoprolol, hydroxypropyl methyl cellulose phthalate HPMCP and the plasticizer in the solid dispersion is 5:6:1-2.

[0018] Preferably, the plasticizer is triethyl citrate.

[0019] Preferably, the hydroxypropyl methyl cellulose phthalate is HP-50 or HP-55.

[0020] Preferably, when benzenesulfonic acid amlodipine is used, the weight ratio of fumarate bisoprolol to benzenesulfonic acid amlodipine is 5:5-7; when benzenesulfonic acid levamlodipine is used, the weight ratio of fumarate bisoprolol to benzenesulfonic acid levamlodipine is 5:2.5-3.5.

[0021] The filler is one or more of microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, mannitol.

[0022] The disintegrant is one or more of cross-linked sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, low-substituted hydroxypropyl cellulose.

[0023] The lubricant is one or more of magnesium stearate, calcium stearate, talc, sodium stearyl fumarate.

[0024] The disintegrant, lubricant and filler are in the conventional amount in the art.

[0025] Preferably, the amount ratio of fumarate bisoprolol to the filler, disintegrant and lubricant is 5:1-120:1-10:0.1-5.

[0026] Preferably, the bisoprolol amlodipine tablet is a plain tablet.

[0027] In a preferred embodiment, the bisoprolol amlodipine tablet is prepared from the following raw materials in the weight ratio:

[0028]

[0029] In a preferred embodiment, the bisoprolol and amlodipine tablet is prepared from the following raw materials in the following weight ratio:

[0030]

[0031]

[0032] In a preferred embodiment, the bisoprolol and amlodipine tablet is prepared from the following raw materials in the following weight ratio:

[0033]

[0034] The fumarate bisoprolol solid dispersion is prepared by the following steps: the hydroxypropyl methyl cellulose phthalate is pulverized, then mixed with fumarate bisoprolol and plasticizer, extruded by a twin-screw hot melt extruder, pulverized after cooling and solidification, and then obtained.

[0035] Preferably, the temperature for heating and melting of the hot melt extruder is 50-80℃, and further preferably 60-70℃.

[0036] The present application also provides a preparation method of the bisoprolol and amlodipine tablet, wherein the fumarate bisoprolol solid dispersion, benzenesulfonic acid amlodipine / benzenesulfonic acid levamlodipine, filler, disintegrant, and lubricant are mixed uniformly, and then tableted.

[0037] The present application has the following advantages:

[0038] Compared with the prior art, the bisoprolol and amlodipine tablet prepared by the present application blocks the contact opportunity of fumarate bisoprolol and amlodipine, fundamentally solves the compatibility problem of the two, has good stability, meets the storage requirements without special packaging, and has a simple preparation process, meeting the industrialization requirements. DETAILED DESCRIPTION

[0039] The present application is further illustrated by the following examples. It should be understood correctly that the examples of the present application are given only for illustrating the present application, and are not a limitation of the present application, so that the simple improvement of the present application under the premise of the method of the present application is within the scope of the present application.

[0040] Example 1

[0041]

[0042] HP-50 is crushed and mixed with bisoprolol fumarate and triethyl citrate. The mixture is extruded by a twin-screw hot-melt extruder. The heating and melting temperature of the hot-melt extruder is 60°C. The extrudate is crushed after cooling and solidification to obtain a bisoprolol fumarate solid dispersion. Then, amlodipine besylate, lactose, microcrystalline cellulose, sodium starch glycolate and talc are added and mixed uniformly. The mixture is tabletted to obtain the tablet.

[0043] Example 2

[0044]

[0045] HP-55 is crushed and mixed with bisoprolol fumarate and triethyl citrate. The mixture is extruded by a twin-screw hot-melt extruder. The heating and melting temperature of the hot-melt extruder is 70°C. The extrudate is crushed after cooling and solidification to obtain a bisoprolol fumarate solid dispersion. Then, levamlodipine besylate, mannitol, microcrystalline cellulose, sodium starch glycolate and talc are added and mixed uniformly. The mixture is tabletted to obtain the tablet.

[0046] Example 3

[0047]

[0048] HP-50 is crushed and mixed with bisoprolol fumarate and triethyl citrate. The mixture is extruded by a twin-screw hot-melt extruder. The heating and melting temperature of the hot-melt extruder is 60°C. The extrudate is crushed after cooling and solidification to obtain a bisoprolol fumarate solid dispersion. Then, amlodipine besylate, mannitol, pregelatinized starch, low-substituted hydroxypropyl cellulose and sodium stearyl fumarate are added and mixed uniformly. The mixture is tabletted to obtain the tablet.

[0049] Example 4

[0050]

[0051] HP-50 is crushed and mixed with bisoprolol fumarate and triethyl citrate. The mixture is extruded by a twin-screw hot-melt extruder. The heating and melting temperature of the hot-melt extruder is 65°C. The extrudate is crushed after cooling and solidification to obtain a bisoprolol fumarate solid dispersion. Then, amlodipine besylate, lactose, starch, sodium starch glycolate and talc are added and mixed uniformly. The mixture is tabletted to obtain the tablet.

[0052] Example 5

[0053]

[0054]

[0055] HP-50 was crushed and mixed with bisoprolol fumarate and triethyl citrate, and then extruded by a twin-screw hot-melt extruder. The heating and melting temperature of the hot-melt extruder was 60°C. After cooling and solidification, the bisoprolat fumarate solid dispersion was obtained by crushing. Then, amlodipine besylate, lactose, microcrystalline cellulose, sodium starch glycolate and talc were added and mixed uniformly, and then compressed into tablets.

[0056] Example 6

[0057]

[0058] HP-50 was crushed and mixed with bisoprolol fumarate and triethyl citrate, and then extruded by a twin-screw hot-melt extruder. The heating and melting temperature of the hot-melt extruder was 60°C. After cooling and solidification, the bisoprolat fumarate solid dispersion was obtained by crushing. Then, amlodipine besylate, lactose, microcrystalline cellulose, sodium starch glycolate and talc were added and mixed uniformly, and then compressed into tablets.

[0059] Example 7

[0060] With reference to Example 1, the HPMCP (HP-50) in Example 1 was replaced by the following materials:

[0061] Name Example 7-1 PVP K30 Example 7-2 Polyethylene glycol 4000

[0062] Example 8

[0063]

[0064]

[0065] The prescription amount of bisoprolol fumarate was added to 200 ml of a mixed solution of dichloromethane and methanol (1:1), stirred and dissolved, and then HPMC and ethyl cellulose were added. After stirring until the solvent was completely volatilized, the bisoprolol fumarate solid dispersion was obtained by crushing. Then, amlodipine besylate, lactose, microcrystalline cellulose, sodium starch glycolate and talc were added and mixed uniformly, and then compressed into tablets.

[0066] Example 9

[0067] With reference to Example 1, the triethyl citrate in Example 1 was replaced by diethyl phthalate, and the other conditions were the same as those in Example 1.

[0068]

[0069] The prescription amount of bisoprolol fumarate was added into 200 ml of a mixed solution of dichloromethane and methanol (1:1), stirred and dissolved, then HP-50 was added, stirred until the solvent was completely volatilized, crushed, to obtain a solid dispersion of bisoprolol fumarate, then amlodipine besylate, lactose, microcrystalline cellulose, sodium carboxymethyl starch and talc were added, mixed uniformly, and compressed into tablets.

[0070] Comparative Example 1

[0071]

[0072]

[0073] HP-50 was crushed and mixed uniformly with amlodipine besylate and triethyl citrate, extruded by a twin-screw hot melt extruder, the heating and melting temperature of the hot melt extruder was 60°C, crushed after cooling and solidification, to obtain a solid dispersion of amlodipine besylate, then bisoprolol fumarate, lactose, microcrystalline cellulose, sodium carboxymethyl starch and talc were added, mixed uniformly, and compressed into tablets.

[0074] Comparative Example 2

[0075]

[0076] Bisoprolol fumarate was mixed with sodium carboxymethyl starch at a speed of 15 r / min for 3 min, and sieved through a 40-mesh sieve to obtain a first premix; amlodipine besylate was mixed with colloidal silicon dioxide at a speed of 15 r / min for 3 min, and sieved through a 40-mesh sieve to obtain a second premix; 50 wt% of microcrystalline cellulose was added to a mixing hopper, then the first premix and the second premix were added, and the remaining microcrystalline cellulose was added, and mixed by a container-type mixer at a speed of 10 r / min for 50 min to obtain a third premix; magnesium stearate was added to the third premix and mixed at a speed of 15 r / min for 5 min, and compressed into tablets.

[0077] Comparative Example 3

[0078]

[0079]

[0080] Bisoprolol fumarate, cross-linked povidone, colloidal silicon dioxide and mannitol were sieved three times by using a 60-mesh sieve using the equal-amount incremental method, magnesium stearate was added and mixed for 3 min, dry granulation was performed, magnesium stearate was added and mixed for 3 min, the tablet core layer was compressed, and a separation layer was prepared by coating on the tablet core layer.

[0081] Amlodipine besylate, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide, anhydrous calcium hydrogen phosphate and microcrystalline cellulose were mixed by using equal amount of incremental method, sieved 3 times using 60 mesh sieve, magnesium stearate was added and mixed for 3 minutes, and then the shell was pressed in the isolation layer to obtain the amlodipine besylate tablets.

[0082] Verification example

[0083] The stability was investigated according to <9001 Raw materials and preparation stability test guidelines> in the fourth part of Chinese Pharmacopoeia 2020.

[0084] Accelerated test: the tablets obtained in the examples and the comparative examples and the commercially available reference preparation (no outer packaging) were placed in a condition of 40℃±2℃, 75%RH±5%RH, and sampled after 6 months, and then detected by HPLC. Three parallel tests were conducted, and the average value was taken.

[0085] Influencing factor test: the tablets (all without outer packaging) obtained in the examples and the comparative examples were respectively placed in a condition of 60℃±2℃ or 90%RH±5%RH, and sampled at the 5th day and the 10th day, and then the content of AML-2 impurities was detected by HPLC. Three parallel tests were conducted, and the average value was taken.

[0086] Table 1: Stability test results

[0087]

[0088]

[0089] Table 2: Influencing factor test results

[0090]

[0091] From the data in the above Tables 1 and 2, it can be seen that the stability of the drug is improved by using the HPMCP carrier material and triethyl citrate in the present application, and the generation of AML-2 impurities is avoided; the two active ingredients cannot be completely separated by using the water-soluble carrier materials PVP and polyethylene glycol; and the stability of the bisoprolol amlodipine tablets obtained by using the water-soluble material HPMC and the poorly soluble carrier material ethyl cellulose CE as the carrier still needs to be improved.

Claims

1. A bisoprolol amlodipine tablet, characterized in that: The invention comprises bisoprolol fumarate solid dispersion, amlodipine besylate / levamlodipine besylate, a filler, a disintegrant and a lubricant.

2. The bisoprolol amlodipine tablets according to claim 1, wherein The bisoprolol fumarate solid dispersion consists of bisoprolol fumarate, hypromellose phthalate and a plasticizer.

3. The bisoprolol amlodipine tablets according to claim 2, wherein The weight ratio of bisoprolol fumarate, hypromellose phthalate and plasticizer in the solid dispersion is 5:5-10:1-4.

4. The bisoprolol amlodipine tablets according to claim 2, wherein The weight ratio of bisoprolol fumarate, hypromellose phthalate and plasticizer in the solid dispersion is 5:6:1-2.

5. The bisoprolol amlodipine tablets according to claim 2, characterized in that The hypromellose phthalate is HP-50 or HP-55.

6. The bisoprolol amlodipine tablets according to claim 2, characterized in that: The plasticizer is triethyl citrate.

7. The bisoprolol amlodipine tablets according to claim 1, characterized in that: When amlodipine besylate is selected, the weight ratio of bisoprolol fumarate to amlodipine besylate is 5:5-7; when levoamlodipine besylate is selected, the weight ratio of bisoprolol fumarate to levoamlodipine besylate is 5:2.5-3.

5.

8. The bisoprolol amlodipine tablets according to claim 1, characterized in that: The disintegrant is one or more of cross-linked sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose; the lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate; and the filler is one or more of microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, and mannitol.

9. A bisoprolol amlodipine tablet according to any one of claims 1 to 8, characterized in that: The bisoprolol fumarate solid dispersion is prepared by the following steps: crushing hypromellose phthalate, then uniformly mixing it with bisoprolol fumarate and a plasticizer, extruding it through a twin-screw hot melt extruder, cooling and solidifying it, and then crushing it to obtain the solid dispersion.

10. A method for preparing the bisoprolol amlodipine tablets according to any one of claims 1 to 8, characterized in that: The bisoprolol fumarate solid dispersion, amlodipine besylate / levamlodipine besylate, filler, disintegrant and lubricant are fully mixed and tableted to obtain the product.

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