A bisoprolol fumarate composition tablet

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a bisoprolol fumarate composition tablet and a preparation method thereof. The bisoprolol fumarate tablet of the present invention is composed of bisoprolol fumarate, chitosan, xylitol, a disintegrant and a lubricant. Among them, chitosan and xylitol synergistically improve the content uniformity of the tablet and have excellent stability. At the same time, the preparation process is simple, direct mixing is adopted, and there is no need for multiple equal-dose progressive mixing, which is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a bisoprolol fumarate composition tablet. Background Art

[0002] Bisoprolol fumarate is a β-blocker with high affinity for β1-receptors in bronchial and vascular smooth muscles, thereby dilating blood vessels and reducing blood pressure. It is applicable to hypertension, coronary heart disease, and moderate to severe chronic stable heart failure, etc. Its structure is as follows:

[0003]

[0004] CN101467985B discloses a bisoprolol fumarate dispersible tablet and its preparation method. The prescription contains 55% calcium hydrogen phosphate. When we conducted experiments according to this prescription, we found that the proportion of calcium hydrogen phosphate was too high, resulting in a problem of blackening during tableting and poor stability during storage. CN103127016B discloses a bisoprolol fumarate tablet composition and its preparation method. In the process, the equal increment addition method is used to mix the raw and auxiliary materials evenly. The equal increment addition method is relatively cumbersome, and there will be problems of equipment mismatch in production, and the need to replace equipment multiple times, which will cause a problem of low final content for small-scale compounds. CN112245401A discloses a drug tablet for treating hypertension and coronary heart disease and its preparation method. The wet granulation process is used in the process, and its stability is not ideal. GB2444904B improves the mixing uniformity by controlling the particle sizes of bisoprolol fumarate and each auxiliary material.

[0005] Formulation and evaluation of bisoprolol fumarate optizorbdispersible tablet to improve tablet disintegration, B. Lavanya et al. J. WorldJournal Of Pharmacy And Pharmaceutical Sciences. 2015, 4(1), 561 - 576. Based on the OptiZorb technology using superdisintegrants such as alginic acid and calcium carbonate, a bisoprolol fumarate dispersible tablet with faster dissolution was obtained, but it was difficult to minimize decomposition and maintain sufficient stability as a tablet in the long term without packaging.

[0006] The marketed product Concor is a film-coated tablet. The solvents used in the coating process may have an adverse effect on the related substances in the preparation. Removing the coating layer can improve the stability of the preparation. However, calcium hydrogen phosphate is used in the original developed preparation. After the covering of the coating layer is lost, the tablet core will appear gray and have a bitter taste.

[0007] In addition, in order to minimize the impact of the preparation process on the stability of substances in the prior art, a direct powder compression process is adopted. However, the direct compression process poses a challenge to the content uniformity of low-dose drugs. Especially in large-scale production, there may be a risk of layering of raw and auxiliary materials during the production process. Bisoprolol fumarate tablets are scored tablets, and the content uniformity of half tablets is an even greater challenge.

[0008] Therefore, there is a need for a bisoprolol fumarate composition tablet with a simple preparation process, high content uniformity, and good stability. Summary of the Invention

[0009] In view of the deficiencies of the existing low-dose bisoprolol fumarate tablets, the present invention provides a bisoprolol fumarate composition tablet. The bisoprolol fumarate composition tablet of the present invention has excellent content uniformity, high stability, good taste, and a simple preparation process.

[0010] The present invention is specifically realized through the following solutions:

[0011] A bisoprolol fumarate composition tablet, comprising bisoprolol fumarate, chitosan, a filler, a disintegrant, and a lubricant.

[0012] Preferably, the filler is xylitol.

[0013] Preferably, the weight ratio of bisoprolol fumarate to chitosan is 1:0.2 - 1.

[0014] More preferably, the weight ratio of bisoprolol fumarate to chitosan is 1:0.5.

[0015] Preferably, the weight ratio of bisoprolol fumarate to xylitol is 1:15 - 25.

[0016] More preferably, the weight ratio of bisoprolol fumarate to xylitol is 1:18 - 23.

[0017] Most preferably, the weight ratio of bisoprolol fumarate to xylitol is 1:20.

[0018] Preferably, the lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium fumarate stearate.

[0019] Preferably, the weight ratio of bisoprolol fumarate to the lubricant is 1:0.2 - 1.

[0020] Preferably, the disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose.

[0021] Preferably, the weight ratio of bisoprolol fumarate to the disintegrant is 1:0.2 - 0.8.

[0022] In a preferred embodiment, the bisoprolol fumarate composition tablet is composed of the following raw materials in parts by weight:

[0023]

[0024]

[0025] In a preferred embodiment, the bisoprolol fumarate composition tablet is composed of the following raw materials in parts by weight:

[0026]

[0027] The present invention also provides a preparation method of the above-mentioned bisoprolol fumarate composition tablet. Bisoprolol fumarate and chitosan are fully mixed, and after adding a filler, mixing is continued until fully mixed. Finally, a disintegrant and a lubricant are added, and after mixing evenly, it is pressed into tablets.

[0028] Compared with the prior art, the present invention has the following advantages: The bisoprolol fumarate composition tablet of the present invention has a good taste, a simple production process, adopts direct mixing, does not require multiple equal-dose progressive mixing, xylitol and chitosan synergistically improve the content uniformity of bisoprolol fumarate, and has good stability, being suitable for industrial production. Detailed Embodiments

[0029] The present invention will be further illustrated by the following examples. It should be correctly understood that: The examples of the present invention are only given for the purpose of illustrating the present invention, rather than limiting the present invention. Therefore, any simple improvement to the present invention under the premise of the method of the present invention falls within the scope of protection required by the present invention.

[0030] The specifications of the bisoprolol fumarate tablets in the examples and comparative examples of the present invention are all 5 mg / tablet.

[0031] Example 1

[0032]

[0033] The prescribed amount of bisoprolol fumarate and chitosan are fully mixed, then xylitol is added, mixed evenly, and finally low-substituted hydroxypropyl cellulose and talc are added. After mixing evenly, it is pressed into tablets.

[0034] Example 2

[0035]

[0036] The prescribed amount of bisoprolol fumarate and chitosan are fully mixed, and then xylitol is added and mixed evenly, and finally sodium carboxymethyl starch and magnesium stearate are added, mixed evenly, and then pressed into tablets.

[0037] Example 3

[0038]

[0039] The prescribed amount of bisoprolol fumarate and chitosan are fully mixed, and then xylitol is added and mixed evenly, and finally cross-linked carboxymethyl cellulose and sodium stearate fumarate are added, mixed evenly, and then pressed into tablets.

[0040] Example 4

[0041]

[0042] The prescribed amount of bisoprolol fumarate and chitosan are fully mixed, and then xylitol is added and mixed evenly, and finally low-substituted hydroxypropyl cellulose and talcum powder are added, mixed evenly, and then pressed into tablets.

[0043] Example 5

[0044]

[0045] The prescribed amount of bisoprolol fumarate and chitosan are fully mixed, and then xylitol is added and mixed evenly, and finally sodium carboxymethyl starch and calcium stearate are added, mixed evenly, and then pressed into tablets.

[0046] Example 6

[0047]

[0048] The prescribed amount of bisoprolol fumarate and chitosan are fully mixed, and then xylitol is added and mixed evenly, and finally low-substituted hydroxypropyl cellulose and talcum powder are added, mixed evenly, and then pressed into tablets.

[0049] Example 7

[0050]

[0051] The prescribed amount of bisoprolol fumarate and chitosan are fully mixed, and then xylitol is added and mixed evenly, and finally low-substituted hydroxypropyl cellulose and talcum powder are added, mixed evenly, and then pressed into tablets.

[0052] Example 8

[0053]

[0054]

[0055] Mix the prescribed amount of bisoprolol fumarate with chitosan thoroughly, then add mannitol and mix evenly. Finally, add low-substituted hydroxypropyl cellulose and talc, mix evenly and press into tablets.

[0056] Example 9

[0057]

[0058] Mix the prescribed amount of bisoprolol fumarate with chitosan thoroughly, then add microcrystalline cellulose and mix evenly. Finally, add low-substituted hydroxypropyl cellulose and talc, mix evenly and press into tablets.

[0059] Example 10

[0060]

[0061] Mix the prescribed amount of bisoprolol fumarate with chitosan thoroughly, then add sorbitol and mix evenly. Finally, add low-substituted hydroxypropyl cellulose and talc, mix evenly and press into tablets.

[0062] Comparative Example 1

[0063]

[0064] Mix the prescribed amount of bisoprolol fumarate with xylitol thoroughly, add low-substituted hydroxypropyl cellulose and talc, mix evenly and press into tablets.

[0065] Comparative Example 2

[0066]

[0067] Mix the prescribed amount of bisoprolol fumarate, alginic acid, calcium carbonate, and lactose, sieve through a No. 22 sieve, place in a mortar, add starch paste and grind and mix, dry, then add magnesium stearate and talc, mix, and press the preparation into tablets using a 16-station rotary tablet press to obtain the product.

[0068] Comparative Example 3

[0069]

[0070] Mix the prescribed amount of bisoprolol, mannitol, starch, and microcrystalline cellulose for 15 minutes, then add magnesium stearate and mix for 2 minutes, and press into tablets to obtain the product.

[0071] Comparative Example 4

[0072]

[0073] Weigh half of the prescription amount of microcrystalline cellulose PH101 and cross-linked povidone, and the prescription amount of calcium hydrogen phosphate; mix them evenly, prepare soft materials with water, granulate through an 18-mesh sieve, dry in an oven at 50 °C for 2 hours, take out and screen the granules through a 30-mesh sieve. After mixing the obtained granules with the prescription amount of bisoprolol fumarate, microcrystalline silica, magnesium stearate, and the remaining microcrystalline cellulose PH101 and cross-linked povidone, press tablets with a 6-mm shallow concave punch to obtain the tablets.

[0074] Comparative Example 5

[0075]

[0076] Weigh each component according to the described prescription amount, and sieve bisoprolol fumarate through a 100-mesh sieve; use the equal increment addition method to mix bisoprolol fumarate, lactose, mannitol 200SD, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and povidone evenly; add the prescription amount of magnesium stearate and mix evenly; press tablets, control the pressure at 1.0 - 3.0 KN to make the hardness of the tablets between 40 - 60 N.

[0077] Comparative Example 6

[0078]

[0079] Add the prescription amount of bisoprolol fumarate, Polyox N12K, carbomer 940P, PVP K-30, and calcium phosphate dibasic to a mortar and grind and mix evenly, sieve through a 60-mesh sieve, add sodium bicarbonate, magnesium stearate, and talc powder, mix thoroughly and then compress. Press tablets using a 9-mm round flat punch on a 9-station rotary tablet press to obtain the tablets.

[0080] Comparative Example 7

[0081]

[0082] Mix bisoprolol fumarate and lactose, put them into a fluidized bed granulator, prepare a 5% ethanol solution of hydroxypropyl cellulose according to the prescription amount and spray it. The obtained powder is dried in the fluidized bed and sieved through a 22-mesh sieve, then add low-substituted hydroxypropyl cellulose and magnesium stearate and mix evenly, and press tablets using a rotary tablet press to obtain the tablets.

[0083] Comparative Example 8

[0084]

[0085] Sieve bisoprolol fumarate, silicified microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, and sodium starch glycolate through a 20-mesh sieve in sequence, add them to a double-cone stirrer (15 ± 2 rpm) and stir and mix evenly. After sieving magnesium stearate through a 20-mesh sieve, add it to the stirrer, continue to stir for 5 min, and press tablets using a rotary tablet press to obtain the tablets.

[0086] Comparative Example 9

[0087]

[0088] Pass the prescribed amount of bisoprolol fumarate and corn starch through a 40-mesh sieve together, then sieve them together with anhydrous calcium hydrogen phosphate. Then add the mixed powder into a wet granulation pot and perform wet granulation with an appropriate amount of water. Add the obtained granules into a fluidized bed for drying until the loss on drying is not more than 2%. Pass the dry granules through a 40-mesh sieve, crush them, and then pass them through a 40-mesh sieve again until all the granules can pass through the 40-mesh sieve. Then pass microcrystalline cellulose, crospovidone, and colloidal silicon dioxide through a 30-mesh sieve together, and then add them into the mixing hopper together with the above-obtained dry granules and mix for 30 minutes. Pass magnesium stearate through a 60-mesh sieve and add it into the mixing hopper for final mixing, and then press tablets to obtain the product.

[0089] Comparative Example 10

[0090]

[0091]

[0092] Mix the prescribed amount of microcrystalline cellulose, lactose, and starch evenly, add a 50% povidone ethanol solution dissolving bisoprolol fumarate, stir evenly to make a soft material, pass it through a 20-mesh sieve to make granules, dry at 60 °C for 30 minutes, pass through an 18-mesh sieve, add magnesium stearate and mix, and then press tablets to obtain the product.

[0093] Comparative Example 11

[0094]

[0095] Pass bisoprolol fumarate and excipients through an 80-mesh sieve, then uniformly mix the drug and all materials, and press them into tablets to obtain the product.

[0096] Comparative Example 12

[0097]

[0098] Dissolve bisoprolol fumarate in a mixed solvent of methanol and dichloromethane (1:1). Then pour a mixture of 4.5 times the drug weight of ethyl cellulose and 4.5 times the drug weight of hypromellose into the solvent containing the drug, stir evenly until the solvent completely evaporates, sieve, and reserve the bisoprolol fumarate solid dispersion powder with a particle size of 100 μm - 200 μm. Mix 50 parts of the bisoprolol fumarate solid dispersion evenly with the prescribed amount of excipients PVP K30, mannitol, and aspartame with a particle size of 100 μm - 200 μm, add magnesium stearate and mix evenly, and then press them into tablets to obtain the product.

[0099] Verification Example

[0100] 1. Taste and Content Uniformity Test

[0101] Taste test: Take the tablets of the examples, comparative examples and reference preparation (remove the coating film), and swallow them with water by healthy volunteers to evaluate the taste.

[0102] The content uniformity was investigated with reference to the "Uniformity of Content Test" (0941) in Part IV of the Chinese Pharmacopoeia 2020 Edition.

[0103] Content uniformity of the whole tablet: Take 10 tablets of the test tablets (the reference preparation Concor needs to remove the coating film), place each tablet in a 50 ml (5 mg specification) volumetric flask, add water to dissolve bisoprolol fumarate and dilute to the scale, shake well, filter, and take the subsequent filtrate as the test solution for content determination. Content uniformity of half tablet: Take 5 tablets of the test tablets (the reference preparation Concor needs to remove the coating film), break them evenly along the center notch into two pieces, place them in 50 ml (5 mg specification) volumetric flasks respectively, add water to dissolve bisoprolol fumarate and dilute to the scale, shake well, filter, and take the subsequent filtrate as the test solution for content determination.

[0104] Table 1 Results of Taste and Content Uniformity Test

[0105]

[0106] After the test, the bisoprolol fumarate composition tablets containing chitosan and xylitol of the present invention have good taste and content uniformity, which are superior to the composition tablets of the prior art.

[0107] 2. Stability Test

[0108] The stability was investigated with reference to the "Guidelines for Stability Testing of Drug Substances and Preparations" (9001) in Part IV of the Chinese Pharmacopoeia 2020 Edition.

[0109] Accelerated test: Take the tablets obtained from the examples, comparative examples and the reference preparation Concor (all remove the outer packaging), place them under the conditions of 40°C ± 2°C and 75% RH ± 5% RH, sample after 6 months, and detect the impurity content by HPLC. Conduct three parallel tests, and the results are averaged.

[0110] HPLC chromatographic conditions for related substances: Use octadecylsilane chemically bonded silica gel as the filler; use 0.05 mol / L ammonium dihydrogen phosphate solution (adjust the pH value to 5.5 with phosphoric acid)-acetonitrile (70:30) as mobile phase A, and use 0.05 mol / L ammonium dihydrogen phosphate solution (adjust the pH value to 5.5 with phosphoric acid)-acetonitrile (35:65) as mobile phase B, and perform gradient elution; the flow rate is 1.0 ml per minute; the column temperature is 25°C; the detection wavelength is 225 nm; the injection volume is 10 μl.

[0111] Table 2 Determination Results of Accelerated Test

[0112]

[0113] After 6 months of accelerated test, the related substances of the bisoprolol fumarate composition tablets containing chitosan and xylitol in the present invention did not increase significantly, indicating excellent stability. In Comparative Example 4, Comparative Example 6, Comparative Example 9 and Comparative Example 12, there were relatively more initial related substances, which might be due to the fact that the preparation methods of Comparative Example 4 and Comparative Example 9 adopted wet granulation and had a longer heating time, and Comparative Example 6 had a grinding operation, resulting in a longer contact time with air.

Claims

1. A bisoprolol fumarate composition tablet, characterized in that: The tablet is composed of bisoprolol fumarate, chitosan, a filler, a disintegrant and a lubricant, and the weight ratio of the bisoprolol fumarate to the chitosan is 1: 0.2-1, the filler is xylitol, the weight ratio of bisoprolol fumarate to xylitol is 1:15-25, the disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose, and the tablet is composed of the following raw materials in parts by weight: Component weight Bisoprolol Fumarate 10 parts Chitosan 2-10 parts Xylitol 150-250 parts Disintegrant 2-8 parts Lubricant 2-10 parts The preparation method of the tablet comprises the following steps: fully mixing bisoprolol fumarate and chitosan, adding a filler and continuing to fully mix, and finally adding a disintegrant and a lubricant, mixing evenly, and pressing the mixture into tablets.

2. The bisoprolol fumarate composition tablet according to claim 1, characterized in that: The weight ratio of bisoprolol fumarate to chitosan is 1:0.

5.

3. The bisoprolol fumarate composition tablet according to claim 1, characterized in that: The weight ratio of the bisoprolol fumarate to xylitol is 1:18-23.

4. The bisoprolol fumarate composition tablet according to claim 1, characterized in that: The lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate.

5. The bisoprolol fumarate composition tablet according to claim 1, characterized in that: It is composed of the following raw materials in parts by weight: Component weight Bisoprolol Fumarate 10 parts Chitosan 5 parts Xylitol 200 parts Disintegrant 2-8 parts Lubricant 2-10 parts.

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