A bisoprolol fumarate tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a bisoprolol fumarate tablet. The bisoprolol fumarate tablet of the invention is composed of bisoprolol fumarate, sodium thiosulfate, a filler, a disintegrant, a binder and a lubricant, has good surface quality, good stability, high dissolution, and a relatively simple preparation process, thereby reducing production costs and being suitable for large-scale industrial production.

Description

Technical Field

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

[0002] The situation of hypertension prevention and control in my country is severe, with the number of patients reaching 245 million, but the control rate is only 16.8%. Bisoprolol fumarate is a beta-receptor blocker with high affinity for the beta1-receptors of bronchial and vascular smooth muscle, thereby dilating blood vessels and lowering blood pressure. It is suitable for hypertension, coronary heart disease, and moderate to severe chronic stable heart failure. Its structure is as follows:

[0003]

[0004] CN101467985B discloses a bisoprolol fumarate dispersible tablet and a preparation method thereof. The prescription contains 55% of calcium hydrogen phosphate. When we conducted experiments according to the prescription, we found that the proportion of calcium hydrogen phosphate was too high, the color turned black when the tablets were pressed, and the stability was poor during storage.

[0005] CN103127016B discloses a bisoprolol fumarate tablet composition and a preparation method thereof, wherein the raw and auxiliary materials are mixed uniformly by an equal amount incremental method. The equal amount incremental method is relatively complicated, and there is equipment mismatch during production, and the equipment needs to be replaced many times, which may cause the problem of low final content for small-sized compounds.

[0006] CN112245401A discloses a pharmaceutical tablet for treating hypertension and coronary heart disease and a preparation method thereof. The wet granulation process is adopted in the process, but the stability and dissolution effect thereof are not ideal.

[0007] Formulation and evaluation of bisoprolol fumarate optizorb dispersible tablets to improve tablet disintegration, B. Lavanya et al. J. World Journal Of Pharmacy And Pharmaceutical Sciences. 2015, 4 (1), 561-576 Based on the OptiZorb technology using super disintegrants such as alginic acid and calcium carbonate, bisoprolol fumarate dispersible tablets with faster dissolution were obtained, but it was difficult to suppress the decomposition to a minimum for a long time in the unpackaged state and maintain sufficient stability as a tablet.

[0008] Evaluation of qualitative and quantitative stability parameters of a new tablet formulation containing bisoprolol fumarate, Alina Diana Panainte etal. J. FARMACIA, 2018, 66(3), 487-193 based on HPMC and ATO5 is used as an excipient and melt granulation technology is used. It is claimed that bisoprolol fumarate sustained-release tablets with good stability in the packaged state are obtained. However, bisoprolol fumarate is unstable to heat. Melting heating is required in this method, and the specific prescription dosage is not disclosed. Its stability cannot be confirmed. Moreover, it is a sustained-release tablet with a slow onset of effect and cannot meet the needs of patients.

[0009] At the same time, the inventor discovered during the development of the formulation that the marketed bisoprolol fumarate product Concor is a film-coated tablet, and the solvent used in the coating process may have an adverse effect on the related substances in the formulation. Removing the coating layer can improve the stability of the formulation, but the original formulation uses calcium hydrogen phosphate. After losing the cover of the coating layer, the core will appear gray, and the tablet does not meet the requirements. The inventor further removed the calcium hydrogen phosphate in the prescription, and the stability deteriorated.

[0010] In view of this, there is an urgent need for a bisoprolol fumarate tablet with simple preparation process, good stability and rapid dissolution. Summary of the invention

[0011] In view of the deficiencies of the prior art, the present invention provides a bisoprolol fumarate tablet. The bisoprolol fumarate tablet does not require a complicated preparation process and has high stability and good solubility.

[0012] During the formulation development process, the inventors found that the dissolution effect of existing rapid-release / dispersible tablet preparations needed to be improved, and it was difficult to suppress decomposition to a minimum for a long time without packaging to maintain sufficient stability as a tablet to achieve better efficacy. Unexpectedly, through a large number of creative experiments, the inventors found that adding sodium thiosulfate to the formulation can not only achieve rapid dissolution of bisoprolol fumarate, but also be beneficial to the stability of the preparation.

[0013] The present invention is specifically implemented through the following solutions:

[0014] A bisoprolol fumarate tablet comprises bisoprolol fumarate, sodium thiosulfate, a filler, a disintegrant, a binder and a lubricant.

[0015] The weight ratio of the bisoprolol fumarate to the sodium thiosulfate is 5:0.1-15.

[0016] Preferably, the weight ratio of bisoprolol mafate to sodium thiosulfate is 5:2-10.

[0017] Further preferably, the weight ratio of bisoprolol mafate to sodium thiosulfate is 5:4-6.

[0018] The filler is one or more of microcrystalline cellulose, lactose, starch and mannitol.

[0019] The weight ratio of the bisoprolol fumarate to the filler is 5:80-100.

[0020] The binder is one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, and copovidone.

[0021] The weight ratio of the bisoprolol fumarate to the binder is 5:2-6.

[0022] The lubricant is one or more of magnesium stearate, calcium stearate, talcum powder, and sodium stearyl fumarate.

[0023] The weight ratio of the bisoprolol fumarate to the lubricant is 5:1-3.

[0024] The disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and calcium carboxymethyl cellulose.

[0025] Preferably, the disintegrant is sodium carboxymethyl starch.

[0026] The weight ratio of the bisoprolol fumarate to the disintegrant is 5:2-6.

[0027] In a preferred embodiment, the bisoprolol fumarate tablets are prepared from the following raw materials in parts by weight:

[0028]

[0029] In a preferred embodiment, the bisoprolol fumarate tablets are prepared from the following raw materials in parts by weight:

[0030]

[0031] In a preferred embodiment, the bisoprolol fumarate tablets are prepared from the following raw materials in parts by weight:

[0032]

[0033] The present invention also provides a method for preparing the bisoprolol fumarate tablets, which comprises fully mixing bisoprolol fumarate and sodium thiosulfate, adding a filler, a disintegrant, a binder and a lubricant, mixing, and tableting to obtain the bisoprolol fumarate tablets.

[0034] Compared with the prior art, the present invention has the following advantages: the bisoprolol fumarate tablets of the present invention do not require coating, have good tablet surface, are simple in process, improve production efficiency, reduce production costs, have good stability, and dissolve quickly. DETAILED DESCRIPTION

[0035] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are provided only for illustrating the present invention, rather than limiting the present invention, and therefore, simple modifications of the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0036] The specification of the bisoprolol fumarate tablets in the embodiment of the present invention and the comparative example is 5 mg / tablet.

[0037] Example 1

[0038]

[0039] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add mannitol, sodium carboxymethyl starch, hydroxypropyl methylcellulose and magnesium stearate, mix, and press into tablets to obtain the product.

[0040] Example 2

[0041]

[0042] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add microcrystalline cellulose, sodium carboxymethyl starch, povidone and talc, mix, and press into tablets to obtain the product.

[0043] Example 3

[0044]

[0045] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add lactose, sodium carboxymethyl starch, hydroxypropyl methylcellulose and calcium stearate, mix, and press into tablets to obtain the product.

[0046] Example 4

[0047]

[0048]

[0049] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add mannitol, carboxymethylcellulose calcium, copovidone and sodium stearyl fumarate, mix, and press into tablets to obtain the product.

[0050] Example 5

[0051]

[0052] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add lactose, sodium carboxymethyl starch, hydroxypropyl cellulose and magnesium stearate, mix, and press into tablets to obtain the product.

[0053] Example 6

[0054]

[0055] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add microcrystalline cellulose, sodium carboxymethyl starch, povidone and talc, mix, and press into tablets to obtain the product.

[0056] Example 7

[0057]

[0058] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add mannitol, sodium carboxymethyl starch, hydroxypropyl cellulose and sodium stearyl fumarate, mix, and press into tablets to obtain the product.

[0059] Example 8

[0060]

[0061] Fully mix the prescribed amount of bisoprolol fumarate and sodium thiosulfate, then add mannitol, sodium carboxymethyl starch, hydroxypropyl methylcellulose and magnesium stearate, mix, and press into tablets to obtain the product.

[0062] Comparative Example 1

[0063] Referring to Example 1, the substances in the following table are substituted for sodium thiosulfate, and the others are the same:

[0064] name Weight Comparative Example 1-1 Sodium metabisulfite 5 servings Comparative Example 1-2 Sodium sulfite 5 servings Comparative Examples 1-3 ascorbic acid 5 servings Comparative Examples 1-4 Sodium Thiosulfate 0 copies

[0065] Comparative Example 2

[0066]

[0067] Add the prescribed amount of bisoprolol fumarate, alginic acid, calcium carbonate and lactose to a No. 22 sieve, mix and sieve, put into a mortar, add starch paste and pestle to mix, dry, then add magnesium stearate and talc, mix, and use a 16-station rotary tablet press to tablet the preparation.

[0068] Comparative Example 3

[0069]

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

[0071] Comparative Example 4

[0072]

[0073] Weigh half of the prescribed amount of microcrystalline cellulose PH101 and cross-linked polyvinylpyrrolidone and the prescribed amount of calcium hydrogen phosphate; mix them evenly, use water to make a soft material, use an 18-mesh sieve to granulate, bake in an oven at 50°C for 2 hours, take out and sieve through a 30-mesh sieve to granulate, mix the obtained granules with the prescribed amount of bisoprolol fumarate, micropowder silica gel, magnesium stearate and the remaining microcrystalline cellulose PH101 and cross-linked polyvinylpyrrolidone, and use 6mm shallow concave punching to obtain tablets.

[0074] Comparative Example 5

[0075]

[0076] Weigh each component according to the prescribed amount, and pass bisoprolol fumarate through a 100-mesh sieve; uniformly mix bisoprolol fumarate, lactose, mannitol 200SD, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and povidone by an equal amount addition method; add a prescribed amount of magnesium stearate and mix uniformly; and compress the tablets, controlling the pressure at 1.0 to 3.0 KN so that the hardness of the tablets is 40 to 60 N.

[0077] Comparative Example 6

[0078]

[0079] Add the prescribed amount of bisoprolol fumarate, Polyox N12K, carbomer 940P, PVP K-30 and dicalcium phosphate into a mortar, grind and mix evenly, pass through a No. 60 sieve, add sodium bicarbonate, magnesium stearate and talcum powder, mix well enough to compress, and use a 9mm round flat punch to press tablets on a 9-station rotary tablet press to obtain the product.

[0080] Comparative Example 7

[0081]

[0082] After mixing bisoprolol fumarate and lactose, put them into a fluidized bed granulator, prepare the prescribed amount of hydroxypropyl cellulose into a 5% ethanol solution of hydroxypropyl cellulose and spray it, dry the obtained powder in a fluidized bed and sieve it with a 22-mesh sieve, then add low-substituted hydroxypropyl cellulose and magnesium stearate and mix well, and use a rotary tablet press to obtain tablets.

[0083] Comparative Example 8

[0084]

[0085] Pass bisoprolol fumarate, silicified microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and sodium starch glycolate through a 20-mesh sieve in sequence, add them into a double-cone blender (15±2rpm) and stir and mix; pass magnesium stearate through a 20-mesh sieve and add it into the blender, continue stirring for 5 minutes, and press the tablets on a rotary tablet press to obtain the product.

[0086] Comparative Example 9

[0087]

[0088] The prescribed amount of bisoprolol fumarate and corn starch are sieved together with a 40-mesh sieve, and then sieved together with anhydrous calcium hydrogen phosphate. The mixed powder is then added to a wet granulation pot, and wet granulation is performed with an appropriate amount of water. The prepared granules are added to a fluidized bed for drying until the drying loss value is not greater than 2%. The dry granules are sieved through a 40-mesh sieve, crushed, and then sieved through a 40-mesh sieve until all the granules can pass through the 40-mesh sieve. Microcrystalline cellulose, cross-linked polyvinylpyrrolidone and colloidal silicon dioxide are sieved together with a 30-mesh sieve, and then added together with the above-prepared dry granules into a mixing hopper for mixing for 30 minutes. Magnesium stearate is sieved through a 60-mesh sieve and added to the mixing hopper for total mixing, and tableting is performed to obtain the product.

[0089] Verification Example

[0090] 1. Accelerated test: Take the tablets obtained in the examples and comparative examples and the reference preparation Concor (all without outer packaging), and conduct stability investigation with reference to Part 4 <9001 Guidelines for Stability Testing of Raw Materials and Preparations> of the 2020 edition of the Chinese Pharmacopoeia. The test conditions are: 40°C ± 2°C, 75% RH ± 5% RH.

[0091] HPLC chromatographic conditions for related substances: octadecylsilane bonded silica gel as filler; 0.05 mol / L diammonium phosphate solution (pH adjusted to 5.5 with phosphoric acid)-acetonitrile (70:30) as mobile phase A, 0.05 mol / L diammonium phosphate solution (pH adjusted to 5.5 with phosphoric acid)-acetonitrile (35:65) as mobile phase B, gradient elution; flow rate 1.0 ml per minute; column temperature 25°C; detection wavelength 225 nm; injection volume 10 μl.

[0092] 2. Dissolution test: Take the tablets obtained in the examples and comparative examples, the reference preparation Concor, and the corresponding preparations after 6 months of accelerated testing, and refer to the third method of <0931 Dissolution and Release Determination Method> of Part IV of the 2020 edition of the Chinese Pharmacopoeia, with 200mL of water as the medium, the speed is 35r / min, take an appropriate amount of solution and filter it through a 0.65μm microporous filter membrane, and take the subsequent filtrate as the test solution. Take an appropriate amount of bisoprolol fumarate reference substance and prepare a 25μg / mL solution with water as the reference solution. Accurately measure 20μL of the above-mentioned reference substance and test solution respectively, inject them into the HPLC instrument, and calculate the dissolution amount of each tablet by peak area according to the external standard method.

[0093] Table 1 Accelerated test results

[0094]

[0095] After testing, the bisoprolol fumarate tablets of the present invention have no obvious increase in related substances after accelerated 6 months, and have excellent stability. Comparative Example 4, Comparative Example 6 and Comparative Example 9 initially have more related substances, which may be related to their preparation process, using wet granulation that is unfavorable to their stability, and using heating or grinding operations.

[0096] Table 2 Dissolution test results

[0097]

[0098]

[0099] According to the test, the bisoprolol fumarate tablets obtained by the present invention dissolve rapidly after 6 months of accelerated dissolution, and the effect is better than that of the prior art.

Claims

1. A bisoprolol fumarate tablet, characterized in that: The invention comprises bisoprolol fumarate, sodium thiosulfate, a filler, a disintegrant, a binder and a lubricant. The preparation method of the bisoprolol fumarate tablet comprises the following steps: fully mixing bisoprolol fumarate and sodium thiosulfate, adding a filler, a disintegrant, a binder and a lubricant, mixing, and tableting to obtain the bisoprolol fumarate tablet.

2. The bisoprolol fumarate tablet according to claim 1, characterized in that The weight ratio of the bisoprolol fumarate to the sodium thiosulfate is 5:0.1-15.

3. The bisoprolol fumarate tablet according to claim 1, characterized in that The weight ratio of the bisoprolol fumarate to the sodium thiosulfate is 5:2-10.

4. The bisoprolol fumarate tablet according to claim 1, characterized in that The weight ratio of the bisoprolol fumarate to the sodium thiosulfate is 5:4-6.

5. The bisoprolol fumarate tablet according to claim 1, characterized in that: The filler is one or more of microcrystalline cellulose, lactose, starch and mannitol.

6. The bisoprolol fumarate tablet according to claim 1, characterized in that: The binder is one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, and copovidone.

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

8. The bisoprolol fumarate tablet according to claim 1, characterized in that: The disintegrant is one or more of sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, and hydroxypropyl starch.

9. The bisoprolol fumarate tablet according to claim 8, characterized in that: The disintegrant is sodium carboxymethyl starch.

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