A mirabegron sustained-release tablet and its preparation method

Abstract

The present invention discloses a mirabegron sustained-release tablet and a preparation method thereof. The weight percentage contents of the components of the mirabegron sustained-release tablet are as follows: mirabegron 0.5% to 25%, hydroxypropyl methylcellulose 1% to 40%, sodium alginate 1% to 40%, polyethylene glycol 10% to 60%, stearic acid 0.5% to 30%, hydroxypropyl cellulose 0.1% to 20%, magnesium stearate 0.01% to 5%, and coating premix 0.5% to 20%. The mirabegron sustained-release tablet provided by the present invention has a long release time, high safety, and complete release, improves the bioavailability, and is simple to prepare and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and mainly relates to a mirabegron sustained-release tablet and a preparation method thereof. Background Art

[0002] The chemical name of mirabegron is (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide, and its molecular formula is C 21 H 24 N 4 O 2 S, and its structural formula is as follows:

[0003]

[0004] Mirabegron is an arylethanolamine β-3 adrenergic agonist developed by Astellas Pharma Inc. in Japan. The tablet was launched in Japan on September 16, 2011, and was approved by the US Food and Drug Administration for the treatment of overactive bladder (OAB) under the trade name Myrbetriq on June 28, 2012. Mirabegron is the first β3 adrenergic receptor agonist drug used to treat overactive bladder, and its successful launch has filled the gap in the treatment of overactive bladder by β adrenergic receptor agonists. Mirabegron mainly acts on the β3 receptor to relax the detrusor muscle of the bladder and increase its stability. In vivo studies have shown that after administration of mirabegron, it can inhibit the average bladder pressure and the number of microcontractions, and effectively promote bladder storage.

[0005] In order to maximize the pharmacological effect on the bladder, it is necessary to develop a formulation of mirabegron for modified release to prolong the drug action time. The distribution and metabolism of mirabegron in the body are easily affected by food. Therefore, a sustained-release preparation is required to release the drug slowly and non-constantly as required, relatively reducing the dosing frequency, significantly increasing the efficacy or compliance of patients, and improving the clinical efficacy.

[0006] Patent application CN105232448A discloses a mirabegron controlled-release pharmaceutical composition, which can improve the reduction of blood drug concentration caused by food. Polyethylene oxide is selected as the sustained-release retarder, and there are a large number of ether bonds in the molecular chain, which are easily oxidized and degraded by external influences. Therefore, dibutylhydroxytoluene is added as an antioxidant, and the distribution degree of the antioxidant will affect the tablet preparation and the tablet release effect. Patent CN104523635B selects hydroxypropyl methylcellulose as the matrix material. The tablet can continuously release for 8 hours after oral administration, does not use an antioxidant, ensures the drug efficacy and safety, but the tablet preparation process is more complex and requires high standards.

[0007] Therefore, there is an urgent need to develop a mirabegron sustained-release tablet that can release non-constantly for a long time, release completely, and has a simple preparation process. Summary of the Invention

[0008] The object of the present invention is to overcome the deficiencies in the prior art and provide a mirabegron sustained-release tablet and a preparation method thereof.

[0009] One of the technical solutions of the present invention is to provide a mirabegron sustained-release tablet, which is composed of mirabegron as an active ingredient and pharmaceutical excipients.

[0010] Specifically, for the mirabegron sustained-release tablet of the present invention, the weight content of each component is as follows:

[0011]

[0012] The number-average molecular weight of the polyethylene glycol is 5000-10000. The polyethylene glycol belongs to a high molecular polymer, which is composed of a homologous mixture with the same chemical composition but different degrees of polymerization. Usually, the average molecular weight is used to characterize the size of the molecule, which is called the number-average molecular weight.

[0013] The weight ratio of hydroxypropyl cellulose to sodium alginate is preferably 1:(0.2-5), and more preferably 1:(0.5-2).

[0014] The weight ratio of polyethylene glycol to stearic acid is preferably 10:(1-7), and more preferably 10:(2-5).

[0015] The coating premix is a commercially purchased gastric-soluble coating premix, which includes 69.653% hydroxypropyl methylcellulose, 13.024% polyethylene glycol 8000, 14.44% iron dye yellow oxide, and 3% iron dye red oxide.

[0016] Preferably, for the mirabegron sustained-release tablet, the weight content of each component is as follows:

[0017]

[0018] In a preferred technical solution, for the mirabegron sustained-release tablet, the weight content of each component is as follows:

[0019]

[0020]

[0021] Another aspect of the present invention is to provide a preparation method of the mirabegron sustained-release tablet, which specifically includes the following steps:

[0022] 1 Pretreatment: Weigh the prescribed amount of polyethylene glycol and stearic acid, crush and sieve them, then weigh the prescribed amount of hydroxypropyl methylcellulose, sodium alginate and mirabegron raw material drug, and mix and sieve them.

[0023] 2 Fluidized bed one-step granulation: Dissolve the prescribed amount of hydroxypropyl cellulose in an appropriate amount of water to prepare a binder solution. Add the premix obtained in step (1) to the fluidized bed and spray the binder solution to form granules in one step.

[0024] 3 Total mixing: Add magnesium stearate to the granules prepared in step (2) and mix evenly.

[0025] 4 Tabletting: Compress the total mixed granules obtained in step (3) into tablets.

[0026] 5 Coating: Dissolve the prescribed amount of gastric-soluble film coating premix in purified water to prepare a uniform suspension. Transfer the plain tablets obtained in step (4) into a coating pan and spray the coating suspension to obtain mirabegron sustained-release tablets.

[0027] Advantages of the present invention

[0028] The present invention provides a mirabegron sustained-release tablet and a preparation method thereof. Compared with the mirabegron sustained-release tablet and the preparation method disclosed in the prior art, the present invention selects hydroxypropyl methylcellulose and sodium alginate as hydrophilic gel matrix materials, which can optimize the release duration and cumulative release amount of the mirabegron active ingredient. In addition, the erodible sustained-release matrix material in the present invention selects polyethylene glycol and stearic acid, and controls the particle size of the excipients so that the raw and auxiliary materials are not easily stratified during the fluidized bed granulation process. Therefore, direct compression can be used for tabletting, and the preparation process is more simple and easy to operate, and is more suitable for industrial production. The mirabegron sustained-release tablet obtained by the technical solution of the present invention can continuously release for 12 hours after oral administration, and the release amount is greater than 90%, and the bioavailability is high. Description of the drawings

[0029] Figure 1 : Dissolution curve investigation chart of the mirabegron sustained-release tablets prepared in Examples 1-6, Comparative Examples 1-2 and the purchased original research product (using pH 6.8 phosphate solution as the dissolution medium) Detailed implementation manners

[0030] In order to better understand the technical solution of the present invention, the following further describes the technical solution of the present invention with specific examples. The examples are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0031] In this example, the mirabegron raw material drug, excipients and coating premix are all obtained by commercial purchase.

[0032] The formulations of the mirabegron sustained-release tablets in Examples 1-6 are shown in the following table (unit: g):

[0033] Constituents Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Mirabegron 25 25 25 25 25 25 Hydroxypropyl methylcellulose 50 40 50 50 40 50 Sodium alginate 50 50 50 50 50 50 Polyethylene glycol 30 100 80 100 80 45 Stearic acid 100 30 30 30 30 55 Hydroxypropyl cellulose 7.5 7.5 7.5 7.5 7.5 7.5 Magnesium stearate 2.5 2.5 2.5 2.5 2.5 2.5 Coating premix 7.5 7.5 7.5 7.5 7.5 7.5 Total 272.5 262.5 252.5 272.5 242.5 272.5

[0034] In the mirabegron sustained-release tablet formulations of the above Examples 1-6, the number-average molecular weight of polyethylene glycol is 5000-10000. Preparation method of mirabegron sustained-release tablets having the formulations of Examples 1-6 above:

[0035] (1) Weigh the prescription amounts of polyethylene glycol and stearic acid, crush them using a traditional Chinese medicine grinder, and pass them all through a 100-mesh sieve. Weigh the prescription amounts of hydroxypropyl methylcellulose, sodium alginate, and mirabegron raw material, mix them manually for 10 minutes, and pass through a sieve to obtain a premix.

[0036] (2) Dissolve the prescription amount of hydroxypropyl cellulose in an appropriate amount of water to make a binder solution. Add the premix obtained in step (1) to a fluidized bed and spray the binder solution to form granules in one step.

[0037] (3) Add magnesium stearate to the granules obtained in step (2) and mix evenly to obtain the total mixed granules.

[0038] (4) Press the total mixed granules obtained in step (3) into tablets.

[0039] (5) Dissolve the prescription amount of gastric-soluble film coating premix in purified water to make a uniform coating suspension. Transfer the plain tablets obtained in step (4) into a coating pan and spray the coating suspension to obtain the mirabegron sustained-release tablets.

[0040] To illustrate that the combined use of polyethylene glycol and stearic acid as erodible sustained-release matrix materials has better effects, the present invention sets Comparative Examples 1-2 in which only one of them is included in two prescriptions.

[0041] The formulations of the mirabegron sustained-release tablets of Comparative Examples 1-2 are shown in the following table (unit: g):

[0042]

[0043]

[0044] Preparation method of mirabegron sustained-release tablets having the formulations of Comparative Examples 1-2 above:

[0045] (1) Weigh the prescription amount of polyethylene glycol or stearic acid, crush it using a traditional Chinese medicine grinder, and pass it through a 100-mesh sieve. Weigh the prescription amounts of hydroxypropyl methylcellulose, sodium alginate, and mirabegron raw material, mix them manually for 10 minutes, and pass through a sieve to obtain a premix.

[0046] (2) Dissolve the prescription amount of hydroxypropyl cellulose in an appropriate amount of water to make a binder solution. Add the premix obtained in step (1) to a fluidized bed and spray the binder solution to form granules in one step.

[0047] (3) Add magnesium stearate to the granules obtained in step (2) and mix evenly to obtain the total mixed granules.

[0048] (4) Compress the total mixed granules obtained in step (3) into tablets.

[0049] (5) Dissolve the prescription amount of gastric-soluble film coating premix in purified water to prepare a uniform coating suspension. Transfer the plain tablets obtained in step (4) into a coating pan and spray the coating suspension to obtain mirabegron sustained-release tablets.

[0050] Test Example 1

[0051] Dissolution test

[0052] According to the dissolution test method of the Chinese Pharmacopoeia, perform dissolution tests on the mirabegron sustained-release tablets prepared in Examples 1-6, Comparative Examples 1-2, and the purchased reference product (trade name: Myrbetriq, specification: 25 mg, licensee: Astellas Pharma Technologies) in 900 mL of pH 6.8 phosphate buffer solution at 37 °C using a paddle method at 100 revolutions per minute.

[0053] The results of the cumulative release rate of mirabegron over time are as Figure 1 shown in Table 1.

[0054] Table 1

[0055]

[0056]

[0057] As can be seen from the above table, the dissolution degree of the examples of the present invention is significantly better than that of the comparative examples and the reference product. For Examples 1-6 using stearic acid and polyethylene glycol as carriers together, compared with Comparative Example 1 using polyethylene glycol alone, Comparative Example 2 using stearic acid alone, and the reference product, the dissolution of the present invention is more complete, and the optimal can reach more than 99%.

[0058] Test Example 2

[0059] Stability test

[0060] Place the mirabegron sustained-release tablets obtained in Example 4 and Control Example 1 at 40 °C ± 2 °C and relative humidity 75% ± 5% for 6 months, and sample for HPLC detection at 0 month, 3 months, and 6 months respectively to determine the content of related substances. The results are shown in Table 2.

[0061] Table 2

[0062]

[0063] As can be seen from the data in Table 2, during the 6-month storage process of the mirabegron sustained-release tablets obtained in Example 4, the change in the total impurity content was only 0.08%. After 6 months of storage, the maximum impurity content of the mirabegron sustained-release tablets obtained in Comparative Example 1 increased by nearly 4 times compared with that at month 0, and the increase in the total impurity content was also close to 3 times.

Claims

1. A mirabegron sustained-release tablet, characterized in that, the weight contents of the components in the mirabegron sustained-release tablet are as follows: Mirabegron 9.17% Hydroxypropyl methylcellulose 18.35% Sodium alginate 18.35% Polyethylene glycol 36.70% Stearic acid 11.01% Hydroxypropyl cellulose 2.75% Magnesium stearate 0.92% Coating premix 2.75% Total 100%.

2. A preparation method of the mirabegron sustained-release tablet according to claim 1, characterized in that, it specifically comprises the following steps: (1) Pretreatment: Weigh the prescribed amount of polyethylene glycol and stearic acid, crush and sieve them, then weigh the prescribed amount of hydroxypropyl methylcellulose, sodium alginate and mirabegron raw material drug, and mix and sieve them; (2) One-step granulation in fluidized bed: Dissolve the prescribed amount of hydroxypropyl cellulose in an appropriate amount of water to make a binder solution, add the premix obtained in step (1) into the fluidized bed, and spray the binder solution to form granules in one step; (3) Total mixing: Add the magnesium stearate to the granules obtained in step (2) and mix evenly; (4) Tabletting: Press the total mixed granules obtained in step (3) into tablets; (5) Coating: Dissolve the prescribed amount of coating premix in purified water to make a uniform suspension, transfer the plain tablets obtained in step (4) into a coating pan, and spray the coating suspension to obtain the mirabegron sustained-release tablet.

3. The preparation method according to claim 2, characterized in that, the sieving in step (1) is sieving through a 100-mesh sieve.

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