A kind of metoprolol succinate sustained-release capsule and preparation method thereof

Abstract

The present invention relates to a metoprolol succinate sustained-release capsule and a preparation method thereof. The metoprolol succinate sustained-release capsule is composed of a capsule shell and a metoprolol succinate sustained-release micro-pill, wherein the sustained-release micro-pill comprises a metoprolol succinate drug-containing pill core and a sustained-release coating layer coating the metoprolol succinate drug-containing pill core, wherein the drug-containing pill core comprises metoprolol succinate, microcrystalline cellulose and polyethylene glycol-polylysine block copolymer. The present invention also provides a preparation method of the metoprolol succinate sustained-release capsule.

Description

Technical Field

[0001] The invention relates to a metoprolol succinate sustained-release capsule and a preparation method thereof, and belongs to the field of pharmaceutical preparations. Background Art

[0002] Metoprolol is a selective β1 receptor blocker and one of the commonly used drugs for the treatment of hypertension, coronary heart disease, chronic heart failure and arrhythmia. The dose of metoprolol required to act on cardiac β1 receptors is lower than the dose required to act on β2 receptors on peripheral blood vessels and bronchi, so the selectivity of metoprolol is dose-dependent. Since the peak blood concentration of sustained-release preparations is significantly lower than that of ordinary preparations of the same dose, the sustained-release preparation of metoprolol has a relatively higher β1 receptor selectivity, which is more in line with the needs of clinical treatment.

[0003] Metoprolol has a variety of hydrochloride forms, such as tartrate, succinate, etc. Among them, the solubility of metoprolol succinate in 37°C water (270 mg / ml) is significantly lower than that of metoprolol tartrate (>700 mg / ml), thereby significantly slowing down the dissolution rate and achieving the purpose of slow and sustained release of metoprolol.

[0004] There are many metoprolol sustained-release preparations on the market, such as Kapspargo Sprinkle, metoprolol tartrate sustained-release tablets, metoprolol controlled-release tablets, etc. These preparations mainly use coating or dispersion technology to control the drug release rate, but there are still some shortcomings. For example, coating technology requires the use of a large amount of polymer materials and solvents, which increases costs and environmental burdens; dispersion technology requires the use of special equipment and processes, and the operation is complex and unstable; the blood drug concentration of these preparations fluctuates greatly after taking them, which may affect the therapeutic effect and safety.

[0005] In order to improve the performance of metoprolol sustained-release preparations, some patents have disclosed different preparation methods. For example, Chinese patent CN102274205B discloses a metoprolol succinate sustained-release capsule and a preparation method thereof, which adopts an extrusion spheronization method or a pan-pill method to prepare a pill core containing a drug, and coats the pill core with a methacrylic resin polymer or ethyl cellulose as a sustained-release coating layer; U.S. Patent US04927640 describes in detail a preparation method of Betaloc sustained-release tablets, which adopts a coating method to coat the drug onto fine glass beads or a silica core, and coats the drug core with ethyl cellulose as a sustained-release coating layer; Chinese patents CN101055579A and CN101055580A disclose two metoprolol sustained-release tablets and preparation methods thereof, both of which adopt a dispersion technology to directly disperse the drug in a skeleton formed by a polymer material.

[0006] However, the above patents still have some shortcomings. For example, both the extrusion spheronization method and the pan-pill method require the use of blank pill cores as carriers, which increases raw material consumption and costs; the coating method requires the use of a large amount of solvents, and the coating process is difficult to control uniformity; the dispersion technology requires the use of special equipment and processes, and the dispersion process is prone to dust pollution. Therefore, the development of a new type of metoprolol sustained-release preparation and its preparation method, which has the advantages of simplicity, economy, stability, safety, etc., is a problem that needs to be solved urgently by those skilled in the art. Summary of the invention

[0007] The first aspect of the present invention is to provide a metoprolol succinate sustained-release capsule, which consists of a capsule shell and metoprolol succinate sustained-release micropellets, wherein the sustained-release micropellets include a metoprolol succinate-containing pellet core and a sustained-release coating layer coating the metoprolol succinate-containing pellet core, wherein the pellet core includes metoprolol succinate, microcrystalline cellulose and a polyethylene glycol-polylysine block copolymer.

[0008] In one embodiment, the drug-containing pellet core comprises 10 parts by weight of metoprolol succinate, 10-30 parts by weight of microcrystalline cellulose and 1-10 parts by weight of polyethylene glycol-polylysine block copolymer. In a further embodiment, the drug-containing pellet core comprises 10 parts by weight of metoprolol succinate, 15-20 parts by weight of microcrystalline cellulose and 3-5 parts by weight of polyethylene glycol-polylysine block copolymer.

[0009] In another embodiment, the sustained-release coating layer comprises ethyl cellulose, triethyl citrate and polylactic acid-alanine copolymer. In a further embodiment, the sustained-release coating layer comprises 10 parts by weight of ethyl cellulose, 1-3 parts by weight of triethyl citrate and 2-4 parts by weight of polylactic acid-alanine copolymer.

[0010] In another embodiment, the sustained-release coating layer has a weight gain of 2-6% based on the weight of the pellet core.

[0011] In another embodiment, the particle size of the sustained-release pellets is 0.1-0.2 mm. The second aspect of the present invention is to provide a method for preparing the metoprolol succinate sustained-release capsules, which comprises:

[0012] 1) passing metoprolol succinate, microcrystalline cellulose and polyethylene glycol-polylysine block copolymer through a 60-mesh sieve, and then placing them in a wet granulator, and using a 3% (weight) PVP30 aqueous solution to prepare a soft material; placing the soft material in an extruder, extruding, spheronizing, and drying in a fluidized bed to obtain a pill core;

[0013] 2) adding ethyl cellulose, triethyl citrate and polylactic acid-alanine copolymer into water, stirring and mixing to obtain a coating solution; placing the pill cores containing the drug in a fluidized bed for coating, drying and sieving to obtain sustained-release pellets;

[0014] 3) Mix the sustained-release pellets and talcum powder in a three-dimensional motion mixer to obtain mixed pellets; and fill the mixed capsules into capsules.

[0015] In one embodiment, in step 1), the mesh size is 0.1-0.25 mm, and the extrusion speed is 20-60 rpm.

[0016] In another embodiment, in step 1), the spheronization speed is 800-1000 rpm.

[0017] In another embodiment, step 2) coating weight gain is 2-6%.

[0018] The present invention improves the coating adhesion problem of small-size drug-containing cores by optimizing the prescription of drug-containing core excipients and the prescription of sustained-release coating excipients, greatly reduces the weight gain of sustained-release coatings while maintaining excellent sustained-release effects and good stability, and can significantly save production costs. Since the particle size of the metoprolol succinate sustained-release capsule micro-pellets of the present invention is small, it is easier to release the drug evenly and be absorbed by individuals, so the bioavailability is greatly improved compared with traditional metoprolol sustained-release capsules.

[0019] The technical solution of the present invention is further described in detail below through embodiments. DETAILED DESCRIPTION

[0020] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0021] Example 1 Preparation of Metoprolol Succinate Sustained-Release Capsules

[0022] The prescriptions for each group are shown in the following table:

[0023]

[0024] Preparation method:

[0025] 1) passing the prescribed amount of metoprolol succinate, microcrystalline cellulose and polyethylene glycol-polylysine block copolymer through a 60-mesh sieve, and then placing them in a wet granulator, and preparing a soft material with a 3% (weight) PVP30 aqueous solution; placing the soft material in an extruder for extrusion, with a sieve aperture of 0.2 mm, an extrusion speed of 50 rpm, spheronization, a spheronization speed of 1000 rpm, and drying in a fluidized bed to obtain a pill core;

[0026] 2) adding the prescribed amount of ethyl cellulose, triethyl citrate and polylactic acid-alanine copolymer into water, stirring and mixing to obtain a coating solution; placing the pill cores containing the drug in a fluidized bed for coating, with a coating weight gain of 4%, drying and sieving to obtain sustained-release pellets;

[0027] 3) Mix the sustained-release pellets and talcum powder in a three-dimensional motion mixer to obtain mixed pellets; and fill the mixed capsules into capsules.

[0028] Test Example 1 Quality Inspection of Pill Cores

[0029] The yield (the percentage of the weight of pellets between 0.1 and 0.2 mm in the total feed) and the critical angle of the plane (to evaluate the roundness of the pellet core containing the drug) of the pellet core obtained in step 1 of Example 1 were measured, and the results were as follows:

[0030] Prescription 1 Prescription 2 Prescription 3 Comparative Example 1 Yield (%) 88.6 93.1 90.2 73.5 Plane critical angle 16.1° 14.4° 18.7° 23.9°

[0031] Comparative Example 1: The preparation method of the pill core is the same as that of Example 1, and its prescription is: 100 g of metoprolol succinate and 179 g of microcrystalline cellulose.

[0032] From the above results, it can be seen that after adding polyethylene glycol-polylysine block copolymer to the formulation containing pill cores, the yield in the preparation of small-size pill cores is significantly improved and the roundness is better.

[0033] Test Example 2 Quality Evaluation of Sustained Release Coating

[0034] The sustained-release pellets obtained in step 2) of Example 1 were subjected to plane critical angle measurement and cumulative release measurement (for test methods and content determination, see the "Metoprolol Tartrate Sustained-Release Tablets" item on page 1423 of the Chinese Pharmacopoeia 2020 edition)

[0035] The results are as follows:

[0036] 1) Plane critical angle

[0037] Prescription 1 Prescription 2 Prescription 3 Comparative Example 2 Plane critical angle 17.5° 15.8° 19.4° 32.1°

[0038] Comparative Example 2: The preparation method of the pill core and the sustained-release coating method are the same as Prescription 2 in Example 1, and the prescription of the sustained-release coating layer is 130 g of ethyl cellulose and 20 g of triethyl citrate.

[0039] Since the particle size of the drug-containing core in Example 1 is relatively small, only about 0.1-0.2 mm, conventional sustained-release coating solutions are prone to adhesion during the coating process. However, after adding polylactic acid-alanine copolymer to the coating solution, the technical problem of adhesion of the small-size drug-containing core coating can be better improved.

[0040] 2) Cumulative release

[0041]

[0042] Experimental Example 3 Effect of coating weight gain on the release rate of sustained-release pellets

[0043] Taking prescription 2 in Example 1 as an example, under the condition that the preparation method remains unchanged, different coating weight gain treatments (coating weight gain of 2%, 4% and 8% respectively) were performed on the pill cores containing the drug, and the cumulative release of each group of sustained-release pellets under different coating weight gain conditions was measured. The specific results are as follows:

[0044]

[0045] From the above results, it can be seen that with the increase of coating weight gain, the drug release rate of the sustained-release micropellets slows down significantly. When the coating weight gain exceeds 8%, the release rate of the sustained-release micropellets may not meet the drug release requirements of the pharmacopoeia for sustained-release drugs.

[0046] Test Example 4: Stability Study of Metoprolol Succinate Sustained-Release Capsules

[0047] Each group of metoprolol succinate sustained-release capsules was placed at 40±2°C and 75±5% relative humidity for 6 months, and the content and release rate (20h) of the main drug in each group were measured.

[0048] Comparative Example 3: The preparation method is the same as Example 1, except that the prescriptions of the pill core and the sustained-release coating layer are different. The prescription of the pill core is: 100 g of metoprolol succinate and 179 g of microcrystalline cellulose; the prescription of the sustained-release coating layer is: 130 g of ethyl cellulose and 20 g of triethyl citrate.

[0049] The specific results are as follows:

[0050]

[0051]

[0052] Experimental Example 5 Effect of sustained-release pellets with different particle sizes on bioavailability

[0053] Test method: 6 beagle dogs (weighing about 8 kg) were randomly divided into two groups, 3 in each group. They were fasted for 12 hours before the test and a single dose test was performed.

[0054] Group 1 was orally administered with metoprolol succinate sustained-release capsules prepared in Prescription 2 of Example 1; the dosage was 47.5 mg / piece;

[0055] Group 2 was orally administered metoprolol succinate sustained-release capsules prepared according to Prescription 2 of Example 1, except that the aperture of the extrusion screen was 800 mm; the dosage was 47.5 mg / each.

[0056] 3 ml of venous blood was collected from the hind limbs at 1, 4, 6, 8, 10, 12, 14, and 24 hours after administration, and the blood was centrifuged (3000 r / min) for 10 minutes to obtain the upper yellow serum.

[0057] Blood sample processing: add 0.2 ml of 4 M / L NaOH solution and 5 ml of ether to 1 ml of serum, vortex for 1 min, centrifuge to obtain the organic phase, add 120 ul of 0.01 M / L H2SO4 solution, vortex for 1 min, centrifuge to obtain the aqueous phase, and use HPLC-UV method for content determination.

[0058] The specific results are as follows:

[0059]

[0060]

[0061] From the above results, it can be seen that under the same conditions of prescription excipients, small particle size microcapsules have better bioavailability and stable drug release rate.

Claims

1. A metoprolol succinate sustained-release capsule, which consists of a capsule shell, a metoprolol succinate sustained-release pellet and talcum powder, wherein the sustained-release pellet comprises a metoprolol succinate-containing pellet core and a sustained-release coating layer coating the metoprolol succinate-containing pellet core, wherein the pellet core comprises 10 parts by weight of metoprolol succinate, 15-20 parts by weight of microcrystalline cellulose and 3-5 parts by weight of a polyethylene glycol-polylysine block copolymer; The sustained-release coating layer comprises 10 parts by weight of ethyl cellulose, 1-3 parts by weight of triethyl citrate and 2-4 parts by weight of polylactic acid-alanine copolymer; the weight gain of the sustained-release coating layer is 2-6% based on the weight of the pill core; and the particle size of the sustained-release micro-pill is 0.1-0.2 mm.

2. The method for preparing metoprolol succinate sustained-release capsules according to claim 1, comprising: 1) Metoprolol succinate, microcrystalline cellulose and polyethylene glycol-polylysine block copolymer are passed through a 60-mesh sieve and then placed in a wet granulator, and a 3% by weight PVP30 aqueous solution is used to prepare a soft material; the soft material is placed in an extruder for extrusion, spheronization, and drying in a fluidized bed to obtain a pill core; 2) Add ethyl cellulose, triethyl citrate and polylactic acid-alanine copolymer into water and stir to obtain coating solution; place the pill cores containing the drug in a fluidized bed for coating, dry and sieve to obtain sustained-release pellets; 3) Mix the sustained-release pellets and talcum powder in a three-dimensional motion mixer to obtain mixed pellets; fill the mixed pellets into capsules.

3. The preparation method according to claim 2, characterized in that: In step 1), the mesh size is 0.1-0.25 mm, and the extrusion speed is 20-60 rpm.

4. The preparation method according to claim 2, characterized in that: In step 1), the spheronization speed is 800-1000 rpm.

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