Mianserin tablet and preparation method thereof

Abstract

The invention discloses a mianserin tablet and a preparation method thereof, the mianserin tablet comprises a solid dispersion and tablet auxiliary materials, the solid dispersion comprises 10-100 parts of mianserin hydrochloride anhydride, 30-80 parts of a water-soluble carrier and 1-5 parts of a stabilizer; the water-soluble carrier is formed by compounding povidone K30 and hydroxypropyl methyl cellulose E5 according to the mass ratio of (2 to 3): 1; a water-soluble carrier and stabilizer compound system is selected to prepare the solid dispersion, so that amorphous dispersion of the medicine is guaranteed to improve dissolution, recrystallization of the medicine can be inhibited, and the effects of high bioavailability and stability are achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a mianserin tablet and its preparation method. Background Technology

[0002] Mianserin hydrochloride (CAS No. 21535-47-7), a tetracyclic antidepressant, has sedative and anxiolytic effects and does not have the anticholinergic adverse reactions of tricyclic antidepressants, making it clinically suitable for elderly patients and patients with cardiovascular disease. However, as a BCSII drug, it has inherent defects such as low solubility and slow dissolution rate, resulting in large fluctuations in the bioavailability of ordinary tablets after oral administration, affecting the consistency of efficacy. Its structural formula is as follows:

[0003] Existing technologies for improving mianserin hydrochloride tablets focus on two directions: 1. Optimization of Crystal Form and Process Stability: For example, CN120678739A discloses a wet granulation process that uses a high-concentration hydroxypropyl methylcellulose (HPMC) binder (10%~18%) and customized granulation parameters (stirring speed 100~125 rpm, granulation time 2~8 min) to solve the problem of anhydrous mianserin hydrochloride transforming into hydrate crystals and reduce the growth of related substances. However, this technology has not been optimized for the core defect of "low solubility," and the dissolution rate still depends on the crystal form of the raw material itself, resulting in limited improvement in bioavailability.

[0004] 2. Compound formulations with reduced toxicity and enhanced efficacy: For example, CN108379383A discloses a compound tablet containing ginseng extract (containing saponins) and rehmannia extract (containing oligosaccharides), which reduces the dosage of mirtazapine and lowers its toxic side effects through the combination of traditional Chinese and Western medicine. However, this technology uses traditional granulation processes, which do not improve drug dissolution performance, and the introduction of traditional Chinese medicine extracts is not combined with formulation dissolution optimization, still resulting in unstable bioavailability.

[0005] Solid dispersion technology can significantly increase the specific surface area of ​​drugs by dispersing them in a molecular, microcrystalline, or amorphous state within a water-soluble carrier, making it a mature technology for solving the dissolution problem of BCS Class II drugs. However, there are no reports in the current technology of combining solid dispersion technology with the requirements of "crystal stability" and "bioavailability" for mianserin hydrochloride. If conventional solid dispersions are used directly for preparation, problems such as drug recrystallization and poor compatibility between the carrier and the drug may be encountered, which may affect the stability.

[0006] Therefore, there is an urgent need to develop a micarin tablet that can simultaneously solve the core problems of slow dissolution and unstable crystal form, in order to fill the gap in existing technology. Summary of the Invention

[0007] This invention provides a mianselin tablet and its preparation method, which solves at least one defect of the prior art, such as slow dissolution and unstable crystal form.

[0008] In view of this, the solution of the present invention is as follows: The first aspect of the invention is to provide a mianserin tablet comprising a solid dispersion and tablet excipients; wherein: The solid dispersion is composed of the following components in parts by weight: 10-100 parts of anhydrous micarin hydrochloride, 30-80 parts of water-soluble carrier, and 1-5 parts of stabilizer; the water-soluble carrier is composed of polyvinylpyrrolidone K30 and hydroxypropyl methylcellulose E5 in a mass ratio of (2-3):1. The tablet excipients, based on 100 parts by weight of solid dispersion, include: 150-300 parts of anhydrous dicalcium phosphate, 10-80 parts of corn starch, 2-10 parts of colloidal silica, 0.1-10 parts of magnesium stearate, and 4-10 parts of film coating agent.

[0009] Furthermore, the stabilizer is selected from one or more of ascorbyl palmitate, butylated hydroxytoluene, tocopherol, sodium metabisulfite, etc.

[0010] Furthermore, the film coating agent is a hydroxypropyl methylcellulose-based coating agent, such as using an 8%~10% aqueous solution of hydroxypropyl methylcellulose for coating.

[0011] A second aspect of the present invention is to provide a method for preparing the mirtazapine tablets described in the first aspect, comprising: S1. Mix the anhydrous micarin hydrochloride, water-soluble carrier, and stabilizer after the first sieve, extrude them using a hot melt extruder, and then sieve them a second time to obtain a solid dispersion. The mesh size of the sieve used for the first sieve is greater than that used for the second sieve. S2. After uniformly mixing the solid dispersion powder with anhydrous dicalcium phosphate, corn starch, colloidal silica and magnesium stearate, the mixture is compressed into tablets and then coated to obtain miancelin tablets.

[0012] Further, in step S1, the first sieve has a mesh size of 80, and / or the second sieve has a mesh size of 60.

[0013] Further, in step S1, the extrusion process parameters are: barrel temperature 110~120℃ / 125~135℃ / 135~140℃, screw speed 80~120rpm, and die temperature 130~135℃.

[0014] Furthermore, in step S2, the wet granulation process adopts spray wet granulation, first mixing at low speed for 300-400s to complete the spraying, and then continuing to mix at high speed for 30-60s to obtain wet granules.

[0015] Furthermore, in step S2, the mixing process first involves uniformly mixing the solid dispersion powder with anhydrous dicalcium phosphate, corn starch, and colloidal silica before adding magnesium stearate.

[0016] Further, in step S2: the pressure of the tableting process is 20~30kN; and / or, the temperature of the coating process is 40~50℃, and the coating weight gain is 2~3%.

[0017] A third aspect of the present invention is the application of mianserin tablets in the preparation of antidepressant drugs, characterized in that the mianserin tablets are the mianserin tablets described in the first aspect, or are prepared by the preparation method described in the second aspect.

[0018] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a solid dispersion prepared by using povidone K30 (PVP K30) and hydroxypropyl methylcellulose E5 (HPMC E5) as a water-soluble carrier and stabilizer compound system. PVP K30 promotes amorphous dispersion of the drug, HPMC E5 inhibits recrystallization, and together with the stabilizer, it can ensure amorphous dispersion of the drug to improve dissolution and inhibit drug recrystallization, thereby achieving the effect of high bioavailability and stability. Detailed Implementation

[0019] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] In one embodiment, a method for preparing Mianserin tablets is provided, comprising two steps: preparation of a solid dispersion and preparation of tablets. Key process parameters have been optimized to balance dissolution, stability, and industrial feasibility. 1. Preparation of solid dispersions Pretreatment: Mianserin hydrochloride anhydrous, PVP K30, HPMC E5 and stabilizer were passed through an 80-mesh sieve and mixed evenly in proportion; Hot melt extrusion: The mixed powder is fed into a hot melt extruder, and the process parameters are set: Barrel temperature: Zone 1 110~120℃, Zone 2 125~135℃, Zone 3 135~140℃ (to avoid drug degradation); Screw speed: 80~120 rpm; Die head temperature: 130~135℃; Cooling and pulverizing: The extrudate was air-cooled to room temperature, pulverized with a pulverizer, and passed through a 60-mesh sieve to obtain mianserin solid dispersion powder (XRPD verification showed that the drug was in an amorphous state).

[0021] The solid dispersion components are as follows:

[0022] 2. Tablet Preparation

[0023] Mixing: Add the solid dispersion powder, anhydrous dicalcium phosphate, corn starch, and colloidal silica into a three-dimensional mixer and mix for 10-15 minutes; Total mixture: Add magnesium stearate and continue mixing for 3-5 minutes; Tableting: A rotary tablet press is used for tableting, with a tableting pressure of 20~30kN and tablet hardness controlled at 9~12kg. Coating: The compressed tablet cores are put into a high-efficiency coating pan, and 8%~10% hydroxypropyl methylcellulose aqueous solution is used as the coating solution. The coating temperature is controlled at 40~50℃, and the weight gain of the coating is 2%~3%, thus obtaining the finished product.

[0024] The components of the tablets are as follows:

[0025] The above preparation method effectively improved the dissolution and stability of mianserin hydrochloride. Specifically, the dissolution rate was measured using pH 4.5 acetate buffer (Chinese Pharmacopoeia 2025 Edition, General Chapter 0931, Method I), achieving a dissolution rate of 97% at 5 minutes and over 98% at 10 minutes. Under accelerated conditions (40℃±2℃, RH 75%±5%), after 6 months of storage, XRPD analysis showed no crystallization (maintaining amorphous characteristics), and the total related substances were below 0.08%. In vivo experiments in Beagle dogs showed that the relative bioavailability of the tablets was over 130% of that of ordinary tablets (formulation CN120678739A).

[0026] Example 1

[0027] 1. Mianselin tablet prescription: 1.1 The solid dispersion formulation is as follows:

[0028] 1.2 The tablet formulation consists of the following:

[0029] 2. Preparation steps

[0030] Preparation of solid dispersion: Mix anhydrous micarin hydrochloride, PVP K30, HPMC E5, and ascorbate palmitate according to the formula, hot melt extrusion (barrel temperature 110℃ / 130℃ / 135℃, screw speed 100rpm), and pulverize through a 60-mesh sieve; Tablet preparation: Mix the solid dispersion with anhydrous dicalcium phosphate, corn starch, and colloidal silica for 12 min, add magnesium stearate and mix for 4 min, compress into tablets (pressure 25 kN, hardness 10~11 kg), and coat (coating solution concentration 9%, tablet bed temperature 45±3℃).

[0031] 3. Performance Testing

[0032] Dissolution: Using pH 4.5 acetate buffer (Chinese Pharmacopoeia 2025 Edition, General Chapter 0931, Method I), the dissolution rate was 92.3% at 5 min and 97.8% at 10 min, which was significantly higher than 88.6% (5 min) and 96.8% (10 min) of Example 8 in CN120678739A. Stability: After 6 months of accelerated storage (40℃±2℃, RH75%±5%), XRPD analysis showed no crystal transformation (still maintaining amorphous characteristics), and the total related substances were 0.08%, lower than the 0.11% in Example 8 of CN120678739A; Bioavailability: In vivo studies in Beagle dogs showed that the relative bioavailability of the tablets in this embodiment was 132.5% of that of the ordinary tablets (CN120678739A formulation).

[0033] Example 2

[0034] 1. Mianserin tablet prescription (based on 1000 tablets)

[0035] 1.1 The solid dispersion formulation is as follows:

[0036] 1.2 The tablet formulation consists of the following:

[0037] 2. Preparation steps

[0038] Preparation of solid dispersion: Mix anhydrous micarin hydrochloride, PVP K30, HPMC E5, and ascorbate palmitate according to the formula, hot melt extrusion (barrel temperature 110℃ / 130℃ / 135℃, screw speed 100rpm), and pulverize through a 60-mesh sieve; Tablet preparation: Mix the solid dispersion with anhydrous dicalcium phosphate, corn starch, and colloidal silica for 12 min, add magnesium stearate and mix for 4 min, compress into tablets (pressure 25 kN, hardness 10~11 kg), and coat (coating solution concentration 9%, tablet bed temperature 45±3℃).

[0039] 3. Performance Testing

[0040] Dissolution: Using pH 4.5 acetate buffer (Chinese Pharmacopoeia 2025 Edition General Chapter 0931 Method I), the dissolution rate was 97.2% at 5 min and 100.1% at 10 min. In this example, the amount of corn starch used as a disintegrant was increased, and the dissolution results were further higher than the dissolution data of Example 1.

[0041] Stability: After being placed under accelerated conditions (40℃±2℃, RH75%±5%) for 6 months, XRPD detection showed no crystal transformation (still maintaining amorphous characteristics), and the total amount of related substances was 0.08%, which is comparable to Example 1 and lower than 0.11% in Example 8 of CN120678739A.

[0042] Bioavailability: In vivo studies in Beagle dogs showed that the relative bioavailability of the tablets in this embodiment was 130.3% of that of the ordinary tablets (CN120678739A formulation).

[0043] Example 3

[0044] 1. Mianserin tablet prescription (based on 1000 tablets)

[0045] 1.2 The tablet formulation consists of the following:

[0046] 2. Preparation steps

[0047] Preparation of solid dispersion: Mix anhydrous micarin hydrochloride, PVP K30, HPMC E5, and ascorbate palmitate according to the formula, hot melt extrusion (barrel temperature 110℃ / 130℃ / 135℃, screw speed 100rpm), and pulverize through a 60-mesh sieve; Tablet preparation: Mix the solid dispersion with anhydrous dicalcium phosphate, corn starch, and colloidal silica for 12 min, add magnesium stearate and mix for 4 min, compress into tablets (pressure 25 kN, hardness 10~11 kg), and coat (coating solution concentration 9%, tablet bed temperature 45±3℃).

[0048] 3. Performance Testing

[0049] Dissolution: Using pH 4.5 acetate buffer (Chinese Pharmacopoeia 2025 Edition General Chapter 0931 Method I), the dissolution rate was 94.5% at 5 min and 98.7% at 10 min. In this example, the amount of anhydrous calcium hydrogen phosphate used as a filler was increased, and the dissolution results were comparable to those in Example 1.

[0050] Stability: After being placed under accelerated conditions (40℃±2℃, RH75%±5%) for 6 months, XRPD detection showed no crystal transformation (still maintaining amorphous characteristics), and the total amount of related substances was 0.06%, which is lower than 0.11% in Example 8 of CN120678739A.

[0051] Bioavailability: In vivo studies in Beagle dogs showed that the relative bioavailability of the tablets in this embodiment was 127.9% of that of the ordinary tablets (formulation CN120678739A).

[0052] Comparative Example 1

[0053] 1. Mianserin tablet prescription (based on 1000 tablets)

[0054] 1.1 The solid dispersion formulation is as follows:

[0055] 1.2 The tablet formulation consists of the following:

[0056] 2. Preparation steps

[0057] Preparation of solid dispersion: Mix anhydrous micarin hydrochloride, PVP K30, and HPMC E5 according to the formula, hot melt extrusion (barrel temperature 110℃ / 130℃ / 135℃, screw speed 100rpm), and pulverize through a 60-mesh sieve; Tablet preparation: Mix the solid dispersion with anhydrous dicalcium phosphate, corn starch, and colloidal silica for 12 min, add magnesium stearate and mix for 4 min, compress into tablets (pressure 25 kN, hardness 10~11 kg), and coat (coating solution concentration 9%, tablet bed temperature 45±3℃).

[0058] 3. Performance Testing

[0059] Stability: After being stored under accelerated conditions (40℃±2℃, RH75%±5%) for 6 months, XRPD analysis showed no crystallization (still maintaining amorphous characteristics), and the total related substances were 0.20%. The stability of the tablets in this comparative example was inferior to that of Example 1, which contained ascorbate palmitate.

[0060] Comparative Example 2

[0061] 1. Mianselin tablet prescription: 1.1 The solid dispersion formulation is as follows:

[0062] 1.2 The tablet formulation consists of the following:

[0063] 2. Preparation steps

[0064] Preparation of solid dispersion: Mix anhydrous micarin hydrochloride, PVP K30, and ascorbate palmitate according to the formula, hot melt extrusion (barrel temperature 110℃ / 130℃ / 135℃, screw speed 100rpm), and pulverize through a 60-mesh sieve; Tablet preparation: Mix the solid dispersion with anhydrous dicalcium phosphate, corn starch, and colloidal silica for 12 min, add magnesium stearate and mix for 4 min, compress into tablets (pressure 25 kN, hardness 10~11 kg), and coat (coating solution concentration 9%, tablet bed temperature 45±3℃).

[0065] 3. Performance Testing

[0066] Dissolution: Using pH 4.5 acetate buffer (Chinese Pharmacopoeia 2025 Edition, General Chapter 0931, Method I), the dissolution rate was 85.7% at 5 min and 86.8% at 10 min, which was significantly lower than that of Example 1 containing HPMC E5.

[0067] Stability: After being placed under accelerated conditions (40℃±2℃, RH75%±5%) for 6 months, XRPD test results showed that the crystallinity was 30% and the total related substances were 0.08%. The possible reason is that HPMC E5 has the effect of inhibiting recrystallization. When HPMC E5 was not added, recrystallization occurred under accelerated conditions.

[0068] Bioavailability: In vivo studies in Beagle dogs showed that the relative bioavailability of this comparative tablet was 100.7% of that of the regular tablet (CN120678739A formulation).

[0069] Comparative Example 3

[0070] 1. Mianselin tablet prescription: 1.1 The solid dispersion formulation is as follows:

[0071] 1.2 The tablet formulation consists of the following:

[0072] 2. Preparation steps

[0073] Preparation of solid dispersion: Mix anhydrous micarin hydrochloride, HPMC E5, and ascorbate palmitate according to the formula, hot melt extrusion (barrel temperature 110℃ / 130℃ / 135℃, screw speed 100rpm), and pulverize through a 60-mesh sieve; Tablet preparation: Mix the solid dispersion with anhydrous dicalcium phosphate, corn starch, and colloidal silica for 12 min, add magnesium stearate and mix for 4 min, compress into tablets (pressure 25 kN, hardness 10~11 kg), and coat (coating solution concentration 9%, tablet bed temperature 45±3℃).

[0074] 3. Performance Testing

[0075] Dissolution: Using pH 4.5 acetate buffer (Chinese Pharmacopoeia 2025 Edition General Chapter 0931 Method I), the dissolution rate was 80.1% at 5 min and 89.2% at 10 min. The dissolution results were low because PVP K30 was not added to the dispersion, which resulted in the incomplete formation of amorphous form of mianserin.

[0076] Stability: After being stored under accelerated conditions (40℃±2℃, RH75%±5%) for 6 months, the crystallinity detected by XRPD was approximately 90%, and the total related substances were 0.10%.

[0077] Bioavailability: In vivo experiments in Beagle dogs showed that the relative bioavailability of this comparative tablet was 98.5% of that of the ordinary tablet (CN120678739A formulation), which was significantly lower than that of Example 1.

[0078] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A mianserin tablet, characterized in that, The solid dispersion and tablet excipients are included; wherein: The solid dispersion is composed of the following components in parts by weight: mianserin hydrochloride anhydrate 10-100 parts, water-soluble carrier 30-80 parts, stabilizer 1-5 parts; the water-soluble carrier is composed of povidone K30 and hydroxypropyl methylcellulose E5 in a mass ratio of (2-3) : 1; The tablet excipients include, in 100 parts by weight of the solid dispersion: anhydrous calcium hydrogen phosphate 150-300 parts, corn starch 10-80 parts, colloidal silicon dioxide 2-10 parts, magnesium stearate 0.1-10 parts, and film coating agent 4-10 parts.

2. The tablet according to claim 1, characterized in that, The stabilizer is selected from one or more of ascorbyl palmitate, butylated hydroxytoluene, tocopherol, sodium metabisulfite, and the like.

3. The tablet according to claim 1, wherein The film coating agent is a hydroxypropyl methylcellulose coating agent.

4. A process for the preparation of the mianserin tablet according to claim 1, characterized in that, The method comprises the following steps: S1. Mianserin hydrochloride anhydrate, water-soluble carrier, and stabilizer are first sieved and mixed, then extruded using a hot melt extruder, and secondly sieved to obtain a solid dispersion; the mesh size of the first sieving is larger than that of the second sieving; S2. The solid dispersion powder is mixed with anhydrous calcium hydrogen phosphate, corn starch, colloidal silicon dioxide, and magnesium stearate, then tableted, and then coated to obtain mianserin tablets.

5. The preparation method according to claim 4, characterized in that, In step S1, the mesh size of the first sieving is 80 mesh, and / or the mesh size of the second sieving is 60 mesh.

6. The preparation method according to claim 4, characterized in that, In step S1, the extrusion process parameters are: barrel temperature 110-120℃ / 125-135℃ / 135-140℃, screw rotation speed 80-120rpm, and die temperature 130-135℃.

7. The preparation method according to claim 4, characterized in that, In step S2, the wet granulation process uses a spray wet granulation method, in which the spray is first completed at low speed for 300-400s, and then high-speed mixing is continued for 30-60s to obtain wet granules.

8. The preparation method according to claim 4, characterized in that, In step S2, the mixing process first mixes the solid dispersion powder with anhydrous calcium hydrogen phosphate, corn starch, and colloidal silicon dioxide, and then adds magnesium stearate.

9. The preparation method according to claim 4, characterized in that, In step S2: the tableting process pressure is 20-30kN; and / or the coating process temperature is 40-50℃, and the coating weight gain is 2-3%.

10. Use of a tablet of mianserin in the preparation of an antidepressant medicament, characterised in that, The mianserin tablets are the mianserin tablets of any one of claims 1-3, or are prepared by the method of any one of claims 4-9.

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