Method for improving biological performance of mirtazapine oral solid preparation

Abstract

The invention relates to a method for improving the biological performance of a mirtazapine oral solid preparation. On one hand, the invention provides a film-coated mirtazapine tablet, and a tablet core of the film-coated mirtazapine tablet comprises mirtazapine, hydroxy propyl cellulose, lactose, corn starch, silicon dioxide and magnesium stearate. The film coating is used for coating the tablet core by using a gastric-soluble film coating material, and the weight of the coating material accounts for 2-4% of the weight of the tablet core. The invention further provides a preparation method of the tablets and application of the tablets in preparation of drugs for treating depression. The mirtazapine tablet disclosed by the invention has excellent performance, and the excellent performance is beneficial to improving the biological performance of the mirtazapine oral solid preparation.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to a mirtazapine oral solid preparation, in particular to a mirtazapine oral tablet. The mirtazapine tablet has excellent properties, and the excellent properties are helpful to improve the biological properties of the mirtazapine oral solid preparation. Background Art

[0002] Mirtazapine, Mirtazapine, molecular formula C17H19N3, molecular weight 265.35, chemical name 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl [2,1-α] pyrido [2,3-c] [2] benzazepine, its chemical structure is: , Mirtazapine API is a white or off-white crystalline powder; odorless; hygroscopic; easily soluble in methanol, ethanol or tetrahydrofuran, soluble in ethyl acetate, and almost insoluble in water; the melting point is 114~118°C.

[0003] Most domestic and foreign pharmacopoeias include the API and preparations of mirtazapine. Typical preparations are solid preparations, especially tablets. For example, the Chinese Pharmacopoeia includes two strengths of mirtazapine, 15 mg and 30 mg film-coated tablets. The typical strength in clinical practice is 15 mg mirtazapine film-coated tablets.

[0004] The prior art discloses some methods for preparing mirtazapine oral solid preparations. For example, CN103520169A (Chinese patent application number: 201310509567.7) relates to a mirtazapine tablet and a preparation method thereof, which consists of a tablet core and a coating layer, wherein each tablet of the tablet core contains 15-45 mg mirtazapine, 40-180 mg lactose, 70-200 mg starch, 8-25 mg hydroxypropyl cellulose, 0.75-3 mg magnesium stearate and 0.75-3 mg micro-powder silica gel; the particle size range of the mirtazapine is 3.0-96.0 μm; and the coating layer is 2.0%-3.0% of the weight of the tablet core. It is believed that the mirtazapine preparation obtained by this invention has stable quality, simple preparation operation and low production cost, and is suitable for large-scale industrial production. The prepared mirtazapine tablets imitate the movement of tablets in the gastrointestinal tract, and the in vitro dissolution curve is measured. The consistency between batches is good, the quality is stable and controllable, and it is consistent with the dissolution behavior of the original preparation in four different media.

[0005] CN116509871A (Chinese patent application number: 202310303847.6) relates to a mirtazapine topical preparation and a preparation method thereof. The mirtazapine topical preparation comprises the following components: mirtazapine, polymer, sodium sulfobutyl beta-cyclodextrin, moisturizer, solubilizer, transdermal enhancer, antioxidant, preservative, pH regulator, and the rest is purified water. The invention also relates to a method for preparing the mirtazapine topical preparation. It is believed that the mirtazapine topical preparation prepared by the inventive method has the advantages of stable quality, long-term storage, cheap and easy-to-obtain raw materials, and suitability for large-scale production.

[0006] CN1378452A (Chinese patent application number: 00814204.1) relates to an oral dosage unit containing the antidepressant mirtazapine as an active ingredient, wherein the dosage unit is orally disintegrating. It is believed that this dosage unit can disintegrate rapidly when administered orally and is bioequivalent to traditional tablets, but has many advantages in terms of side effects, efficacy, antianxiety effect, sleep improvement effect and onset of action.

[0007] CN101824035A (Chinese patent application number: 201010174000.5) provides pharmaceutically suitable non-sublimated solid salts of mirtazapine enantiomers, in particular mirtazapine salts selected from maleate, hydrobromide and fumarate, and also provides the use of the salts in the preparation of pharmaceutical compositions containing S- or R-mirtazapine salts.

[0008] CN114917194A (Chinese patent application number: 202210473658.9) provides a mirtazapine tablet API and its preparation and preparation method, wherein mannitol, malic acid, cross-linked polyvinylpyrrolidone and dextrin are added to the API, and the API includes mirtazapine, lactose, mannitol, malic acid, a water-soluble component, cross-linked polyvinylpyrrolidone, pregelatinized starch, a lubricant and dextrin; the lubricant is magnesium stearate, calcium stearate, sodium stearate, silica gel, colloidal silicon dioxide or a combination thereof; the water-soluble component is hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose or a combination thereof; it is believed that the product of the invention can relieve the patient's confusion and depression, and the malic acid block or flake can be quickly dissolved in water after entering the stomach to form a weak acid environment, which can quickly dissolve mannitol and other mixtures, facilitate human absorption, and can be quickly absorbed by the human body, which is helpful for patients with acute quality.

[0009] CN111714463A (Chinese patent application number: 202010815918.7) relates to a mirtazapine oral preparation and a preparation method thereof. The components of the mirtazapine oral preparation are: mirtazapine 2-6%, diluent 75-85%, disintegrant 3-10%, binder 3-8%, and glidant 0.3-2%. It is believed that the beneficial effects of the invention include: by comprehensively adjusting the dosage of auxiliary materials such as diluents, disintegrants, binders and glidants, a specific mirtazapine oral preparation raw material formula is formed, and the oral preparation prepared by this formula has a good palatability effect, and pets can actively eat. At the same time, the raw material formula is suitable for dry pressing tableting, with good molding effect, and mirtazapine is evenly distributed in the obtained tablets. In addition, the disintegration and solubility of the oral preparation are also good.

[0010] CN108853042A (Chinese patent application number: 201811101902.9) discloses a mirtazapine freeze-dried orodisintegrating tablet, comprising 15 parts of mirtazapine, 5-10 parts of a skeleton support, 10-20 parts of a freeze-drying protective agent, 39-45 parts of a solubilizing agent and 1.5-2 parts of a flavoring agent, and the particle size of mirtazapine is less than or equal to 50 um, and the mirtazapine is prepared by a freeze-drying method, and the application of the mirtazapine freeze-dried orodisintegrating tablet of the present invention in the preparation of an antidepressant is provided.

[0011] CN106943368A (Chinese patent application number: 201710188989.7) proposes a mirtazapine tablet, which consists of a tablet core and a coating layer. The tablet core includes the following raw materials and auxiliary materials: 20-45 parts of mirtazapine, 120-240 parts of lactose, 40-80 parts of sodium carboxymethyl starch, 30-60 parts of microcrystalline cellulose, 15-30 parts of low-substituted hydroxypropyl cellulose, 1-3 parts of magnesium stearate and 1-3 parts of micropowder silica gel; the coating layer is a polymer coating layer containing titanium dioxide and polyethylene glycol. The preparation method comprises the following steps: 1) sieving the raw materials and auxiliary materials of the tablet core for standby use; 2) wet granulating the raw materials of the tablet core to obtain the tablet core; 3) coating the tablet core to obtain a mirtazapine tablet. It is believed that the tablet dissolution is particle size-dependent, the drug release rate is stable, and the problem of side effects caused by fluctuations in the drug release rate can be avoided.

[0012] CN106822022A (Chinese patent application number: 201710118523.X) discloses a mirtazapine tablet, including 20-40 parts by weight of mirtazapine, 150-260 parts by weight of lactose, 5-12 parts by weight of high-substituted hydroxypropyl cellulose, 15-30 parts by weight of corn starch, 1-5 parts by weight of anhydrous silica gel, 15-30 parts by weight of low-substituted hydroxypropyl cellulose, 1-2 parts by weight of magnesium stearate, and 2-7 parts by weight of sustained-release material. It is believed that the mirtazapine tablet in the invention not only has a good therapeutic effect on depression, but also can reduce the incidence of adverse reactions of mirtazapine; and the mirtazapine tablet provided has a good sustained-release effect, can control the stable release of mirtazapine in the human body, so that the mirtazapine tablet has a long-term effect, and can avoid the side effects caused by the fluctuation of the release rate of traditional mirtazapine tablets in the human body. In addition, the above-mentioned formula is low in cost, good in efficacy, and good in long-term effect, so that the number of medications can be reduced, and the cost of treatment is also greatly reduced.

[0013] CN104095824A (Chinese patent application number: 201310122287.0) relates to a mirtazapine sustained-release tablet and a preparation method thereof. The sustained-release tablet consists of a tablet core, a sustained-release layer and a quick-release layer, wherein the quick-release layer ensures that part of the drug can be released quickly and take effect quickly; while the sustained-release layer ensures that the mirtazapine in the tablet core is released linearly by adjusting the dosage and ratio of hypromellose and resin, and can be completely released within 24 hours.

[0014] However, those skilled in the art still expect new methods to prepare mirtazapine oral solid preparations such as tablets, so that such oral solid preparations can exhibit certain or some excellent properties. Summary of the invention

[0015] One of the purposes of the present invention is to provide a new method for preparing mirtazapine oral solid preparations such as tablets, so that such oral solid preparations can present certain or some excellent properties. It has been unexpectedly found that the mirtazapine tablets prepared by the method of the present invention have excellent pharmaceutical properties, and these excellent pharmaceutical properties help to improve the biological properties of mirtazapine oral solid preparations. The present invention is completed based on such findings.

[0016] To this end, the first aspect of the present invention provides a film-coated mirtazapine tablet, the tablet core of which comprises: mirtazapine, hydroxypropyl cellulose, lactose, corn starch, silicon dioxide, and magnesium stearate.

[0017] According to the mirtazapine tablets of the first aspect of the present invention, the film coating is performed by coating the tablet core with a gastric soluble film coating material.

[0018] According to the mirtazapine tablets of the first aspect of the present invention, the film coating is performed using a gastric soluble film coating material to coat the tablet core, and the weight of the coating material accounts for 2-4% of the weight of the tablet core, such as 2.5-4% of the weight of the tablet core, such as 3-4% of the weight of the tablet core.

[0019] According to the mirtazapine tablets of the first aspect of the present invention, the film coating is performed using a gastric soluble film coating material, which is a gastric soluble film coating powder that is prepared with water to a solid concentration of 15-30%, especially 15-25%, before coating.

[0020] According to the first aspect of the present invention, the mirtazapine tablets, the tablet core comprises the following components in weight proportion: 15 parts by weight of mirtazapine, 8-12 parts by weight of hydroxypropyl cellulose, 80-100 (e.g. 83-96 parts by weight) of lactose, 16-25 parts by weight of corn starch, 2.7-3.3 parts by weight of silicon dioxide, and 1.8-2.2 parts by weight of magnesium stearate.

[0021] According to the mirtazapine tablets of the first aspect of the present invention, the tablet core further comprises 2.7 to 3.3 parts by weight of vitazanate per 15 parts by weight of mirtazapine.

[0022] According to the mirtazapine tablets of the first aspect of the present invention, the tablet core further comprises 1.8 to 2.2 parts by weight of octadecanol per 15 parts by weight of mirtazapine.

[0023] The mirtazapine tablets according to the first aspect of the present invention are prepared according to a method comprising the following steps: (1) adding mirtazapine, vitamins and octadecanol to ethanol with a weight of 2.5 to 3.5 times, for example, 2.7 to 3.3 times, of mirtazapine, and stirring to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 200-250 rpm for 4-6 min, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 230-270 rpm and a cutting speed of 1600-2000 rpm within 4-6 min, and then continuing to add an appropriate amount of water (equivalent to 1-3 times the weight of mirtazapine) within 2-4 min until the granules have a moderate humidity. After the addition of liquid is completed, granulation is continued at a stirring speed of 280-320 rpm and a cutting speed of 1800-2200 rpm for 5 min, and then the wet granules are sized with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then pass it through a granulator with a mesh size of 1.5 mm for granulation. Then, mix it with silicon dioxide and magnesium stearate in a mixer at a speed of 14 to 16 rpm for 5 to 7 minutes to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0024] According to the first aspect of the present invention, the mirtazapine tablets have a prescription of: 15 parts by weight of mirtazapine, 3 parts by weight of vitamins, 2 parts by weight of octadecanol, 10 parts by weight of hydroxypropyl cellulose, 90 parts by weight of lactose, 20 parts by weight of corn starch, 3 parts by weight of silicon dioxide, 2 parts by weight of magnesium stearate, and 5 parts by weight of gastric soluble film coating powder; for example, further, the preparation method thereof is: (1) Add mirtazapine, vitamins and octadecanol to ethanol 3 times the weight of mirtazapine and stir to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 220 rpm for 5 min, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 250 rpm and a cutting speed of 1800 rpm within 5 min, and then continuing to add an appropriate amount of water (equivalent to 1 to 3 times the weight of mirtazapine) within 3 min until the granules have a moderate moisture content. After the addition of liquid is completed, granulation is continued at a stirring speed of 300 rpm and a cutting speed of 2000 rpm for 5 min, and then the wet granules are sized with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then granulate it in a granulator with a mesh size of 1.5 mm. Then, mix it with silicon dioxide and magnesium stearate in a mixer at a speed of 15 rpm for 6 min to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a rotary tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0025] According to the first aspect of the present invention, the mirtazapine tablets have a prescription of: 15 parts by weight of mirtazapine, 3.3 parts by weight of vitamins, 1.8 parts by weight of octadecanol, 8 parts by weight of hydroxypropyl cellulose, 95.3 parts by weight of lactose, 16 parts by weight of corn starch, 3.3 parts by weight of silicon dioxide, 1.8 parts by weight of magnesium stearate, and 5.5 parts by weight of gastric soluble film coating powder; for example, further, the preparation method thereof is: (1) Add mirtazapine, vitamins and octadecanol to ethanol 2.7 times the weight of mirtazapine and stir to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 250 rpm for 4 minutes, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 230 rpm and a cutting speed of 2000 rpm within 4 minutes, and then continuing to add an appropriate amount of water (equivalent to 1 to 3 times the weight of mirtazapine) within 2 minutes until the granules have a moderate humidity. After the addition of liquid is completed, granulation is continued at a stirring speed of 320 rpm and a cutting speed of 1800 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then use a granulator with a mesh size of 1.5 mm to granulate the material. Then, mix the material with silicon dioxide and magnesium stearate in a mixer at a speed of 16 rpm for 5 min to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a rotary tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0026] According to the first aspect of the present invention, the mirtazapine tablets have a prescription of: 15 parts by weight of mirtazapine, 2.7 parts by weight of vitamins, 2.2 parts by weight of octadecanol, 12 parts by weight of hydroxypropyl cellulose, 83.7 parts by weight of lactose, 25 parts by weight of corn starch, 2.7 parts by weight of silicon dioxide, 2.2 parts by weight of magnesium stearate, and 4.5 parts by weight of gastric soluble film coating powder; for example, further, the preparation method thereof is: (1) Add mirtazapine, vitamins and octadecanol to 3.3 times the weight of ethanol of mirtazapine and stir to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 200 rpm for 6 minutes, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 270 rpm and a cutting speed of 1600 rpm within 6 minutes, and then continuing to add an appropriate amount of water (equivalent to 1 to 3 times the weight of mirtazapine) within 4 minutes until the granules have a moderate moisture content, and after the addition of liquid is completed, continuing granulation at a stirring speed of 280 rpm and a cutting speed of 2200 rpm for 5 minutes, and then sizing the wet granules with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then use a granulator with a mesh size of 1.5 mm to granulate the material. Then, mix the material with silicon dioxide and magnesium stearate in a mixer at a speed of 14 rpm for 7 min to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a rotary tablet press with a tablet weight of 15 parts by weight of mirtazapine per tablet and an average hardness of 50-60N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0027] Furthermore, the second aspect of the present invention provides a method for preparing mirtazapine tablets, such as the mirtazapine tablets described in any one of the first aspects of the present invention, comprising the following steps: (1) adding mirtazapine, vitamins and octadecanol to ethanol with a weight of 2.5 to 3.5 times, for example, 2.7 to 3.3 times, of mirtazapine, and stirring to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 200-250 rpm for 4-6 min, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 230-270 rpm and a cutting speed of 1600-2000 rpm within 4-6 min, and then continuing to add an appropriate amount of water (equivalent to 1-3 times the weight of mirtazapine) within 2-4 min until the granules have a moderate humidity. After the addition of liquid is completed, granulation is continued at a stirring speed of 280-320 rpm and a cutting speed of 1800-2200 rpm for 5 min, and then the wet granules are sized with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then pass it through a granulator with a mesh size of 1.5 mm for granulation. Then, mix it with silicon dioxide and magnesium stearate in a mixer at a speed of 14 to 16 rpm for 5 to 7 minutes to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0028] According to the method of the second aspect of the present invention, the mirtazapine tablets are as described in any one of the first aspect of the present invention.

[0029] Furthermore, the second aspect of the present invention provides use of the mirtazapine tablets described in any one of the first aspects of the present invention in the preparation of a medicament for treating depression.

[0030] It is known that mirtazapine has a tetracyclic structure and belongs to the piperazine-diazepine class of compounds. The mechanism of action of this product in the treatment of severe depression is still unclear. Preclinical trials have shown that this product can enhance the activity of central norepinephrine and 5-hydroxytryptamine, which may be related to the fact that this product is a central presynaptic inhibitory α2 adrenergic receptor antagonist. Mirtazapine is a strong antagonist of 5-HT2 and 5-HT3 receptors, but has no obvious affinity for 5-HT1A and 5-HT1B receptors. At the same time, mirtazapine is a strong antagonist of H1 receptors, which can explain its obvious sedative effect; mirtazapine has a moderate antagonistic effect on α1 adrenergic receptors, which can explain the occasional orthostatic hypotension reported during its use; mirtazapine has a moderate antagonistic effect on M receptors, which can explain its relatively low incidence of anticholinergic side effects.

[0031] After oral administration, the active ingredient mirtazapine is quickly absorbed (bioavailability is about 50%). The plasma concentration reaches a peak after about two hours. About 85% of mirtazapine is bound to plasma proteins. The average half-life is 20 to 40 hours; occasionally a half-life of up to 65 hours is seen; shorter half-lives are also occasionally seen in young people. The size of the elimination half-life is suitable for a once-daily dosing regimen. The plasma concentration reaches a steady state 3 to 4 days after taking the drug, and there will be no accumulation in the body thereafter. Within the recommended dose range, mirtazapine has linear pharmacokinetics. Taking it with food will not affect the pharmacokinetic characteristics of mirtazapine. Mirtazapine is mostly metabolized and excreted from the body through urine and feces within a few days after taking the drug. Its main biotransformation is demethylation and oxidation reactions, followed by conjugation reactions. In vitro studies on human liver microsomes have shown that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of mirtazapine's 8-hydroxy metabolites. CYP3A4 is believed to be responsible for the formation of N-desmethyl and N-oxide metabolites. The demethylated metabolites are still pharmacologically active and have the same pharmacokinetic properties as the parent compound.

[0032] The mirtazapine tablets prepared by the present invention exhibit excellent effects as described above and below, especially the prepared mirtazapine tablets have excellent pharmaceutical properties, and these excellent pharmaceutical properties are helpful to improve the biological properties of mirtazapine oral solid preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 : Chromatogram of blank solution.

[0034] Figure 2 :Sensitivity solution (about 0.75μg / ml) chromatogram Figure 3 : Chromatogram of control solution (about 3 μg / ml).

[0035] Figure 4 : Chromatogram of the test sample (Tablets of Example 1, about 1500 μg / ml)).

[0036] Figure 5 : Typical HPLC chromatogram of reference solution.

[0037] Figure 6 : Typical HPLC chromatogram of the test solution (Tablets of Example 1).

[0038] Figure 7 : Chromatogram of Example 1 tablet after being placed at 50°C for 3 months.

[0039] Figure 8 : Chromatogram of Example 6 tablets after being placed at 50°C for 3 months.

[0040] Fig. 9: Chromatogram of Example 10 tablet after being placed at 50°C for 3 months. DETAILED DESCRIPTION

[0041] The following examples provided by the present invention are only for explanation purposes and are not intended to be used for, nor should they be construed as limiting the present invention in any way. Those skilled in the art will recognize that conventional changes and modifications may be made to the following examples without exceeding the spirit or scope of the present invention. The present invention provides a general and / or specific description of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described in as much detail as possible herein. It is clear to those skilled in the art that, hereinafter, if not specifically stated, the materials and operating methods used in the present invention are well known in the art.

[0042] For the convenience of description, when preparing mirtazapine tablets in the following examples of the present invention, unless otherwise stated, the tablets were compressed into a specification of 15 mg mirtazapine per tablet.

[0043] Example 1: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, Vitamine ester 3mg, Octadecanol 2mg, Hydroxypropyl cellulose 10mg, Lactose 90mg, Corn starch 20mg, Silicon dioxide 3mg, Magnesium stearate 2mg, Gastric soluble film-coated powder 5mg.

[0044] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) Add mirtazapine, vitamins and octadecanol to ethanol 3 times the weight of mirtazapine and stir to dissolve; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator (Glatt), mixed at a stirring speed of 220 rpm for 5 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 250 rpm and a cutting speed of 1800 rpm within 5 minutes, and then an appropriate amount of water (equivalent to about 1 to 3 times the weight of mirtazapine to a moderate granule moisture content) is added within 3 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 300 rpm and a cutting speed of 2000 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve; (3) The material was dried in a fluidized bed dryer (Chongqing Nanfang) at an inlet air temperature of 50 ± 2 °C until the moisture content was less than 1.5%, and then granulated by a granulator (Canaan Pharmaceutical) with a mesh size of 1.5 mm. The granulator was then mixed with silicon dioxide and magnesium stearate in a mixer (single-arm fixed hopper mixer, Canaan Technology) at a speed of 15 rpm for 6 min to obtain the final mixed granules, and the mirtazapine content was determined; (4) compressing the final mixed granules on a rotary tablet press (IMA) with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets, which may also be referred to as tablet cores; (5) The gastric soluble film coating powder was added to an appropriate amount of water and stirred until the coating powder was evenly dispersed (so that the solid concentration reached 18% to 20%). The coating was carried out in a high-efficiency coating machine (Zhejiang Xiaolun) under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15 ± 2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0045] In the present invention, the prepared film-coated mirtazapine tablets can be further packaged using polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil.

[0046] In the present invention, vitamin E succinate is the abbreviation of polyethylene glycol succinate, which is made by esterification of vitamin E succinate and polyethylene glycol, and is generally used as a pharmaceutical excipient for solubilization and emulsification in pharmacy. In the present invention, if not otherwise specified, the coating powder used is a gastric soluble film coating powder (Anhui Shanhe, F20209990512).

[0047] Example 2: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, Vitamine ester 3.3mg, Octadecanol 1.8mg, Hydroxypropyl cellulose 8mg, Lactose 95.3mg, Corn starch 16mg, Silicon dioxide 3.3 mg, Magnesium stearate 1.8mg, Gastric soluble film-coated powder 5.5mg.

[0048] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) Add mirtazapine, vitamins and octadecanol to ethanol 2.7 times the weight of mirtazapine and stir to dissolve; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator (Glatt), mixed at a stirring speed of 250 rpm for 4 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 230 rpm and a cutting speed of 2000 rpm within 4 minutes, and then an appropriate amount of water (equivalent to about 1 to 3 times the weight of mirtazapine to a moderate granule moisture content) is added within 2 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 320 rpm and a cutting speed of 1800 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve; (3) The material was dried in a fluidized bed dryer (Chongqing Nanfang) at an inlet air temperature of 50 ± 2 °C until the moisture content was less than 1.5%, and then granulated by a granulator (Canaan Pharmaceutical) with a mesh size of 1.5 mm. The granulator was then mixed with silicon dioxide and magnesium stearate in a mixer (single-arm fixed hopper mixer, Canaan Technology) at a speed of 16 rpm for 5 min to obtain the final mixed granules, and the mirtazapine content was determined; (4) compressing the final mixed granules on a rotary tablet press (IMA) with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) The gastric soluble film coating powder was added to an appropriate amount of water and stirred until the coating powder was evenly dispersed (so that the solid concentration reached 18% to 20%). The coating was carried out in a high-efficiency coating machine (Zhejiang Xiaolun) under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15 ± 2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0049] Example 3: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, 2.7 mg of vinblastine Octadecanol 2.2mg, Hydroxypropyl cellulose 12mg, Lactose 83.7mg, Corn starch 25mg, Silicon dioxide 2.7 mg, Magnesium stearate 2.2mg, Gastric soluble film-coated powder 4.5mg.

[0050] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) Add mirtazapine, vitamins and octadecanol to 3.3 times the weight of ethanol of mirtazapine and stir to dissolve; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator (Glatt), mixed at a stirring speed of 200 rpm for 6 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 270 rpm and a cutting speed of 1600 rpm within 6 minutes, and then a proper amount of water (equivalent to about 1 to 3 times the weight of mirtazapine to a moderate granule moisture content) is added within 4 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 280 rpm and a cutting speed of 2200 rpm for 5 minutes, and then the wet granules are sieved with a 6*6 mm screen; (3) The material was dried in a fluidized bed dryer (Chongqing Nanfang) at an inlet air temperature of 50 ± 2 °C until the moisture content was less than 1.5%, and then granulated by a granulator (Canaan Pharmaceutical) with a mesh size of 1.5 mm. The granules were then mixed with silicon dioxide and magnesium stearate in a mixer (single-arm fixed hopper mixer, Canaan Technology) at a speed of 14 rpm for 7 min to obtain final mixed granules, and the mirtazapine content was determined; (4) compressing the final mixed granules on a rotary tablet press (IMA) with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) The gastric soluble film coating powder was added to an appropriate amount of water and stirred until the coating powder was evenly dispersed (so that the solid concentration reached 18% to 20%). The coating was carried out in a high-efficiency coating machine (Zhejiang Xiaolun) under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15 ± 2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0051] Example 4: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 3000g, Viscum 600g, 400g of octadecyl alcohol, Hydroxypropyl cellulose 2000g, Lactose 18000g, 4000g corn starch, Silicon dioxide 600g, Magnesium stearate 400g, Gastric soluble film coating powder 1000g.

[0052] Preparation method (with a scale of 200,000 tablets): (1) Add mirtazapine, vitamins and octadecanol to ethanol 3 times the weight of mirtazapine and stir to dissolve; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator (Glatt), mixed at a stirring speed of 220 rpm for 5 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 250 rpm and a cutting speed of 1800 rpm within 5 minutes, and then an appropriate amount of water (equivalent to about 1 to 3 times the weight of mirtazapine to a moderate granule moisture content) is added within 3 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 300 rpm and a cutting speed of 2000 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve; (3) The material was dried in a fluidized bed dryer (Chongqing Nanfang) at an inlet air temperature of 50 ± 2 °C until the moisture content was less than 1.5%, and then granulated by a granulator (Canaan Pharmaceutical) with a mesh size of 1.5 mm. The granulator was then mixed with silicon dioxide and magnesium stearate in a mixer (single-arm fixed hopper mixer, Canaan Technology) at a speed of 15 rpm for 6 min to obtain the final mixed granules, and the mirtazapine content was determined; (4) compressing the final mixed granules on a rotary tablet press (IMA) with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) The gastric soluble film coating powder was added to an appropriate amount of water and stirred until the coating powder was evenly dispersed (so that the solid concentration reached 18% to 20%). The coating was carried out in a high-efficiency coating machine (Zhejiang Xiaolun) under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15 ± 2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

[0053] Example 5: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, Octadecanol 2mg, Hydroxypropyl cellulose 10mg, Lactose 93mg, Corn starch 20mg, Silicon dioxide 3mg, Magnesium stearate 2mg, Gastric soluble film-coated powder 5mg.

[0054] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) Add mirtazapine and octadecyl alcohol to ethanol 3 times the weight of mirtazapine and stir to dissolve; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator (Glatt), mixed at a stirring speed of 220 rpm for 5 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 250 rpm and a cutting speed of 1800 rpm within 5 minutes, and then an appropriate amount of water (equivalent to about 1 to 3 times the weight of mirtazapine to a moderate granule moisture content) is added within 3 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 300 rpm and a cutting speed of 2000 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve; Then, the film-coated mirtazapine tablets were prepared according to the operations of steps (3) to (5) of Example 1.

[0055] Example 6: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, Vitamine ester 3mg, Hydroxypropyl cellulose 10mg, Lactose 92mg, Corn starch 20mg, Silicon dioxide 3mg, Magnesium stearate 2mg, Gastric soluble film-coated powder 5mg.

[0056] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) adding mirtazapine and vitazapine to ethanol 3 times the weight of mirtazapine and stirring to dissolve; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator (Glatt), mixed at a stirring speed of 220 rpm for 5 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 250 rpm and a cutting speed of 1800 rpm within 5 minutes, and then an appropriate amount of water (equivalent to about 1 to 3 times the weight of mirtazapine to a moderate granule moisture content) is added within 3 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 300 rpm and a cutting speed of 2000 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve; Then, the film-coated mirtazapine tablets were prepared according to the operations of steps (3) to (5) of Example 1.

[0057] Example 7: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, Hydroxypropyl cellulose 10mg, Lactose 95mg, Corn starch 20mg, Silicon dioxide 3mg, Magnesium stearate 2mg, Gastric soluble film-coated powder 5mg.

[0058] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) Dissolve mirtazapine in ethanol at a weight of 2 times its weight; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator (Glatt), mixed at a stirring speed of 220 rpm for 5 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 250 rpm and a cutting speed of 1800 rpm within 5 minutes, and then an appropriate amount of water (equivalent to about 1 to 3 times the weight of mirtazapine to a moderate granule moisture content) is added within 3 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 300 rpm and a cutting speed of 2000 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve; Then, the film-coated mirtazapine tablets were prepared according to the operations of steps (3) to (5) of Example 1.

[0059] Example 8: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, Vitamine ester 3mg, Octadecanol 2mg, Hydroxypropyl cellulose 10mg, Lactose 90mg, Corn starch 20mg, Silicon dioxide 3mg, Magnesium stearate 2mg, Gastric soluble film-coated powder 5mg.

[0060] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) Add mirtazapine to 2 times the weight of ethanol and stir to dissolve; (2) Hydroxypropyl cellulose, lactose, corn starch, vitamins and octadecyl alcohol are placed in a wet granulator (Glatt), mixed at a stirring speed of 230 rpm for 7 minutes, and then the drug solution obtained in step (1) is added to the powder material at a stirring speed of 270 rpm and a cutting speed of 2000 rpm within 7 minutes, and then a proper amount of water (equivalent to about 2 to 4 times the weight of mirtazapine to a moderate granule moisture content) is added within 3 minutes. After the addition of liquid is completed, granulation is continued at a stirring speed of 320 rpm and a cutting speed of 2200 rpm for 6 minutes, and then the wet granules are sieved with a 6*6 mm screen; Then, the film-coated mirtazapine tablets were prepared according to the operations of steps (3) to (5) of Example 1.

[0061] Example 9: Preparation of Mirtazapine Tablets Prescription (based on 1 tablet): Mirtazapine 15 mg, Vitamine ester 3mg, Octadecanol 2mg, Hydroxypropyl cellulose 10mg, Lactose 90mg, Corn starch 20mg, Silicon dioxide 3mg, Magnesium stearate 2mg, Gastric soluble film-coated powder 5mg.

[0062] Preparation method (during actual preparation, feed materials according to the scale of preparing 50,000 tablets): (1) Put mirtazapine, vitamins, octadecyl alcohol, hydroxypropyl cellulose, lactose and corn starch into a wet granulator (Glatt), mix at a stirring speed of 250 rpm for 10 minutes, then add an appropriate amount of water (equivalent to 3 to 6 times the weight of mirtazapine to a moderate granule moisture content, which can be easily controlled by the operator based on experience) at a stirring speed of 270 rpm and a cutting speed of 2000 rpm within 8 minutes, and continue granulation at a stirring speed of 320 rpm and a cutting speed of 2200 rpm for 8 minutes after the addition of liquid. Then, the wet granules are sized with a 6*6 mm sieve; Then, the film-coated mirtazapine tablets were prepared according to the operations of steps (3) to (5) of Example 1.

[0063] Example 10: Preparation of Mirtazapine Tablets Mirtazapine tablets were prepared with reference to the formula and preparation method of Example 1 of CN103520169B (201310509567.7).

[0064] Prescription: mirtazapine 300g, lactose 400g, starch 2000g, 10% hydroxypropyl cellulose aqueous solution 2000ml, magnesium stearate 7.5g, micro-powder silica gel 7.5g.

[0065] Preparation method: lactose and starch are passed through a 80-mesh sieve; micronized mirtazapine (particle size measurement: Dav=15.47, D10=7.93 μm, D50=17.86 μm, D90=31.26 μm) is uniformly mixed with lactose and starch according to the equal-increment method; a hydroxypropyl cellulose aqueous solution is added to prepare a soft material; granulation is performed through a 24-mesh sieve; and then film-coated mirtazapine tablets are prepared according to the operations of step (3) to step (5) of Example 1 of the present invention, wherein the coating increases the weight of the plain tablet by 3%, and each tablet contains 15 mg of mirtazapine.

[0066] Example 11: Preparation of Mirtazapine Tablets Mirtazapine tablets were prepared with reference to the formula and preparation method of Example 1 of CN111714463B (202010815918.7).

[0067] Prescription: mirtazapine 250g, anhydrous lactose (direct compression type) 2100g, microcrystalline cellulose (direct compression type) 1500g, mannitol 500g, sodium carboxymethyl starch 300g, β-cyclodextrin 250g, micropowder silica gel 50g, citric acid 50g, sucralose 0.5g.

[0068] Preparation method: weigh the materials according to the prescription, pass mirtazapine through a 100-mesh sieve, and pass other raw materials through a 40-mesh sieve for later use; mix mirtazapine, β-cyclodextrin, and sodium carboxymethyl starch uniformly to obtain a mixture a, mix citric acid and sucralose uniformly to obtain a mixture b, add mannitol and 1 / 3 amount of lactose to the mixture a and the mixture b, and then add the remaining amount of lactose, microcrystalline cellulose, and micropowdered silica gel to mix uniformly; then, according to the operation of step (4) to step (5) of Example 1 of the present invention, prepare film-coated mirtazapine tablets, the coating increases the weight of the plain tablet by 3%, and each tablet contains 15 mg of mirtazapine.

[0069] Test Example 1: Quality inspection of mirtazapine tablets The quality standards for mirtazapine tablets are included in Part II of the 2020 edition of the Chinese Pharmacopoeia. This test example refers to this quality standard to examine the mirtazapine tablets prepared in each embodiment of the present invention to determine whether they meet the quality standards.

[0070]

Properties

[0071]

Identification 1

[0072]

Identification 2

[0073]

Identification 3

[0074]

Related substances

[0075] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (the specific chromatographic column used was Agilent Eclipse XDB-C18, 4.6 mm×250 mm, 5 μm); methanol-tetrahydrofuran-acetonitrile-tetramethylammonium hydroxide buffer solution (36.0 g of tetramethylammonium hydroxide (molecular weight 91.15) was added to 1900 ml of water, shaken, the pH value was adjusted to 7.4 with phosphoric acid, diluted to 2000 ml with water, and shaken well) (12.5:7.5:15:65) was used as mobile phase; the detection wavelength was 240 nm; the injection volume was 10 μl; System suitability requirements: The number of theoretical plates calculated based on the mirtazapine peak should be no less than 1500, and the separation degree between the mirtazapine peak and the adjacent impurity peak should meet the requirements; in the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10; Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram to twice the retention time of the main component peak; The limits specified in the pharmacopoeia standard are: if there are impurity peaks in the chromatogram of the test solution, the area of ​​a single impurity peak shall not be greater than the main peak area of ​​the control solution (0.2%), the sum of the areas of each impurity peak shall not be greater than 5 times the main peak area of ​​the control solution (1.0%), and the chromatographic peaks less than 1 / 2 of the main peak area of ​​the sensitivity solution shall be ignored. After measurement, the areas of a single impurity peak in the chromatogram of the test solution of all tablets obtained in Examples 1 to 11 of the present invention are all less than 1 / 2 of the main peak area of ​​the control solution (0.1%), and the sum of the areas of each impurity peak is less than 2.5 times (0.5%) of the main peak area of ​​the control solution.

[0076] Typically, for example, a blank solution chromatogram is Figure 1 As shown in Figure 2, typical solvent peaks are before 2.3 min and at about 3.9 min; the chromatogram of the sensitivity solution (about 0.75 μg / ml) is shown in Figure 2. Figure 2 As shown, the peak area is 4787, S / N=38; the chromatogram of the control solution (about 3μg / ml) is as follows Figure 3 As shown, the peak area is 20257, the theoretical plate number of mirtazapine peak is 11757, and the retention time of mirtazapine peak is 19.311min; the chromatogram of the test sample (tablets of Example 1, about 1500μg / ml)) is as follows Figure 4 As shown, the peak area is 10711150, the theoretical plate number of mirtazapine peak is 8062, the retention time of mirtazapine peak is 18.246min, and an impurity peak of 0.02% appears at 2.965min (relative retention time rrt=0.163 relative to the main peak). The figure shows that an impurity that does not meet the peak requirement appears at about 3.685min (relative retention time rrt=0.202 relative to the main peak); By comparing with domestic and international standards such as the European Pharmacopoeia and the United States Pharmacopoeia and related literature, it has been confirmed that the peak of rrt = 0.163 is an impurity: 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-2-oxide, whose English name is: 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepin e-2-oxide; rrt=0.202 peak is an impurity: N-[2-(5,10-dihydro-10-oxo-11H-pyrido[2,3-c][2]benzazepin-11-yl)ethyl]-N-methyl-formamide, its English name is: N-[2-(5,10-dihydro-10-oxo-11H-pyrido[2,3-c][2]benzazepin-11-yl)ethyl]-N-methyl-formamide. The two impurities can be separately referred to as rrt0.16 impurity and rrt0.20 impurity in this article.

[0077] The same batch of mirtazapine API was used to prepare the tablets in each embodiment of the present invention. It was found that rrt0.16 impurity and rrt0.20 impurity could also be detected in the API, but both were less than 1 / 2 of the main peak area of ​​the sensitivity solution and could be ignored. However, the inventors found in some early studies that in some cases, rrt0.16 impurity and rrt0.20 impurity in the prepared mirtazapine tablets would increase significantly as the stability test time was prolonged. Therefore, the present invention paid special attention to these two impurities in some studies, and attempted to calculate their percentage content even if they were small (not reaching the integration standard).

[0078] For all the tablets obtained in Examples 1 to 11, when they were prepared without stability testing, in the [Related Substances] inspection of this test example, the rrt0.16 impurity was less than 0.02% (all within the range of 0.01 to 0.02%, for example, this impurity for the tablets in Example 4 was 0.016%), the rrt0.20 impurity was less than 0.02% (all within the range of 0 to 0.015%, for example, this impurity for the tablets in Example 4 was 0.011%), the peak areas of other individual impurities were less than 0.05% (for example, no other integrable impurity peaks were detected for the tablets in Example 4), and the sum of the peak areas of each impurity was less than 0.2% (for example, the sum of the peak areas of each impurity detected for the tablets in Example 4 was 0.024%).

[0079] The mirtazapine raw material used in the preparation of tablets was inspected according to the method of [Related Substances]. The results showed that the rrt0.16 impurity was 0.014%, the rrt0.20 impurity was 0.008%, and no other integrable impurity peaks were detected, indicating that the impurity spectrum and impurity quality of the raw material remained basically unchanged during the tablet preparation process.

[0080] In addition, the inventors have found that the above two typical impurities will increase significantly over time when the tablets are treated in long-term stability tests, and these significant increases can be overcome through the special formulation design of the present invention, as described in detail below.

[0081]

Content uniformity (15mg specification)

[0082]

Dissolution

[0083]

Content determination

[0084] The results of the determination are as follows: the contents of the four batches of tablets of Examples 1 to 4 are 100.27%, 99.43%, 99.82%, and 100.06% of the labeled amount, respectively; the contents of the five batches of tablets of Examples 5 to 9 are 99.93%, 98.57%, 100.63%, 98.86%, and 99.43% of the labeled amount, respectively; the contents of the two batches of tablets of Examples 10 to 11 are 100.74% and 99.26% of the labeled amount, respectively. The differences in the contents of the tablets only reflect the normal fluctuations of the preparation process, do not indicate that their quality is different, and clearly indicate that the theoretical feed amount is consistent with the process adjustment of the tablet weight.

[0085] A typical HPLC chromatogram of a reference solution is shown in Figure 5 As shown, a typical HPLC chromatogram of the test solution (Tablets of Example 1) is as follows Figure 6 shown.

[0086] Test Example 2: Tablet Stability Study As mentioned above, the rrt0.16 impurity and the rrt0.20 impurity in the tablets increase significantly after long-term storage. This test example investigates the changes in such impurities, and the specific method is as follows.

[0087] The coated tablets (commercially available packaging) and mirtazapine API (ampoule packaging) prepared in Examples 1 to 11 were sealed and protected from light in a 50°C constant humidity chamber for 3 months, thereby simulating the conditions of 40°C for 6 months in the stability study in this field to speed up the research work. Samples were taken in October and March, and their related substances were determined according to the method described in Test Example 1, especially the changes in rrt0.16 impurity and rrt0.20 impurity. The results are as follows: API: rrt0.16 impurity 0.014% in October, 0.017% in March, and an increase of 21.4% in March; rrt0.20 impurity 0.008% in October, 0.011% in March, and an increase of 37.5% in March; Tablets of Example 1: rrt0.16 impurity 0 0.016% in October, 0.031% in March, and an increase of 93.8% in March; rrt0.20 impurity 0.012% in October, 0.021% in March, and an increase of 75.0% in March; Example 2 tablets: rrt0.16 impurity 0.015% in October, 0.028% in March, and an increase of 86.7% in March; rrt0.20 impurity 0.011% in October, 0.023% in March, and an increase of 109.1% in March; Example 3 tablets: rrt0.16 impurity 0.017% in October, 0.030% in March, and an increase of 76.5% in March; rrt0.20 impurity 0.014% in October, 0.029% in March, and an increase of 107.1% in March; Example 4 tablets: rrt0.16 impurity 0. 016%, March 0.027%, March increase of 68.8%, rrt0.20 impurity October 0.011%, March 0.020%, March increase of 81.8%; Example 5 tablets: rrt0.16 impurity October 0.015%, March 0.083%, March increase of 453.3%, rrt0.20 impurity October 0.014%, March 0.090%, March increase of 542.9%; Example 6 tablets: rrt0.16 impurity October 0.017%, March 0.063%, March increase of 270.6%, rrt0.20 impurity October 0.011%, March 0.043%, March increase of 290.9%; Example 7 tablets: rrt0.16 impurity October 0.0 16%, March 0.093%, March increase of 481.2%, rrt0.20 impurity 0.013% in October, March 0.081%, March increase of 523.1%; Example 8 tablets: rrt0.16 impurity 0.017% in October, March 0.077%, March increase of 352.9%, rrt0.20 impurity 0.012% in October, March 0.058%, March increase of 383.3%; Example 9 tablets: rrt0.16 impurity 0.016% in October, March 0.071%, March increase of 343.8%, rrt0.20 impurity 0.014% in October, March 0.067%, March increase of 378.6%; Example 10 tablets: rrt0.16 impurity 0.018%, 0.093% in March, and an increase of 416.7% in March; rrt0.20 impurity 0.015% in October, 0.098% in March, and an increase of 553.3% in March; Example 11 tablets: rrt0.16 impurity 0.016% in October, 0.093% in March, and an increase of 481.2% in March; rrt0.20 impurity 0.012% in October, 0.082% in March, and an increase of 583.3% in March. .

[0088] Typical HPLC chart, for example, the chromatogram of Example 1 tablet after being placed at 50°C for 3 months is as follows: Figure 7 As shown, the chromatogram of Example 6 tablets after being placed at 50°C for 3 months is as follows Figure 8 As shown, the chromatogram of Example 10 tablets after being placed at 50°C for 3 months is as follows Fig. 9 In addition, other impurities in each tablet were not significantly increased.

[0089] According to the above results, it is unexpectedly found that the tablets of Examples 1 to 4 are prepared by dissolving mirtazapine, vitamins and octadecyl alcohol in ethanol in step (1) and then granulating the tablets. The growth rate of the two typical impurities in the stability study is significantly lower than that of the tablets without vitamins or octadecyl alcohol or without adding both at the same time or not adding them and mirtazapine in ethanol. In addition, although the contents of the two typical impurities, rrt0.16 impurity and rrt0.20 impurity, in the tablets of Examples 5 to 11 after being placed at 50°C for 3 months did not exceed the provisions of the pharmacopoeia standard for a single impurity not exceeding 0.2%, the results that most of them are close to 0.1% are still undesirable, because the storage and transportation conditions of the tablets are different, and a wider impurity allowance is expected in production practice. In addition, in view of the low impurity content of the tablets obtained in Example 1 of the present invention, it is expected to avoid adverse reactions, thereby improving the biological properties of the tablets.

[0090] Test Example 3: Tablet Stability Study According to the above results, the tablets obtained by the special formulation and special preparation method of Examples 1 to 4 of the present invention have better stability. Therefore, in this test example, these tablets were subjected to a more conventional accelerated stability test at 40°C for 6 months to match the production practice as much as possible.

[0091] The tablets of Examples 1 to 4 were placed in commercial packaging at 40° C. in the dark for 6 months. At 6 months, the various indicators and methods of Test Example 1 of the present invention were measured, and the results were as follows.

[0092] [Properties] The four batches of tablets in Examples 1 to 4 are all film-coated tablets, which appear white or off-white after removing the film coating.

[0093] [Identification 1] When potassium bismuth iodide test solution was added dropwise to the treated filtrate of the four batches of tablets in Examples 1 to 4, an orange-red precipitate was generated.

[0094] [Identification 2] In the chromatograms recorded for the four batches of tablets in Examples 1 to 4, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.

[0095] [Identification 3] The four batches of tablets in Examples 1 to 4 all have maximum absorption at wavelengths of 253±1nm and 315±1nm.

[0096] [Related substances] The peak areas of individual impurities in the chromatograms of the test solutions of the four batches of tablets in Examples 1 to 4 were all less than 1 / 4 of the main peak area of ​​the control solution (0.05%), and the sum of the peak areas of all impurities was less than the main peak area of ​​the control solution (0.2%); for example, the rrt0.16 impurity and rrt0.20 impurity of the tablets in Example 4 were 0.029% and 0.022% at 6 months, respectively, and no other impurities were detected.

[0097] [Content Uniformity] The A+2.2S values ​​of the four batches of tablets in Examples 1 to 4 after being stored at 40°C in the dark for 6 months were 5.17, 4.42, 6.28 and 5.36, respectively, all less than 15.0.

[0098] [Dissolution] The dissolution rates of the four batches of tablets in Examples 1 to 4 after being stored at 40°C in the dark for 6 months were 94.74%, 95.25%, 96.23% and 94.87%, respectively.

[0099] [Content Determination] The contents of the four batches of tablets in Examples 1 to 4 after being stored at 40°C in the dark for 6 months were 99.83%, 100.31%, 100.07% and 99.92% of the labeled amount, respectively.

[0100] These results show that the mirtazapine tablets prepared using the prescription and preparation method of the present invention have excellent stability.

[0101] The present invention illustrates the detailed method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed method, that is, it does not mean that the present invention must rely on the above-mentioned detailed method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A film-coated mirtazapine tablet, wherein the tablet core comprises: mirtazapine, hydroxypropyl cellulose, lactose, corn starch, silicon dioxide, and magnesium stearate.

2. According to claim 1, mirtazapine tablets, wherein the film coating is a gastric soluble film coating material used to coat the tablet core; or, further, the weight of the coating material accounts for 2-4% of the weight of the tablet core, such as 2.5-4% of the weight of the tablet core, such as 3-4% of the weight of the tablet core.

3. The mirtazapine tablets according to claim 1, wherein the film coating is performed using a gastric soluble film coating material, which is a gastric soluble film coating powder that is prepared with water to a solid concentration of 15-30%, especially 15-25%, before coating.

4. According to claim 1, the mirtazapine tablet, the core of which comprises the following components in weight proportion: 15 parts by weight of mirtazapine, 8-12 parts by weight of hydroxypropyl cellulose, 80-100 parts by weight of lactose, for example, 83-96 parts by weight, 16-25 parts by weight of corn starch, 2.7-3.3 parts by weight of silicon dioxide, and 1.8-2.2 parts by weight of magnesium stearate; for example, per 15 parts by weight of mirtazapine, the core of which further comprises 2.7-3.3 parts by weight of vitazanate; for example, per 15 parts by weight of mirtazapine, the core of which further comprises 1.8-2.2 parts by weight of octadecanol.

5. The mirtazapine tablet according to claim 1, which is prepared by a method comprising the following steps: (1) adding mirtazapine, vitamins and octadecanol to ethanol with a weight of 2.5 to 3.5 times, for example, 2.7 to 3.3 times, of mirtazapine, and stirring to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 200-250 rpm for 4-6 min, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 230-270 rpm and a cutting speed of 1600-2000 rpm within 4-6 min, and then continuing to add an appropriate amount of water (equivalent to 1-3 times the weight of mirtazapine) within 2-4 min until the granules have a moderate humidity. After the addition of liquid is completed, granulation is continued at a stirring speed of 280-320 rpm and a cutting speed of 1800-2200 rpm for 5 min, and then the wet granules are sized with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then pass it through a granulator with a mesh size of 1.5 mm for granulation. Then, mix it with silicon dioxide and magnesium stearate in a mixer at a speed of 14 to 16 rpm for 5 to 7 minutes to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

6. The mirtazapine tablet according to claim 1, wherein the prescription is: 15 parts by weight of mirtazapine, 3 parts by weight of vitamins, 2 parts by weight of octadecanol, 10 parts by weight of hydroxypropyl cellulose, 90 parts by weight of lactose, 20 parts by weight of corn starch, 3 parts by weight of silicon dioxide, 2 parts by weight of magnesium stearate, and 5 parts by weight of gastric soluble film coating powder; for example, further, the preparation method is: (1) Add mirtazapine, vitamins and octadecanol to ethanol 3 times the weight of mirtazapine and stir to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 220 rpm for 5 min, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 250 rpm and a cutting speed of 1800 rpm within 5 min, and then continuing to add an appropriate amount of water (equivalent to 1 to 3 times the weight of mirtazapine) within 3 min until the granules have a moderate moisture content. After the addition of liquid is completed, granulation is continued at a stirring speed of 300 rpm and a cutting speed of 2000 rpm for 5 min, and then the wet granules are sized with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then granulate it in a granulator with a mesh size of 1.5 mm. Then, mix it with silicon dioxide and magnesium stearate in a mixer at a speed of 15 rpm for 6 min to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a rotary tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

7. The mirtazapine tablet according to claim 1, wherein the prescription is: 15 parts by weight of mirtazapine, 3.3 parts by weight of vitamins, 1.8 parts by weight of octadecanol, 8 parts by weight of hydroxypropylcellulose, 95.3 parts by weight of lactose, 16 parts by weight of corn starch, 3.3 parts by weight of silicon dioxide, 1.8 parts by weight of magnesium stearate, and 5.5 parts by weight of gastric soluble film coating powder; for example, further, the preparation method is: (1) Add mirtazapine, vitamins and octadecanol to ethanol 2.7 times the weight of mirtazapine and stir to dissolve; (2) Hydroxypropyl cellulose, lactose and corn starch are placed in a wet granulator and mixed at a stirring speed of 250 rpm for 4 minutes. Then, the drug solution obtained in step (1) is added to the powder material at a stirring speed of 230 rpm and a cutting speed of 2000 rpm within 4 minutes. Then, an appropriate amount of water (equivalent to 1 to 3 times the weight of mirtazapine) is added within 2 minutes until the granules have a moderate moisture content. After the addition of liquid is completed, granulation is continued at a stirring speed of 320 rpm and a cutting speed of 1800 rpm for 5 minutes, and then the wet granules are sized with a 6*6 mm sieve. (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then use a granulator with a mesh size of 1.5 mm to granulate the material. Then, mix the material with silicon dioxide and magnesium stearate in a mixer at a speed of 16 rpm for 5 min to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a rotary tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

8. The mirtazapine tablet according to claim 1, wherein the prescription is: 15 parts by weight of mirtazapine, 2.7 parts by weight of vitamins, 2.2 parts by weight of octadecanol, 12 parts by weight of hydroxypropylcellulose, 83.7 parts by weight of lactose, 25 parts by weight of corn starch, 2.7 parts by weight of silicon dioxide, 2.2 parts by weight of magnesium stearate, and 4.5 parts by weight of gastric soluble film coating powder; for example, further, the preparation method is: (1) Add mirtazapine, vitamins and octadecanol to 3.3 times the weight of ethanol of mirtazapine and stir to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 200 rpm for 6 minutes, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 270 rpm and a cutting speed of 1600 rpm within 6 minutes, and then continuing to add an appropriate amount of water (equivalent to 1 to 3 times the weight of mirtazapine) within 4 minutes until the granules have a moderate moisture content, and after the addition of liquid is completed, continuing granulation at a stirring speed of 280 rpm and a cutting speed of 2200 rpm for 5 minutes, and then sizing the wet granules with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then use a granulator with a mesh size of 1.5 mm to granulate the material. Then, mix the material with silicon dioxide and magnesium stearate in a mixer at a speed of 14 rpm for 7 min to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a rotary tablet press with a tablet weight of 15 parts by weight of mirtazapine per tablet and an average hardness of 50-60N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

9. A method for preparing the mirtazapine tablets according to any one of claims 1 to 8, comprising the steps of: (1) adding mirtazapine, vitamins and octadecanol to ethanol with a weight of 2.5 to 3.5 times, for example, 2.7 to 3.3 times, of mirtazapine, and stirring to dissolve; (2) putting hydroxypropyl cellulose, lactose and corn starch into a wet granulator, mixing at a stirring speed of 200-250 rpm for 4-6 min, then adding the drug solution obtained in step (1) to the powder material at a stirring speed of 230-270 rpm and a cutting speed of 1600-2000 rpm within 4-6 min, and then continuing to add an appropriate amount of water (equivalent to 1-3 times the weight of mirtazapine) within 2-4 min until the granules have a moderate humidity. After the addition of liquid is completed, granulation is continued at a stirring speed of 280-320 rpm and a cutting speed of 1800-2200 rpm for 5 min, and then the wet granules are sized with a 6*6 mm sieve; (3) Dry the material in a fluidized bed dryer at an air inlet temperature of 50 ± 2 °C to a moisture content of less than 1.5%, and then pass it through a granulator with a mesh size of 1.5 mm for granulation. Then, mix it with silicon dioxide and magnesium stearate in a mixer at a speed of 14 to 16 rpm for 5 to 7 minutes to obtain final mixed granules, and determine the mirtazapine content. (4) compressing the final mixed granules on a tablet press with a tablet weight of 15 mg of mirtazapine per tablet and an average hardness of 50-60 N to obtain mirtazapine tablets; (5) Add the gastric soluble film coating powder to an appropriate amount of water and stir until the coating powder is evenly dispersed (so that the solid concentration reaches 18% to 20%). Coating is performed in a high-efficiency coating machine under the conditions of a coating pan speed of 7 to 9 rpm, an inlet air temperature of 45 to 50°C, a spray rate of 15±2 g / min, and an atomization pressure of 0.3 to 0.4 MPa to obtain film-coated mirtazapine tablets.

10. Use of the mirtazapine tablets according to any one of claims 1 to 8 in the preparation of a medicament for treating depression.

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