Alprazolam oral solid composition and preparation method thereof

Abstract

The invention relates to an alprazolam oral solid composition and a preparation method thereof. In one aspect, the invention relates to an alprazolam tablet, which is prepared by preparing premixed particles containing alprazolam in advance and then preparing the tablet by a wet granulation and tabletting method. The premixed particles comprise alprazolam, microcrystalline cellulose and the like, and the tablet further comprises microcrystalline cellulose, corn starch, silicon dioxide, magnesium stearate and the like. The alprazolam tablet disclosed by the invention can be used as a medicine for resisting anxiety, tension, depression, excitation, hypnosis, panic, relieving acute alcohol withdrawal symptoms and resisting drug-induced intractable hiccup, and has certain excellent performance.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to a pharmaceutical composition with alprazolam as an active ingredient, and in particular to an oral solid pharmaceutical composition of alprazolam. The present invention also relates to a preparation method of the oral solid pharmaceutical composition of alprazolam, and in particular, the preparation method can easily obtain a highly uniform solid preparation. Background Art

[0002] Alprazolam, molecular formula: C17H13ClN4, molecular weight: 308.77, CAS registration number: 28981-97-7, chemical name: 1-methyl-6-phenyl-8-chloro-4H-(1,2,4-triazole) [4,3-α][1,4]-benzodiazepine, chemical structure: .

[0003] Alprazolam is a benzodiazepine hypnotic sedative and antianxiety drug with similar pharmacological effects to diazepam, including anti-anxiety, anti-depression, sedation, hypnosis, anticonvulsant and muscle relaxation. Alprazolam acts on the benzodiazepine receptors (BZR) of the central nervous system, enhancing the central inhibitory neurotransmitter γ-aminobutyric acid (GABA) and GABA A The binding of the receptor promotes the opening of chloride channels, hyperpolarizes cells, enhances synaptic inhibition mediated by GABA neurons, and reduces the excitability of neurons. BZ receptors are divided into type I and type II. It is believed that the excitation of type I receptors can explain the antianxiety effect of BZ drugs, while type II receptors are related to the sedative and skeletal muscle relaxation effects of this type of drugs. It can cause inhibition in different parts of the central nervous system. As the dosage increases, the clinical manifestations can range from mild sedation to hypnosis and even coma. It can pass through the placenta and can be secreted into breast milk. It is addictive and can cause allergies in a few patients. Its antianxiety effect is 10 times stronger than diazepam, and its mechanism of action may be related to the β-adrenergic receptors in the brain. Alprazolam is rapidly and completely absorbed orally, reaching peak blood concentration in 1 to 2 hours, with a plasma half-life of 12 to 18 hours, and a steady-state blood concentration in 2 to 3 days. The plasma protein binding rate is about 80%. After absorption, it is distributed throughout the body and can pass through the placental barrier. The drug is also present in breast milk. It is metabolized into the active substance α-hydroxytriazolamide by the liver CYP3A enzyme system, but the concentration is too low to have clinical significance. It is finally excreted from the body through the kidneys, with very little accumulation in the body, and is cleared quickly after discontinuation of the drug.

[0004] Alprazolam is mainly used in clinical practice for anxiety, tension, depression, and agitation. It can also be used as an auxiliary medication for hypnosis or anxiety, as an anti-panic drug, and can relieve acute alcohol withdrawal symptoms. In addition, alprazolam has a good therapeutic effect on drug-induced intractable hiccups.

[0005] The prior art discloses some preparation methods of pharmaceutical compositions containing alprazolam. For example, CN118453525A (Chinese patent application number: 202410358600.9) discloses an alprazolam tablet, which includes alprazolam, lactose and an adjuvant; in terms of mass fraction, alprazolam: lactose: adjuvant = 0.2~0.3:70~75:17~20; the lactose particle size specification requirement is: 100 mesh-200 mesh; the adjuvant includes: a binder, a disintegrant, a glidant and a lubricant, and in terms of mass ratio, the binder: disintegrant is 0.2~0.3:70~75:17~20. Disintegrant: glidant: lubricant = 9~10: 9~10: 0.5~1: 0.4~0.5; the binder is selected from: corn starch, sodium carboxymethyl starch, microcrystalline cellulose or cross-linked sodium carboxymethyl cellulose, one or a mixture of several in any proportion; the disintegrant is selected from: corn starch, sodium carboxymethyl starch, microcrystalline cellulose or cross-linked sodium carboxymethyl cellulose, one or a mixture of several in any proportion; the glidant is selected from: silicon dioxide, talc or magnesium stearate or a mixture of any proportion; the lubricant is selected from: magnesium stearate, stearic acid or polyethylene glycol, or a mixture of any proportion; the alprazolam tablets are prepared by the following steps: preparing a mother powder, adding the required lactose and half of the disintegrant into a wet granulator, mixing them evenly, adding alprazolam dissolved in ethanol in advance, mixing them evenly, granulating and discharging, and drying them as mother powder for standby use, wherein the ethanol is ethanol with a purity of not less than 90%; wet granulation: adding the dried mother powder into a wet granulator, adding the remaining amount of lactose, disintegrant and the whole amount of retention aid, mixing them evenly, adding a pre-dissolved binder aqueous solution, mixing them evenly, granulating and discharging them as "soft material"; then using a granulator to wet granulate the "soft material", and drying them as dry granules; tableting: putting the dry granules into a granulator for dry granulation, after the granulation is completed, mixing the granules with the lubricant evenly and tableting them to prepare the finished alprazolam tablets.

[0006] CN113908295A (Chinese patent application number: 202111336991.7) relates to an alprazolam inclusion compound and a preparation method thereof. The alprazolam inclusion compound comprises alprazolam, cucurbituril or cucurbituril derivatives, and a stabilizer. It is said that the invention includes alprazolam in a material with a hole structure to form an inclusion compound, which solves the problem of low solubility of alprazolam; by optimizing the type of inclusion material and stabilizer and the ratio with alprazolam, the inclusion rate and stability of the inclusion compound are improved, the content of related substances is reduced, the preparation method is simple, and it is suitable for large-scale production.

[0007] CN104622823A (Chinese patent application number: 201410827253.6) provides an alprazolam composition freeze-dried tablet and a preparation method thereof. The freeze-dried tablet contains alprazolam, starch, and sucrose. Starch and sucrose are used as auxiliary materials. The ordinary corn starch is subjected to a heating process to improve the adhesion and disintegration of starch in the tablet, and improve the tablet's formability. The alprazolam composition freeze-dried tablet only requires two auxiliary materials, starch and sucrose. It is said that the invention alprazolam composition freeze-dried tablet adopts a two-drop and two-rise freeze-drying process. Two coolings and two heatings can make the tablet formability better, which improves the dissolution of the tablet, thereby improving the bioavailability of the tablet; overcomes the shortcomings of ordinary alprazolam tablets, reduces the types and amounts of auxiliary materials in alprazolam tablets, and the tablet has a large dissolution rate and high bioavailability, ensuring the efficacy and safety of clinical medication.

[0008] CN102106839A (Chinese patent application number: 200910243688.5) relates to an alprazolam sustained-release preparation and a preparation method thereof, characterized in that the alprazolam sustained-release preparation is composed of a main drug alprazolam, a skeleton material, a filler, a lubricant, and a film-forming material. It belongs to the technical field of pharmaceutical preparations. One purpose of the invention is to provide an alprazolam sustained-release preparation and a preparation method thereof with good patient compliance, small side effects, lasting efficacy, and stable therapeutic effect. It is said that the alprazolam sustained-release preparation of the invention releases the drug steadily and slowly, avoiding the "peak and valley" phenomenon that is easy to occur in the release of ordinary preparations, and the drug effect is more lasting, stably existing in the blood for up to 24 hours, and widely distributed throughout the body, with high bioavailability, convenient administration, low toxicity and side effects, stable efficacy, and the characteristics of less medication times and long medication time, avoiding abuse and easy discontinuation.

[0009] In addition, CN118831072A (Chinese patent application number: 202411329672.7) relates to an alprazolam nasal inhalation preparation and a preparation method thereof, and the provided alprazolam nasal inhalation preparation includes alprazolam gel particles with dual properties of rapid release and sustained release, and the alprazolam gel particles at least contain alprazolam, albumin and sodium alginate, wherein the mass ratio of the alprazolam to the albumin is 1: (1.3-1.5), and the mass ratio of the alprazolam to the sodium alginate is 1: (0.6-1.8). Compared with the alprazolam nasal spray of the prior art, it is said that the blood-brain barrier permeability of the alprazolam nasal inhalation preparation provided by the invention is significantly improved, the bioavailability is high, and it can take effect quickly (for example, within 2 minutes).

[0010] Alprazolam is included in the pharmacopoeias of many countries, and is also included in multiple versions of the Chinese Pharmacopoeia. The specifications of alprazolam tablets included in the Chinese Pharmacopoeia and produced by Chinese companies are all 0.4 mg / tablet. The specifications of alprazolam tablets listed in the United States, India and other countries are 0.25 mg / tablet, 0.5 mg / tablet, and 1 mg / tablet. For oral solid preparations, alprazolam tablets are typical small-dose preparations. An important technical indicator of small-dose oral solid preparations is content uniformity. For highly active chemical ingredients such as alprazolam, it is particularly important to pay attention to the fluctuation of the active ingredients of each tablet. However, the prior art has not seen reports on improving the uniformity of alprazolam drug content by improving technical processes. Therefore, it is of considerable practical significance to improve the preparation process to achieve improved drug content uniformity. Summary of the invention

[0011] One of the objects of the present invention is to provide a pharmaceutical composition with alprazolam as an active ingredient, in particular to provide an oral solid pharmaceutical composition of alprazolam, or, the present invention aims to provide a method for preparing an oral solid pharmaceutical composition of alprazolam, in particular, the preparation method can easily obtain a highly uniform solid preparation. It has been unexpectedly found that, through the present invention, the oral solid pharmaceutical composition of alprazolam prepared exhibits the excellent effects as described in the context of the present invention, and the present invention has been completed based on such a finding.

[0012] To this end, the first aspect of the present invention provides an alprazolam tablet, which is prepared by pre-preparing premixed granules containing alprazolam and then preparing tablets by wet granulation and tableting.

[0013] According to the alprazolam tablet of the first aspect of the present invention, the premixed granules contain: 0.4 parts by weight of alprazolam, 0.5-0.7 parts by weight of citric acid, 2.5-3.5 parts by weight of zein, and 15-17 parts by weight of microcrystalline cellulose, for example, 15.6-16.4 parts by weight. For example, when preparing the premixed granules, 14-16 parts by weight of 85%-90% ethanol is also used based on 0.4 parts by weight of alprazolam.

[0014] According to the alprazolam tablet of the first aspect of the present invention, the premixed granules contain: 0.4 parts by weight of alprazolam, 0.6 parts by weight of citric acid, 3 parts by weight of zein, and 16 parts by weight of microcrystalline cellulose. For example, when preparing the premixed granules, 15 parts by weight of 88% ethanol is also used based on 0.4 parts by weight of alprazolam.

[0015] According to the alprazolam tablet of the first aspect of the present invention, the premixed granules contain: 0.4 parts by weight of alprazolam, 0.5 parts by weight of citric acid, 3.5 parts by weight of zein, and 15.6 parts by weight of microcrystalline cellulose. For example, when preparing the premixed granules, 16 parts by weight of 85% ethanol is also used based on 0.4 parts by weight of alprazolam.

[0016] According to the alprazolam tablet of the first aspect of the present invention, the premixed granules contain: 0.4 parts by weight of alprazolam, 0.7 parts by weight of citric acid, 2.5 parts by weight of zein, and 16.4 parts by weight of microcrystalline cellulose. For example, when preparing the premixed granules, 14 parts by weight of 90% ethanol is also used based on 0.4 parts by weight of alprazolam.

[0017] According to the alprazolam tablets of the first aspect of the present invention, the premixed particles are prepared according to a method comprising the following steps: (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) adding microcrystalline cellulose to the material tank of a planetary mixer, stirring the powder material, then adding the liquid obtained in step (1) to the stirred powder material, and after the addition is completed, continuing to stir and discharge the material; (3) The wet material is spread flat on a material tray, dried under ventilation, and sieved to obtain alprazolam premixed granules.

[0018] According to the alprazolam tablets of the first aspect of the present invention, the premixed particles are prepared according to a method comprising the following steps: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) adding 15 to 17 parts by weight, for example 15.6 to 16.4 parts by weight, of microcrystalline cellulose to a material tank of a planetary mixer, stirring the powder material, and then adding the liquid obtained in step (1) to the stirred powder material. After the addition is completed, continue stirring and discharge the material; (3) The wet material is spread flat on a material tray, dried under ventilation, and sieved to obtain alprazolam premixed granules.

[0019] In any embodiment of the present invention, when a planetary mixer is used to process materials, unless otherwise specified, the total materials account for 30-70% of the working volume of the cylinder of the planetary mixer.

[0020] According to the alprazolam tablets of the first aspect of the present invention, the premixed particles are prepared according to a method comprising the following steps: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) 15 to 17 parts by weight of microcrystalline cellulose, for example 15.6 to 16.4 parts by weight, are added to the cylinder of a planetary mixer so that the total material occupies 30 to 70% of the working volume of the cylinder of the planetary mixer. The powder material is stirred at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm. Then, the drug solution obtained in step (1) is added to the stirred powder material at a uniform speed of 5 minutes. After the addition is completed, stirring is continued for 30 minutes, and the material is discharged; (3) The wet material was spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

[0021] The alprazolam tablet according to the first aspect of the present invention comprises: 20 parts by weight of alprazolam premixed granules, 87-91 parts by weight of microcrystalline cellulose, 18-22 parts by weight of corn starch, 0.5 parts by weight of silicon dioxide, and 0.5 parts by weight of magnesium stearate. For example, the tablet further uses 8.2-8.8 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation.

[0022] The alprazolam tablet according to the first aspect of the present invention comprises: 20 parts by weight of alprazolam premixed granules, 89 parts by weight of microcrystalline cellulose, 20 parts by weight of corn starch, 0.5 parts by weight of silicon dioxide, and 0.5 parts by weight of magnesium stearate. For example, the tablet further uses 8.5 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation.

[0023] The alprazolam tablet according to the first aspect of the present invention comprises: 20 parts by weight of alprazolam premixed granules, 91 parts by weight of microcrystalline cellulose, 18 parts by weight of corn starch, 0.5 parts by weight of silicon dioxide, and 0.5 parts by weight of magnesium stearate. For example, the tablet further uses 8.2 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation.

[0024] The alprazolam tablet according to the first aspect of the present invention comprises: 20 parts by weight of alprazolam premixed granules, 87 parts by weight of microcrystalline cellulose, 22 parts by weight of corn starch, 0.5 parts by weight of silicon dioxide, and 0.5 parts by weight of magnesium stearate. For example, the tablet further uses 8.8 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation.

[0025] The alprazolam tablet according to the first aspect of the present invention is prepared according to a method comprising the following steps: (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the material tank of a planetary mixer, and the powder material was stirred. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a constant speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes, and the material was discharged; (5) The wet material is placed in a material tray, dried through ventilation until the moisture content is less than 2%, and sieved through a 24-mesh sieve to size the particles. The material is then transferred to a V-shaped mixer, 18 to 22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Compressing the product on a rotary tablet press to obtain alprazolam tablets.

[0026] The alprazolam tablet according to the first aspect of the present invention is prepared according to a method comprising the following steps: (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the cylinder of a planetary mixer so that the total material accounted for 30-70% of the working volume of the cylinder of the planetary mixer. The powder material was stirred at a dispersion speed of 850-950 rpm, a planetary revolution speed of 38-42 rpm, and a stirring shaft rotation speed of 55-65 rpm. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a uniform speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes before discharging. (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. through ventilation until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve to size particles. The material is then transferred to a V-shaped mixer, 18-22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each of which contained 0.4 mg of alprazolam in theory.

[0027] The alprazolam tablet according to the first aspect of the present invention is prepared according to a method comprising the following steps: (4) 20 parts by weight of alprazolam premixed granules and 89 parts by weight of microcrystalline cellulose were added to the cylinder of a planetary mixer so that the total material accounted for 30-70% of the working volume of the cylinder of the planetary mixer. The powder material was stirred at a dispersion speed of 900 rpm, a planetary revolution speed of 40 rpm, and a stirring shaft rotation speed of 60 rpm. Then, 8.5 parts by weight of purified water were added to the stirred powder material at a uniform speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes before discharging. (5) The wet material is spread in a material plate with a thickness of 1 to 1.5 cm, and dried at 50° C. through ventilation until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve to size particles. The material is then transferred to a V-shaped mixer, 20 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each of which contained 0.4 mg of alprazolam in theory.

[0028] The alprazolam tablet according to the first aspect of the present invention is prepared according to a method comprising the following steps: (4) 20 parts by weight of alprazolam premixed granules and 91 parts by weight of microcrystalline cellulose were added to the cylinder of a planetary mixer so that the total material accounted for 30-70% of the working volume of the cylinder of the planetary mixer. The powder material was stirred at a dispersion speed of 950 rpm, a planetary revolution speed of 38 rpm, and a stirring shaft rotation speed of 55 rpm. Then, 8.2 parts by weight of purified water were added to the stirred powder material at a uniform speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes before discharging. (5) The wet material is spread in a material plate with a thickness of 1 to 1.5 cm, and dried at 50° C. through ventilation until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve to size particles. The material is then transferred to a V-shaped mixer, 18 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each of which contained 0.4 mg of alprazolam in theory.

[0029] The alprazolam tablet according to the first aspect of the present invention is prepared according to a method comprising the following steps: (4) 20 parts by weight of alprazolam premixed granules and 87 parts by weight of microcrystalline cellulose were added to the cylinder of a planetary mixer so that the total material accounted for 30-70% of the working volume of the cylinder of the planetary mixer. The powder material was stirred at a dispersion speed of 850 rpm, a planetary revolution speed of 42 rpm, and a stirring shaft rotation speed of 65 rpm. Then, 8.8 parts by weight of purified water were added to the stirred powder material at a uniform speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes before discharging. (5) The wet material is spread in a material plate with a thickness of 1 to 1.5 cm, and dried at 50° C. through ventilation until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve to size particles. The material is then transferred to a V-shaped mixer, 22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each of which contained 0.4 mg of alprazolam in theory.

[0030] Furthermore, the second aspect of the present invention provides a method for preparing an alprazolam tablet, such as the alprazolam tablet according to any one of the first aspects of the present invention, comprising the following steps: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) adding 15 to 17 parts by weight, for example 15.6 to 16.4 parts by weight, of microcrystalline cellulose to a material tank of a planetary mixer, stirring the powder material, and then adding the liquid obtained in step (1) to the stirred powder material. After the addition is completed, continue stirring and discharge the material; (3) placing the wet material in a material tray, spreading it flat, drying it through ventilation, and sieving it to obtain alprazolam premixed granules; (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the material tank of a planetary mixer, and the powder material was stirred. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a constant speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes, and the material was discharged; (5) The wet material is placed in a material tray, dried through ventilation until the moisture content is less than 2%, and sieved through a 24-mesh sieve to size the particles. The material is then transferred to a V-shaped mixer, 18 to 22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) tabletting on a rotary tablet press to obtain alprazolam tablets, each tablet having a theoretical alprazolam content of 0.2 to 1 mg, for example, 0.4 mg.

[0031] The method according to the second aspect of the present invention comprises the following steps: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) 15 to 17 parts by weight of microcrystalline cellulose, for example 15.6 to 16.4 parts by weight, are added to the cylinder of a planetary mixer so that the total material occupies 30 to 70% of the working volume of the cylinder of the planetary mixer. The powder material is stirred at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm. Then, the drug solution obtained in step (1) is added to the stirred powder material at a uniform speed of 5 minutes. After the addition is completed, stirring is continued for 30 minutes, and the material is discharged; (3) The wet material is spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules; (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the cylinder of a planetary mixer so that the total material accounted for 30-70% of the working volume of the cylinder of the planetary mixer. The powder material was stirred at a dispersion speed of 850-950 rpm, a planetary revolution speed of 38-42 rpm, and a stirring shaft rotation speed of 55-65 rpm. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a uniform speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes before discharging. (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. through ventilation until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve to size particles. The material is then transferred to a V-shaped mixer, 18-22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each of which contained 0.4 mg of alprazolam in theory.

[0032] Use of the alprazolam tablets described in any one of the first aspects of the present invention in the preparation of drugs for anti-anxiety, anti-tension, anti-depression, anti-excitement, hypnosis, anti-panic, relief of acute alcohol withdrawal symptoms, and resistance to drug-induced refractory hiccups.

[0033] The alprazolam tablets prepared by the present invention exhibit excellent effects as described above and below. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 : Typical chromatogram of system suitability test solution.

[0035] Figure 2 : Typical chromatogram of the test solution for content determination.

[0036] Figure 3 : HPLC chart of related substance check solvent blank excipient.

[0037] Figure 4 : Sensitivity solution HPLC chromatogram.

[0038] Figure 5 : System suitability solution chromatogram for related substance inspection.

[0039] Figure 6 : Tablet Preparation Example 4 Related substance inspection HPLC chart of the obtained tablets. DETAILED DESCRIPTION

[0040] 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.

[0041] The planetary mixer used in the present invention below is a planetary mixer commonly used in the pharmaceutical industry and easily available on the market. Specifically used are planetary mixers of the Rumi® brand model RMXJ-0.5, RMXJ-5 or RMXJ-20, whose working volumes are 0.5L, 5L and 20L respectively. The appropriate model can be selected according to the material volume. Usually, the volume of powder materials should be within the range of 10% to 90% of the working volume, preferably within the range of 20% to 80%. If not otherwise specified, the principle of selecting the model of the planetary mixer when using the planetary mixer in various examples of the present invention is that the total material accounts for 30% to 70% of the working volume of the planetary mixer cylinder, and the dispersion speed, planetary revolution speed and stirring shaft rotation speed can be adjusted according to the actual application materials and operating experience.

[0042] Example 1: Preparation of premixed particles Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.6 parts by weight of citric acid, 3 parts by weight of zein, 15 parts by weight of 88% ethanol, and 16 parts by weight of microcrystalline cellulose.

[0043] Preparation method (adding material proportion of 4g of alprazolam, equivalent to 10,000 tablets of material, total solid material 200g): (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) Add microcrystalline cellulose to the cylinder of a planetary mixer with a working volume of 0.5 L, stir the powder material at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm, then add the drug solution obtained in step (1) to the stirred powder material at a uniform speed of 5 min. After the addition is completed, continue stirring for 30 min and discharge the material; (3) The wet material was spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

[0044] Example 2: Preparation of premixed particles Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.5 parts by weight of citric acid, 3.5 parts by weight of zein, 16 parts by weight of 85% ethanol, and 15.6 parts by weight of microcrystalline cellulose.

[0045] Preparation method (adding material proportion of 4g of alprazolam, equivalent to 10,000 tablets of material, total solid material 200g): (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) Add microcrystalline cellulose to the cylinder of a planetary mixer with a working volume of 0.5 L, stir the powder material at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm, then add the drug solution obtained in step (1) to the stirred powder material at a uniform speed of 5 min. After the addition is completed, continue stirring for 30 min and discharge the material; (3) The wet material was spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

[0046] Example 3: Preparation of premixed particles Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.7 parts by weight of citric acid, 2.5 parts by weight of zein, 14 parts by weight of 90% ethanol, and 16.4 parts by weight of microcrystalline cellulose.

[0047] Preparation method (adding material proportion of 4g of alprazolam, equivalent to 10,000 tablets of material, total solid material 200g): (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) Add microcrystalline cellulose to the cylinder of a planetary mixer with a working volume of 0.5 L, stir the powder material at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm, then add the drug solution obtained in step (1) to the stirred powder material at a uniform speed of 5 min. After the addition is completed, continue stirring for 30 min and discharge the material; (3) The wet material was spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

[0048] Example 4: Preparation of premixed particles Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.6 parts by weight of citric acid, 3 parts by weight of zein, 15 parts by weight of 88% ethanol, and 16 parts by weight of microcrystalline cellulose.

[0049] Preparation method (adding material proportion of 40g of alprazolam, equivalent to 100,000 tablets, total solid material 2kg): (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) Add microcrystalline cellulose to the material cylinder of a planetary mixer with a working volume of 5 L, stir the powder material at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm, then add the drug solution obtained in step (1) to the stirred powder material at a uniform speed of 5 min. After the addition is completed, continue stirring for 30 min and discharge the material; (3) The wet material was spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

[0050] Example 5: Preparation of premixed granules Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.5 parts by weight of citric acid, 3.5 parts by weight of zein, 16 parts by weight of 85% ethanol, and 15.6 parts by weight of microcrystalline cellulose.

[0051] Preparation method (adding material proportion of 40g of alprazolam, equivalent to 100,000 tablets, total solid material 2kg): (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) Add microcrystalline cellulose to the cylinder of a planetary mixer with a working volume of 5 L, stir the powder material at a dispersion speed of 820 rpm, a planetary revolution speed of 38 rpm, and a stirring shaft rotation speed of 45 rpm, then add the drug solution obtained in step (1) to the stirred powder material at a uniform speed of 4 min. After the addition is completed, continue stirring for 30 min and discharge the material; (3) The wet material was spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

[0052] Example 6: Preparation of premixed granules Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.7 parts by weight of citric acid, 2.5 parts by weight of zein, 14 parts by weight of 90% ethanol, and 16.4 parts by weight of microcrystalline cellulose.

[0053] Preparation method (adding material proportion of 40g of alprazolam, equivalent to 100,000 tablets, total solid material 2kg): (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) Add microcrystalline cellulose to the material cylinder of a planetary mixer with a working volume of 5 L, stir the powder material at a dispersion speed of 880 rpm, a planetary revolution speed of 33 rpm, and a stirring shaft rotation speed of 55 rpm, then add the drug solution obtained in step (1) to the stirred powder material at a uniform speed of 8 minutes. After the addition is completed, continue stirring for 30 minutes and discharge the material; (3) The wet material was spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

[0054] Tablet Preparation Example 1: (4) 200 g of the alprazolam premixed granules obtained in Example 1 and 890 g of microcrystalline cellulose were added to the cylinder of a planetary mixer with a working volume of 5 L, and the powder material was stirred at a dispersion speed of 900 rpm, a planetary revolution speed of 40 rpm, and a stirring shaft rotation speed of 60 rpm. Then, 85 g of purified water was added to the stirred powder at a uniform speed over 5 min. After the addition was completed, stirring was continued for 15 min, and the material was discharged; (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. for about 3 hours until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve and sized. The material is then transferred to a V-shaped mixer, 200 g of corn starch is added and mixed for 15 minutes, and then 5 g of silicon dioxide and 5 g of magnesium stearate are added and mixed for 20 minutes to obtain final mixed granules. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each with a theoretical tablet weight of 130 mg and a theoretical alprazolam content of 0.4 mg.

[0055] Note: The weight of 200 g of alprazolam premixed granules in step (4) is the theoretical yield of Example 1. The actual amount of mixed granules in this preparation example is 180 g. The amount of each material in steps (4) and (5) is also 90% of the recorded value. For example, the actual amount of microcrystalline cellulose recorded in step (4) is 890 g, and the actual amount is 801 g. The labeled amounts of materials in other tablet preparation examples also have similar meanings.

[0056] Tablet Preparation Example 2: (4) 200 g of the alprazolam premixed granules obtained in Example 2 and 910 g of microcrystalline cellulose were added to the cylinder of a planetary mixer with a working volume of 5 L, and the powder material was stirred at a dispersion speed of 950 rpm, a planetary revolution speed of 38 rpm, and a stirring shaft rotation speed of 55 rpm. Then, 82 g of purified water was added to the stirred powder material at a uniform speed over 5 min. After the addition was completed, stirring was continued for 15 min, and the material was discharged; (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. (about 3 hours) until the moisture content is less than 2%, and sieved through a 24-mesh sieve to size the particles. The material is then transferred to a V-shaped mixer, 180 g of corn starch is added, and mixed for 15 minutes. Then, 5 g of silicon dioxide and 5 g of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each with a theoretical tablet weight of 130 mg and a theoretical alprazolam content of 0.4 mg.

[0057] Tablet Preparation Example 3: (4) 200 g of the alprazolam premixed granules obtained in Example 3 and 870 g of microcrystalline cellulose were added to the material cylinder of a planetary mixer with a working volume of 5 L, and the powder material was stirred at a dispersion speed of 850 rpm, a planetary revolution speed of 42 rpm, and a stirring shaft rotation speed of 65 rpm. Then, 88 g of purified water was added to the stirred powder at a uniform speed over 5 min. After the addition was completed, stirring was continued for 15 min, and the material was discharged; (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. (about 3 hours) until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve and sized. The material is then transferred to a V-shaped mixer, 220 g of corn starch is added and mixed for 15 minutes, and then 5 g of silicon dioxide and 5 g of magnesium stearate are added and mixed for 20 minutes to obtain final mixed granules. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each with a theoretical tablet weight of 130 mg and a theoretical alprazolam content of 0.4 mg.

[0058] Tablet Preparation Example 4: (4) 2000 g of the alprazolam premixed granules obtained in Example 4 and 8900 g of microcrystalline cellulose were added to the cylinder of a planetary mixer with a working volume of 20 L, and the powder material was stirred at a dispersion speed of 900 rpm, a planetary revolution speed of 40 rpm, and a stirring shaft rotation speed of 60 rpm. Then, 850 g of purified water was added to the stirred powder at a uniform speed of 7 min. After the addition was completed, stirring was continued for 20 min, and the material was discharged; (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. for about 3 hours until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve and granulated. The material is then transferred to a V-shaped mixer, 2000 g of corn starch is added and mixed for 18 minutes, and then 50 g of silicon dioxide and 50 g of magnesium stearate are added and mixed for 25 minutes to obtain final mixed granules. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each with a theoretical tablet weight of 130 mg and a theoretical alprazolam content of 0.4 mg.

[0059] Tablet Preparation Example 5: (4) 2000 g of the alprazolam premixed granules obtained in Example 5 and 9100 g of microcrystalline cellulose were added to the cylinder of a planetary mixer with a working volume of 20 L, and the powder material was stirred at a dispersion speed of 950 rpm, a planetary revolution speed of 38 rpm, and a stirring shaft rotation speed of 55 rpm. Then, 820 g of purified water was added to the stirred powder at a uniform speed over 7 min. After the addition was completed, stirring was continued for 20 min, and the material was discharged; (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. for about 3 hours until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve and granulated. The material is then transferred to a V-shaped mixer, 1800 g of corn starch is added and mixed for 18 minutes, and then 50 g of silicon dioxide and 50 g of magnesium stearate are added and mixed for 25 minutes to obtain final mixed granules. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each with a theoretical tablet weight of 130 mg and a theoretical alprazolam content of 0.4 mg.

[0060] Tablet Preparation Example 6: (4) 2000 g of the alprazolam premixed granules obtained in Example 5 and 8700 g of microcrystalline cellulose were added to the cylinder of a planetary mixer with a working volume of 20 L, and the powder material was stirred at a dispersion speed of 850 rpm, a planetary revolution speed of 42 rpm, and a stirring shaft rotation speed of 65 rpm. Then, 880 g of purified water was added to the stirred powder at a uniform speed over 7 min. After the addition was completed, stirring was continued for 20 min, and the material was discharged; (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. for about 3 hours until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve and granulated. The material is then transferred to a V-shaped mixer, 2200 g of corn starch is added and mixed for 18 minutes, and then 50 g of silicon dioxide and 50 g of magnesium stearate are added and mixed for 25 minutes to obtain final mixed granules. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each with a theoretical tablet weight of 130 mg and a theoretical alprazolam content of 0.4 mg.

[0061] Tablet Preparation Example 7: The difference between this example and Example 1 and Tablet Preparation Example 1 is that no zein was used.

[0062] Refer to Example 1, except that: corn gluten is replaced by an equal amount of microcrystalline cellulose and added in step (2); in step (1), alprazolam and citric acid are dissolved in ethanol to prepare premixed granules; then, referring to the operation of Tablet Preparation Example 1, the premixed granules obtained in this example are used to obtain final mixed granules in step (5); and alprazolam tablets are obtained in step (6).

[0063] Tablet Preparation Example 8: The difference between this example and Example 4 and Tablet Preparation Example 4 is that no zein was used.

[0064] Refer to Example 4, except that: corn protein is replaced by an equal amount of microcrystalline cellulose and added in step (2); in step (1), alprazolam and citric acid are dissolved in ethanol to prepare premixed granules; then, referring to the operation of Tablet Preparation Example 4, the premixed granules obtained in this example are used to obtain final mixed granules in step (5); and alprazolam tablets are obtained in step (6).

[0065] Tablet Preparation Example 9: The difference between this example and Example 1 and Tablet Preparation Example 1 is that citric acid was not used.

[0066] Refer to Example 1, except that: citric acid is replaced by an equal amount of microcrystalline cellulose and added in step (2); in step (1), alprazolam and zein are dissolved in ethanol to prepare premixed granules; then, referring to the operation of Tablet Preparation Example 1, the premixed granules obtained in this example are used to obtain final mixed granules in step (5); and alprazolam tablets are obtained in step (6).

[0067] Tablet Preparation Example 10: The difference between this example and Example 4 and Tablet Preparation Example 4 is that citric acid was not used.

[0068] Refer to Example 4, except that: citric acid is replaced by an equal amount of microcrystalline cellulose and added in step (2); in step (1), alprazolam and zein are dissolved in ethanol to prepare premixed granules; then, referring to the operation of Tablet Preparation Example 4, the premixed granules obtained in this example are used to obtain final mixed granules in step (5); and alprazolam tablets are obtained in step (6).

[0069] Tablet Preparation Example 11: The difference between this example and Example 1 and Tablet Preparation Example 1 is that neither citric acid nor corn protein is used.

[0070] Refer to Example 1, except that: citric acid and zein are replaced by equal amounts of microcrystalline cellulose and added in step (2), and alprazolam is dissolved in ethanol in step (1) to prepare premixed granules; then, referring to the operation of Tablet Preparation Example 1, the premixed granules obtained in this example are used to obtain final mixed granules in step (5), and alprazolam tablets are obtained in step (6).

[0071] Tablet Preparation Example 12: The difference between this example and Example 4 and Tablet Preparation Example 4 is that neither citric acid nor corn protein is used.

[0072] Refer to Example 4, except that: citric acid and zein are replaced by equal amounts of microcrystalline cellulose and added in step (2), and alprazolam is dissolved in ethanol in step (1) to prepare premixed granules; then, referring to the operation of Tablet Preparation Example 4, the premixed granules obtained in this example are used to obtain final mixed granules in step (5), and alprazolam tablets are obtained in step (6).

[0073] Tablet Preparation Example 13: With reference to the prescription and process of Example 1 of CN118453525A (CN202410358600.9), and with reference to the process, equipment and parameters of Example 1 and Tablet Preparation Example 1 of the present invention, 0.4 mg / tablet alprazolam tablets were prepared as follows: (1) Preparation of mother powder: 350g lactose and 87g microcrystalline cellulose were added to the cylinder of a planetary mixer with a working volume of 0.5L, and the powder material was stirred at a dispersion speed of 850rpm, a planetary revolution speed of 35rpm, and a stirring shaft rotation speed of 50rpm. Then, a solution of 2g alprazolam previously dissolved in 80ml of 95% ethanol was added to the stirred powder at a uniform speed over 5min. After the addition was completed, stirring was continued for 30min. The material was discharged, spread with a thickness of 1-1.5cm, ventilated and dried at 40°C for 2 hours, and passed through a 60-mesh sieve for standby use as a mother powder; (2) Wet granulation: The master powder obtained in step (1), 350g lactose, 87g microcrystalline cellulose and 7g silicon dioxide are added to the cylinder of a planetary mixer with a working volume of 5L, and the powder material is stirred at a dispersion speed of 900rpm, a planetary revolution speed of 40rpm and a stirring shaft rotation speed of 60rpm. Then, the pre-dissolved adhesive corn starch slurry is added to the stirred powder at a uniform speed for 5min (first, 13g corn starch and 20g water are stirred and dispersed, and then 200g boiling water is added and continued to stir to obtain the obtained product). After the addition is completed, stirring is continued for 15min and the material is discharged; the wet material is placed in a material tray with a thickness of 1-1.5cm, and ventilated and dried at 50°C (about 3 hours) until the moisture is less than 2%, and granulated through a 24-mesh sieve. Then, the material is moved to a V-shaped mixer, 4g magnesium stearate is added and mixed for 20 minutes to obtain final mixed particles; (3) Tableting: Tablets were pressed on a rotary tablet press using a φ7.5 mm flat punch with an average hardness of 3.0 kg and a pressure to obtain alprazolam tablets, each with a theoretical tablet weight of 180 mg and a theoretical alprazolam content of 0.4 mg.

[0074] Test Example 1: Quality inspection of alprazolam tablets With reference to the items under "Alprazolam Tablets" on page 708 of the 2020 edition of the Chinese Pharmacopoeia, some tablets prepared above in the present invention were examined.

[0075]

Properties

[0076]

Identification 1

[0077]

Identification 2

[0078]

Content uniformity a

[0079] The general requirement in this field is: if A+2.2S≤15.0, the content uniformity of the test sample complies with the regulations; if A+S>15.0, it does not comply with the regulations; if A+2.2S>15.0 and A+S≤15.0, 20 more test samples should be taken for retesting.

[0080] Results: The A+2.2S values ​​of 6 batches of tablets obtained from Tablet Preparation Examples 1-6 (adding citric acid and corn gluten) were 2.14, 1.89, 2.26, 1.63, 2.32, and 1.94, respectively; the A+2.2S values ​​of 2 batches of tablets obtained from Tablet Preparation Examples 7-8 (without adding corn gluten) were 13.53 and 14.37, respectively; the A+2.2S values ​​of 2 batches of tablets obtained from Tablet Preparation Examples 9-10 (without adding citric acid) were 2.35 and 2.06, respectively; the A+2.2S values ​​of 3 batches of tablets obtained from Tablet Preparation Examples 11-13 (without adding citric acid and corn gluten) were 12.25, 15.17 (where X=94.69, A=5.31, S=4.48, A+2.2S=15.17, A+S=9.79), and 13.73, respectively.

[0081] In view of the fact that the above Tablet Preparation Examples 7-8 and Tablet Preparation Examples 11-13 are both relatively high, although they all meet the requirements of the Pharmacopoeia, they are obviously close to the critical value of failure. Therefore, for these 5 tablet preparation examples, the tablet preparation test was repeated twice (they can be respectively called Tablet Preparation Example 7a and Tablet Preparation Example 7b, or simply referred to as Example 7a and Example 7b, and the other 4 tablet preparation examples are also similarly named), and the results of the content uniformity of the obtained tablets are as follows: The A+2.2S values ​​of the two batches of tablets of Tablet Preparation Example 7 (Example 7a and Example 7b) are 12.83 and 14.22, respectively, and the A+2.2S values ​​of the two batches of tablets of Tablet Preparation Example 8 are 15.61 (where X=95.57, A=4.43) and 15.62 (where X=95.57, A=4.43). , S=5.08, A+2.2S=15.61, A+S=9.51) and 14.18, the A+2.2S values ​​of the two batches of tablets in Tablet Preparation Example 11 were 13.57 and 12.84, respectively, the A+2.2S values ​​of the two batches of tablets in Tablet Preparation Example 12 were 14.62 and 16.34 (where X=93.32, A=6.68, S=4.39, A+2.2S=16.34, A+S=11.07), and the A+2.2S values ​​of the two batches of tablets in Tablet Preparation Example 13 were 12.86 and 14.03, respectively. These repeated test results still show that the content uniformity of tablets without corn protein addition is close to the unqualified limit, which is not desirable.

[0082] The above-mentioned [content uniformity a] results show that the alprazolam tablets prepared by the method of the present invention and adding an appropriate amount of corn protein exhibit significantly better content uniformity.

[0083] The above-mentioned [content uniformity a] reflects the difference in active ingredients between each tablet in a batch of tablets, and this difference is also related to the difference in tablet weight during tableting. In order to overcome the difference in tablet weight during tableting, the present inventors determined the uniformity of the active ingredients in the final mixed granules obtained in each tablet preparation example according to the following [content uniformity b] method.

[0084]

Content uniformity b

[0085] The results show that the content uniformity results of the final mixed granules obtained in each tablet preparation example are consistent with the tablets. In view of the fact that the results of Tablet Preparation Examples 7-8 and Tablet Preparation Examples 11-13 are both relatively high, the inventors used the content uniformity method b to measure the content uniformity of the final mixed granules obtained by repeating the above test of preparing tablets twice (Examples 7a and 7b, Examples 8a and 8b, etc.), and the results are as follows: The A+2.2S values ​​of the final mixed granules of Examples 7a and 7b are 13.17 and 13.63, respectively, and the A+2.2S values ​​of the final mixed granules of Examples 8a and 8b are 15.38, respectively (where X=96.13, A=3.87, S=5.23 , A+2.2S=15.38, A+S=9.10) and 14.43, the A+2.2S values ​​of the final mixed granules of Example 11a and Example 11b are 13.23 and 14.07 respectively, the A+2.2S values ​​of the final mixed granules of Example 12a and Example 12b are 13.84 and 15.91 respectively (where X=93.53, A=6.47, S=4.29, A+2.2S=15.91, A+S=10.76), and the A+2.2S values ​​of the final mixed granules of Example 13a and Example 13b are 12.57 and 14.16 respectively. These repeated test results still show that the content uniformity of the final mixed granules used to prepare tablets without adding corn protein is close to the unqualified limit, which is not desirable.

[0086] The above-mentioned [Content Uniformity b] results show that the final mixed granules before tableting of alprazolam tablets prepared by the method of the present invention and adding an appropriate amount of corn protein show significantly better uniformity of active ingredient content.

[0087]

Dissolution

[0088] Results: The solubility of 6 batches of tablets obtained from Tablet Preparation Examples 1-6 (adding citric acid and corn protein) were 95.82%, 94.37%, 92.43%, 96.24%, 93.74% and 94.36%, respectively; the solubility of 2 batches of tablets obtained from Tablet Preparation Examples 7-8 (without adding corn protein) were 93.87% and 95.11%, respectively; the solubility of 2 batches of tablets obtained from Tablet Preparation Examples 9-10 (without adding citric acid) were 72.26% and 70.53%, respectively; the solubility of 3 batches of tablets obtained from Tablet Preparation Examples 11-13 (without adding citric acid and corn protein) were 92.64%, 94.23% and 90.87%, respectively.

[0089] The above results indicate that when tablets are prepared by a method similar to Tablet Preparation Example 1, under the condition of adding corn gluten but not adding citric acid at the same time, the dissolution of the obtained tablets does not meet the standard requirements. To verify this result, the two tablet preparation examples of Tablet Preparation Examples 9 and 10 were repeated twice for the preparation of tablets (which can be referred to as Example 9a and Example 9b, Example 10a and Example 10b, respectively), and the tablet dissolution results obtained are as follows: Example 9a and Example 9b are 73.36% and 72.17%, respectively, and Example 10a and Example 10b are 70.83% and 71.24%, respectively. These repeated test results still show that the dissolution of the tablets with corn gluten added but not citric acid added at the same time under specific preparation process conditions is unqualified. These findings of this dissolution result and the content uniformity results described above indicate that it is not advisable not to add corn gluten and citric acid at the same time under this preparation process condition.

[0090]

Content determination

[0091] Generally, the pharmacopoeia stipulates that the alprazolam (C17H13ClN4) content in alprazolam tablets should be 90.0%~110.0% of the labeled amount.

[0092] After determination, the contents of all tablets obtained in Tablet Preparation Examples 1 to 13 were within the range of 94% to 103% of the labeled amount. For example, the contents of the two batches of tablets in Tablet Preparation Example 1 and Tablet Preparation Example 4 were 98.37% and 100.42% of the labeled amount, respectively. A typical chromatogram of the system suitability test solution is shown in Figure 1. Figure 1 As shown in the figure, the peak with a retention time of about 4.85 min is triazolam, and the peak with a retention time of about 5.58 min is alprazolam. The theoretical plate number is 8542 calculated based on the alprazolam peak. The separation between the alprazolam peak and the triazolam peak is greater than 3, which meets the determination requirements. The typical chromatogram of the test solution for content determination (tablets of Tablet Preparation Example 1) is shown in Figure 2 shown.

[0093] The above results show that when alprazolam tablets are prepared by using a prescription process similar to Example 1 of the present invention and Tablet Preparation Example 1, alprazolam, corn gluten, and citric acid are dissolved in 85% to 90% ethanol in step (1), and then sprayed onto an appropriate amount of microcrystalline cellulose in step (2) to obtain premixed particles, and finally tablets are prepared by a conventional tableting process. The obtained tablets show excellent content uniformity and dissolution performance, and other quality indicators also meet the standard requirements. However, when corn gluten is not added in the process of Example 1 of the present invention and Tablet Preparation Example 1, the content uniformity is significantly worse, although it still meets the standard requirements but is close to an unacceptable level (at this time, it is necessary to improve the content uniformity by extending the alprazolam solution addition time and the material mixing time, see the following tablet preparation example), but if citric acid is not added at the same time after the addition of corn gluten, the dissolution will not meet the standard requirements.

[0094] Tablet Preparation Example 14: Refer to the scheme of Tablet Preparation Example 8 (which refers to Example 4 and Tablet Preparation Example 4), but extend the time for adding the alprazolam solution and the time for mixing the materials. The details are as follows.

[0095] Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.6 parts by weight of citric acid, 15 parts by weight of 88% ethanol, and 19 parts by weight of microcrystalline cellulose.

[0096] Preparation method (adding material proportion of 40g of alprazolam, equivalent to 100,000 tablets, total solid material 2kg): (1) Add alprazolam to 88% ethanol and stir to dissolve, then add citric acid and stir to dissolve; (2) Add microcrystalline cellulose to the material cylinder of a planetary mixer with a working volume of 5 L, stir the powder material at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm, then add the drug solution obtained in step (1) to the stirred powder material at a uniform speed for 20 minutes. After the addition is completed, continue stirring for 60 minutes and discharge the material; (3) The wet material is spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules; (4) 2000 g of alprazolam premixed granules and 8900 g of microcrystalline cellulose were added to the cylinder of a planetary mixer with a working volume of 20 L, and the powder material was stirred at a dispersion speed of 900 rpm, a planetary revolution speed of 40 rpm, and a stirring shaft rotation speed of 60 rpm. Then, 850 g of purified water was added to the stirred powder at a uniform speed over 7 min. After the addition was completed, stirring was continued for 45 min, and the material was discharged; (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. for about 3 hours until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve and sized. The material is then transferred to a V-shaped mixer, 2000 g of corn starch is added and mixed for 30 minutes, and then 50 g of silicon dioxide and 50 g of magnesium stearate are added and mixed for 45 minutes to obtain final mixed granules. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each with a theoretical tablet weight of 130 mg and a theoretical alprazolam content of 0.4 mg.

[0097] The A+2.2S value of the tablets obtained in this tablet preparation example was measured using the method of content uniformity a in Test Example 1 of the present invention, and was 8.65. The A+2.2S value of the tablets obtained in this tablet preparation example was measured using the method of content uniformity b in the present invention, and was 9.04.

[0098] If the mixing operation and liquid addition operation time in Tablet Preparation Example 14 are further extended, A+2.2S will be slightly reduced but still cannot achieve the effect of Tablet Preparation Example 4. Specifically, the formulation of Tablet Preparation Example 14 is referred to, but: Step (2) adds the drug solution for 30 minutes and then stirs for 90 minutes, Step (4) stirs for 90 minutes after adding water, Step (5) adds corn starch and then mixes for 60 minutes and then mixes for 90 minutes after adding magnesium stearate, and a batch of tablets are prepared. The A+2.2S values ​​are 6.36 and 6.73 respectively measured by the method of content uniformity a and content uniformity b in Test Example 1. It can be seen that the present invention can produce tablets with excellent content uniformity in a significantly shorter process cycle.

[0099] Tablet Preparation Example 15: The formulation and preparation method of Reference Example 4 and Tablet Preparation Example 4 are the same, but zein is not added to the solution but mixed with microcrystalline cellulose. The details are as follows.

[0100] Materials and weight proportions: 0.4 parts by weight of alprazolam, 0.6 parts by weight of citric acid, 3 parts by weight of zein, 15 parts by weight of 88% ethanol, and 16 parts by weight of microcrystalline cellulose.

[0101] Preparation method (adding material proportion of 40g of alprazolam, equivalent to 100,000 tablets, total solid material 2kg): (1) Add alprazolam to 88% ethanol and stir to dissolve, then add citric acid and stir to dissolve; (2) Add microcrystalline cellulose and corn protein to the cylinder of a planetary mixer with a working volume of 5 L, stir the powder material at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm, then add the drug solution obtained in step (1) to the stirred powder at a uniform speed of 5 min. After the addition is completed, continue stirring for 30 min and discharge the material; (3) The wet material is spread in a material tray with a thickness of 1-1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules. Then, the premixed granules are used to prepare alprazolam tablets according to steps (4) to (6) of Tablet Preparation Example 4.

[0102] The A+2.2S value of the tablets obtained in this tablet preparation example was measured using the method of content uniformity a of Test Example 1 of the present invention, and was 9.37. The A+2.2S value of the tablets obtained in this tablet preparation example was measured using the method of content uniformity b of the present invention, and was 8.42.

[0103] Tablet Preparation Example 16: The reference example 1 and the tablet preparation example 1 prescription and preparation method are different in that the citric acid therein is replaced with an equal amount of sodium citrate, tartaric acid, and malic acid to prepare 3 batches of alprazolam tablets. Referring to the dissolution determination method of the test example 1 of the present invention, the dissolution of the 3 batches of tablets was determined, and the results were 74.35%, 84.16%, and 81.24%, respectively. The reference example 4 and the tablet preparation example 4 prescription and preparation method are different in that the citric acid therein is replaced with an equal amount of sodium citrate, tartaric acid, and malic acid to prepare 3 batches of alprazolam tablets. Referring to the dissolution determination method of the test example 1 of the present invention, the dissolution of the 3 batches of tablets was determined, and the results were 73.14%, 82.42%, and 83.57%, respectively. These results show that even with the prescription process of the reference example 1 and the tablet preparation example 1, the dissolution effect of the tablets obtained without citric acid or with other organic acids is significantly worse.

[0104] Test Example 2: Inspection of related substances in tablets In this test example, high performance liquid chromatography was used to determine the related substances of the alprazolam tablets obtained in Tablet Preparation Examples 1 to 6 to further investigate the performance of the tablets, as follows.

[0105] Test solution: Take 10 tablets from a batch, place them in a suitable volumetric flask, accurately add 10 ml of methanol-water (4:6), shake to disintegrate, ultrasonicate for 15 minutes (shake once every 5 minutes), let it cool to room temperature, centrifuge the upper liquid, and take the supernatant.

[0106] Reference solution: Take an appropriate amount of alprazolam reference substance, weigh accurately, dissolve in methanol-water (4:6) and quantitatively dilute to make a solution containing approximately 0.8 μg per 1 ml.

[0107] Sensitivity solution: Accurately measure an appropriate amount of the reference solution and dilute it with methanol-water (4:6) to make a solution containing approximately 0.2 μg per 1 ml.

[0108] System suitability solution: Take appropriate amount of alprazolam reference substance and triazolam reference substance, dissolve and dilute with methanol-water (6:4) to make a solution containing approximately 0.8 μg of alprazolam and triazolam per 1 ml.

[0109] Chromatographic conditions: Phenylsilane bonded silica gel was used as filler (column size 4.6 mm × 200 mm, 5 μm), 0.1 mol / L ammonium acetate buffer (pH adjusted to 5.5 by ammonia or glacial acetic acid)-methanol (95:5) was used as mobile phase A, 0.2 mol / L ammonium acetate buffer (pH adjusted to 5.5 by ammonia or glacial acetic acid)-methanol (5:95) was used as mobile phase B, and gradient elution was performed according to the table below; the flow rate was 2.0 ml per minute; the detection wavelength was 254 nm; the injection volume was 20 μl.

[0110]

[0111] System suitability requirements: In the system suitability solution chromatogram, the peak order is triazolam, then alprazolam, and the separation between the triazolam peak and the alprazolam peak shall not be less than 1.5. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height shall not be less than 10.

[0112] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Deduct the blank solvent peak and the blank excipient peak, and calculate the peak area percentage of each impurity by the normalization method.

[0113] It was determined that the related substances of the six batches of alprazolam tablets obtained in Tablet Preparation Examples 1 to 6 were all greater than 99.7% calculated by the main component peak area normalization method, the sum of each impurity was less than 0.3%, and the maximum impurity was less than 0.1%. For example, the tablets obtained in Tablet Preparation Example 4 had a main component peak area normalization percentage of 99.872%, the sum of each impurity was 0.128%, and the maximum impurity was less than 0.051%. Among them, Figure 3 A typical HPLC profile of a solvent blank excipient is shown; Figure 4 The sensitivity solution HPLC chromatogram is shown, with an alprazolam retention time of approximately 36.6 min and a signal-to-noise ratio of 246; Figure 5The system suitability solution chromatogram is shown, in which the retention times of triazolam and alprazolam are about 36.6 min and about 35.5 min, respectively, and the resolution between the two is 2.58; Figure 6 The HPLC chart of the related substances of the tablets obtained in Tablet Preparation Example 4 was examined.

[0114] 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. An alprazolam tablet, which is prepared by preparing premixed granules containing alprazolam in advance and then preparing tablets by wet granulation tableting method.

2. The alprazolam tablet according to claim 1, wherein the premixed granules comprise: 0.4 weight part of alprazolam, 0.5-0.7 weight part of citric acid, 2.5-3.5 weight parts of zein, 15-17 weight parts of microcrystalline cellulose, for example, 15.6-16.4 weight parts; for example, when preparing the premixed granules, 14-16 weight parts of 85%-90% ethanol are also used based on 0.4 weight part of alprazolam; for example, the premixed granules comprise: 0.4 weight part of alprazolam, 0.6 weight part of citric acid, 3 weight parts of zein, and 16 weight parts of microcrystalline cellulose; for example, when preparing the premixed granules, 0.4 weight part of alprazolam is used. .4 weight part, 15 weight parts of 88% ethanol are also used; for example, the premixed granules contain: 0.4 weight part of alprazolam, 0.5 weight part of citric acid, 3.5 weight parts of zein, and 15.6 weight parts of microcrystalline cellulose; for example, when preparing the premixed granules, 16 weight parts of 85% ethanol are also used based on 0.4 weight part of alprazolam; for example, the premixed granules contain: 0.4 weight part of alprazolam, 0.7 weight part of citric acid, 2.5 weight parts of zein, and 16.4 weight parts of microcrystalline cellulose; for example, when preparing the premixed granules, 14 weight parts of 90% ethanol are also used based on 0.4 weight part of alprazolam.

3. The alprazolam tablet according to claim 2, wherein the premixed granules are prepared according to a method comprising the following steps: (1) adding alprazolam and zein to ethanol and stirring to dissolve, and then adding citric acid and stirring to dissolve; (2) adding microcrystalline cellulose to the material tank of a planetary mixer, stirring the powder material, then adding the liquid obtained in step (1) to the stirred powder material, and after the addition is completed, continuing to stir and discharge the material; (3) The wet material is spread flat on a material tray, dried under ventilation, and sieved to obtain alprazolam premixed granules.

4. The alprazolam tablet according to claim 3, wherein the premixed granules are prepared according to a method comprising the following steps: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) adding 15 to 17 parts by weight, for example 15.6 to 16.4 parts by weight, of microcrystalline cellulose to a material tank of a planetary mixer, stirring the powder material, and then adding the liquid obtained in step (1) to the stirred powder material. After the addition is completed, continue stirring and discharge the material; (3) The wet material is spread flat on a material tray, dried under ventilation, and sieved to obtain alprazolam premixed granules.

5. The alprazolam tablet according to claim 3, wherein the premixed granules are prepared according to a method comprising the following steps: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) 15 to 17 parts by weight of microcrystalline cellulose, for example 15.6 to 16.4 parts by weight, are added to the cylinder of a planetary mixer so that the total material occupies 30 to 70% of the working volume of the cylinder of the planetary mixer. The powder material is stirred at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm. Then, the drug solution obtained in step (1) is added to the stirred powder material at a uniform speed of 5 minutes. After the addition is completed, stirring is continued for 30 minutes, and the material is discharged; (3) The wet material is spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules.

6. The alprazolam tablet according to any one of claims 2 to 5, comprising: 20 parts by weight of alprazolam premixed granules, 87 to 91 parts by weight of microcrystalline cellulose, 18 to 22 parts by weight of corn starch, 0.5 parts by weight of silicon dioxide, and 0.5 parts by weight of magnesium stearate; for example, the tablet further uses 8.2 to 8.8 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation; for example, the tablet further uses 8.2 to 8.8 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation; for example, the tablet further uses 8.2 to 8.8 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation; for example, the tablet further uses 8.2 to 8.8 parts by weight of purified water based on 20 parts by weight of the premixed granules during wet granulation 8.5 parts by weight of purified water are also used; for example, the tablet comprises: 20 parts by weight of alprazolam premixed granules, 91 parts by weight of microcrystalline cellulose, 18 parts by weight of corn starch, 0.5 parts by weight of silicon dioxide, and 0.5 parts by weight of magnesium stearate; for example, the tablet comprises: 8.2 parts by weight of purified water based on 20 parts by weight of premixed granules during wet granulation; for example, the tablet comprises: 20 parts by weight of alprazolam premixed granules, 87 parts by weight of microcrystalline cellulose, 22 parts by weight of corn starch, 0.5 parts by weight of silicon dioxide, and 0.5 parts by weight of magnesium stearate; for example, the tablet comprises: 8.8 parts by weight of purified water based on 20 parts by weight of premixed granules during wet granulation.

7. The alprazolam tablet according to any one of claims 1 to 6, which is prepared by a method comprising the following steps: (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the material tank of a planetary mixer, and the powder material was stirred. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a constant speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes, and the material was discharged; (5) The wet material is placed in a material tray, dried through ventilation until the moisture content is less than 2%, and sieved through a 24-mesh sieve to size the particles. The material is then transferred to a V-shaped mixer, 18 to 22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) tableting on a rotary tablet press to obtain alprazolam tablets; Alternatively, it is prepared according to a method comprising the following steps: (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the cylinder of a planetary mixer so that the total material accounted for 30-70% of the working volume of the cylinder of the planetary mixer. The powder material was stirred at a dispersion speed of 850-950 rpm, a planetary revolution speed of 38-42 rpm, and a stirring shaft rotation speed of 55-65 rpm. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a uniform speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes before discharging. (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. through ventilation until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve to size particles. The material is then transferred to a V-shaped mixer, 18-22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each of which contained 0.4 mg of alprazolam in theory.

8. A method for preparing the alprazolam tablets according to any one of claims 1 to 7, comprising the following steps: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) adding 15 to 17 parts by weight, for example 15.6 to 16.4 parts by weight, of microcrystalline cellulose to a material tank of a planetary mixer, stirring the powder material, and then adding the liquid obtained in step (1) to the stirred powder material. After the addition is completed, continue stirring and discharge the material; (3) placing the wet material in a material tray, spreading it flat, drying it through ventilation, and sieving it to obtain alprazolam premixed granules; (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the material tank of a planetary mixer, and the powder material was stirred. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a constant speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes, and the material was discharged; (5) The wet material is placed in a material tray, dried through ventilation until the moisture content is less than 2%, and sieved through a 24-mesh sieve to size the particles. The material is then transferred to a V-shaped mixer, 18 to 22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) tabletting on a rotary tablet press to obtain alprazolam tablets, each tablet having a theoretical alprazolam content of 0.2 to 1 mg, for example, 0.4 mg.

9. The method according to claim 8, comprising the steps of: (1) adding 0.4 parts by weight of alprazolam and 2.5-3.5 parts by weight of zein to 14-16 parts by weight of 85%-90% ethanol and stirring to dissolve, and then adding 0.5-0.7 parts by weight of citric acid and stirring to dissolve; (2) 15 to 17 parts by weight of microcrystalline cellulose, for example 15.6 to 16.4 parts by weight, are added to the cylinder of a planetary mixer so that the total material occupies 30 to 70% of the working volume of the cylinder of the planetary mixer. The powder material is stirred at a dispersion speed of 850 rpm, a planetary revolution speed of 35 rpm, and a stirring shaft rotation speed of 50 rpm. Then, the drug solution obtained in step (1) is added to the stirred powder material at a uniform speed of 5 minutes. After the addition is completed, stirring is continued for 30 minutes, and the material is discharged; (3) The wet material is spread on a material plate with a thickness of 1 to 1.5 cm, dried at 40° C. for 2 hours, and passed through a 60-mesh sieve to obtain alprazolam premixed granules; (4) 20 parts by weight of alprazolam premixed granules and 87-91 parts by weight of microcrystalline cellulose were added to the cylinder of a planetary mixer so that the total material accounted for 30-70% of the working volume of the cylinder of the planetary mixer. The powder material was stirred at a dispersion speed of 850-950 rpm, a planetary revolution speed of 38-42 rpm, and a stirring shaft rotation speed of 55-65 rpm. Then, 8.2-8.8 parts by weight of purified water were added to the stirred powder material at a uniform speed over 5 minutes. After the addition was completed, stirring was continued for 15 minutes before discharging. (5) The wet material is spread in a material plate with a thickness of 1-1.5 cm, and dried at 50° C. through ventilation until the moisture content is less than 2%. The material is sieved through a 24-mesh sieve to size particles. The material is then transferred to a V-shaped mixer, 18-22 parts by weight of corn starch is added and mixed for 15 minutes, and then 0.5 parts by weight of silicon dioxide and 0.5 parts by weight of magnesium stearate are added and mixed for 20 minutes to obtain final mixed particles. (6) Tablets were pressed using a φ6.5 mm flat punch with an average hardness of 3.0 kg and a pressure of 3.0 kg on a rotary tablet press to obtain alprazolam tablets, each of which contained 0.4 mg of alprazolam in theory.

10. Use of the alprazolam tablets according to any one of claims 1 to 7 in the preparation of drugs for antianxiety, antianxiety, antidepression, anti-excitement, hypnosis, anti-panic, relief of acute alcohol withdrawal symptoms, and resistance to drug-induced refractory hiccups.

Images