CN1188131C - Orally taken pulsed releasing system of phenyl diazepine medicine and its prepn. - Google Patents

Abstract

The invention discloses a benzodiazepine drug pulse release system comprising diazepam, estazolam and triazolam for treating patients with early awakening and a preparation method thereof. Dialkyl sodium sulfate and other auxiliary materials are mixed to make tablet cores, coated with acrylic resin polymers, hydrophobic polymers and plasticizers suspended in ethanol, the preparation has good bioavailability, no drowsiness and side effects, and the preparation method is heavy. The invention has good reproducibility, can ensure accurate drug dosage, has simple process and low production cost, and is beneficial to industrialized production.

Description

Benzodiazepine oral pulse release system and preparation method thereof

technical field

The invention relates to an oral pulse drug release system for benzodiazepines and a preparation method thereof, in particular to an oral pulse drug release system for treating early awakening such as diazepam, estazolam and triazolam and a preparation method thereof.

Background technique

Among the benzodiazepines, sedative, hypnotic, and anti-anxiety drugs include diazepam, estazolam, triazolam, etc. Their common feature is that they are almost insoluble in water, have a certain solubility in the stomach, and are absorbed in the intestine Rapid, and the effective dose of clinical application is small.

With the acceleration of the pace of work and the growth of age, early awakening is a common disease among middle-aged and elderly people. Clinically, diazepam, estazolam, triazolam, etc. are used for treatment. For example, diazepam, the first-choice drug for sedation, hypnosis and anti-anxiety in clinical practice, is rapidly absorbed after oral administration and reaches the peak plasma concentration within 0.5 to 1 hour. There are two dosage forms of ordinary tablets and sustained-release tablets. Ordinary diazepam tablets are usually taken before going to bed. Because the drug has a short action time, it often cannot meet the requirements of patients who have difficulty falling asleep after waking up early at 3 to 4 in the morning. As a result, patients often need to get up in the middle of the night to take medicine again. For this reason, the United States Roche Company has developed and listed diazepam sustained-release capsules. The trade name is Valrelease. Each capsule contains 15 mg of the main drug. Take 1 to 2 capsules per day. The average peak time is 5.3 hours. The main advantage is the long-lasting drug release. , can maintain long-acting effect, patients do not need frequent medication. However, the side effect of this drug is obvious, that is, the patient has a very heavy drowsiness the next day, thereby affecting the normal work during the day. Therefore, clinically used diazepam ordinary tablets and overseas marketed sustained-release capsules are not only less effective in treating patients who fall asleep easily but wake up early in the morning, but also have shortcomings that cannot be ignored in actual use.

Oral pulse drug release system is a new dosage form developed in recent years to release drugs regularly and quantitatively according to physiological and therapeutic needs. It can be divided into osmotic pump pulse system, coated pulse system and timed pulse plug capsule. The coated pulsation system means that after the patient takes the preparation, it does not show zero-order release immediately, but begins to release the drug after an obvious time interval, that is, there is a "time lag". The film coating technology in the coating pulse system usually uses sugar granules as the core, and after outsourcing the drug, it is then coated with a disintegrating substance, and finally coated with an insoluble coating material with a pore-forming agent as a controlled release film (see: oral pulse and Timed drug release system, "Foreign Medicine and Pharmacy Volume", 1999, Volume 26, No. 1: 33 pages). This kind of film coating process has high technical requirements. When coating the drug on the sugar core, it is difficult to control the amount of drug coated, especially for some drugs with strong pharmacological effects and small effective doses. This method has practical application in the pharmaceutical industry. It must be difficult.

Contents of the invention

The technical problem to be solved by the present invention is to provide an oral pulse drug release system for insoluble benzodiazepines for the treatment of early awakening. Released from the tablet, the plasma concentration presents a pulsating peak. As long as the patient takes the medicine before going to bed, a certain dose of medicine can be released suddenly before waking up early at night, which has a sedative and hypnotic effect and makes the patient sleep again. Patients do not need to get up in the middle of the night to take medicine again, and there is no delayed drug effect of sustained-release tablets, such as drowsiness, which will not affect the work of the next day.

That is to say, the oral pulse-release preparation of the insoluble benzodiazepines of the present invention can be released after a considerable period of time after the patient takes it, but once released, the entire drug dose will be released quickly, thereby having the best biological effect. Utilization. Moreover, the drug release rate is not affected by the pressure of the tablet core, which can ensure the stability of the quality of the preparation.

In addition, the present invention expects to achieve the purpose of effective treatment with the minimum dose through the timed and quantitative release of the drug.

If necessary, the oral pulse-release preparation of insoluble benzodiazepines of the present invention can be administered in combination with ordinary tablets. Those who wake up sleep peacefully until the morning.

The technical problem to be solved by the present invention also includes the preparation method of developing an oral pulse release preparation of insoluble benzodiazepines. Because the pharmacological effects of this type of drug are strong and the effective dose is small, the preparation method must be able to ensure accurate drug content. , the method has good reproducibility, for example, the drug release rate is not affected by the tablet core pressure, etc., the cost is low, and it is suitable for industrial production.

In order to solve the problems of the technologies described above, the present invention provides the following technical solutions:

A pulse tablet for treating early awakening, which contains benzodiazepine compound diazepam, estazolam or triazolam, and is characterized in that: the tablet core is basically composed of benzodiazepine compound and surfactant Composed of sodium lauryl sulfate, disintegrant, and filler; the outer pulse coating layer is composed of acrylic resin polymer, ethyl cellulose or trimethylammonium ethyl methacrylate-acrylate copolymer and plasticizer.

The aforementioned pulse tablet for treating early awakening is characterized in that: in the tablet core, the disintegrants include sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked povidone and/or or sodium starch glycolate, the filler is starch, lactose, microcrystalline cellulose and/or pregelatinized starch; in the outer pulse coating layer, the acrylic resin polymer is enteric-coated type II acrylic resin, enteric-coated type III Acrylic resin, hypromellose phthalate and/or hypromellose succinate, plasticizers are propylene glycol, polyethylene glycol, castor oil, cetyl alcohol, Tween-80, phthalate Diethyl formate and/or triethyl citrate.

The pulse tablet for treating early awakening is characterized in that: in the tablet core, the ratio of benzodiazepine compound, surfactant sodium lauryl sulfate, disintegrant, and filler is 1:0.1 by weight ～0.3:1.0～5.5:16～113; in the outer pulse coating layer, the weight ratio of acrylic resin polymer, ethyl cellulose or trimethylammonium ethyl methacrylate-acrylate copolymer to plasticizer is 1:0.2 ~0.3: 0.4~1.0.

In addition, in the aforementioned pulsating tablet for treating early awakening, povidone and/or hypromellose can be added as a binder in the tablet core; talcum powder, micronized silica gel and/or magnesium stearate can also be added as a lubricant.

The pulse tablet for treating early awakening is characterized in that by weight ratio: tablet core is diazepam 1: sodium lauryl sulfate 0.3: lactose and/or pregelatinized starch 12-17: sodium carboxymethyl starch 0.7 ~1.5; in the outer pulse coating layer, enteric-coated No. II acrylic resin 1: ethyl cellulose 0.2-0.3: propylene glycol and/or diethyl phthalate 0.4-0.7.

The pulse tablet for treating early awakening is characterized in that by weight ratio: tablet core is estazolam 1: sodium lauryl sulfate 0.3: microcrystalline cellulose and/or pregelatinized starch 36-45: carboxymethyl Sodium starch glycolate 1.0-3.0; in the outer pulse coating layer, enteric-coated type II acrylic resin 1: ethyl cellulose 0.2-0.3: Tween-80 and/or triethyl citrate 0.4-0.5.

The pulse tablet for treating early awakening is characterized in that by weight ratio: tablet core is triazolam 1: sodium lauryl sulfate 0.1: starch and/or microcrystalline cellulose 112-113: cross-linked carboxymethyl cellulose Sodium 3.6-5.5; in the pulse coating layer, EudragitS100 1: EudragitRL100 0.2-0.3: castor oil and/or triethyl citrate 0.5-0.6.

A preparation method for pulse tablets for treating early awakening, characterized in that:

1) Mixing benzodiazepines, surfactant sodium lauryl sulfate, disintegrant and filler, and compressing it into a tablet core;

2) A suspension is formed by dispersing acrylic resin polymer, ethyl cellulose or trimethylammonium ethyl methacrylate-acrylate copolymer and plasticizer in ethanol;

3) The tablet core 1) is coated with the suspension 2).

The pulse sheet preparation method is characterized in that:

1) The preparation of the tablet core, after dry mixing the benzodiazepine compound and the surfactant sodium lauryl sulfate, the disintegrating agent added is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked Sodium carboxymethylcellulose, crospovidone and/or sodium starch glycolate; added fillers are starch, lactose, microcrystalline cellulose and/or pregelatinized starch; compressed into tablet cores;

2) Preparation of pulse coating suspension, acrylic resin polymer is enteric type II acrylic resin, enteric type III acrylic resin, hypromellose phthalate and/or hypromellose succinate esters; hydrophobic ethyl cellulose or trimethylammonium ethyl methacrylate-acrylate copolymer; plasticizers are propylene glycol, polyethylene glycol, castor oil, cetyl alcohol, Tween-80, phthalic acid Diethyl ester and/or triethyl citrate; dispersed in 95% ethanol.

3) The tablet core 1) is coated with the suspension 2).

The preparation method of the above pulse tablet is characterized in that: in the tablet core, the weight ratio of the benzodiazepine compound to the surfactant sodium lauryl sulfate, the disintegrant, and the filler is 1: 0.2～0.5: 0.5～ 3.0:11~43; in the outer pulse coating layer, the weight/volume ratio of acrylic resin polymer, ethyl cellulose or trimethylammonium ethyl methacrylate-acrylate copolymer, plasticizer and ethanol is 1:0.2~ 0.3: 0.4~1.0: 10.0~20.0.

The preparation method of the pulse tablet is characterized in that: an appropriate amount of povidone and/or hypromellose can be added as a binder in the tablet core as usual; an appropriate amount of talcum powder, micropowder silica gel and/or stearin can also be added Magnesium acid is used as a lubricant; it can be compressed into tablets after granulation. The drying temperature of the tablet core wet granules is 50-60°C, and the drying time is 1-3 hours.

The present invention relates to the compound of formula I for the treatment of early awakening, which is benzodiazepines, such drugs include: diazepam, estazolam, triazolam, which not only have a common mother nucleus in chemical structure, but also have a physical and chemical They have some common characteristics in terms of pharmaceutical properties and pharmaceutical properties, for example, they are almost insoluble in water, have certain solubility in the stomach, and are rapidly absorbed in the intestine. The extent of drug absorption is related to intestinal pH, so the main factors affecting bioavailability are drug burst release time and solubility. In the present invention, surfactant sodium lauryl sulfate is added to increase the hydrophilicity of insoluble drugs, prevent drug aggregation, increase the stripping rate of main drug components, and promote rapid dissolution.

Tablet core prescription provided by the present invention, disintegrating agent mainly contains sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate; filling Agents, mainly starch, lactose, microcrystalline cellulose and/or pregelatinized starch, etc. Binders and/or lubricants can be added, but are not essential, or can be omitted. Adhesives can be povidone or hypromellose. Lubricants can be talcum powder, micronized silica gel or magnesium stearate, etc.

In the invention, the materials used for film coating or coating layer include; acrylic resin polymers, such as: enteric type II acrylic resin (such as Eudragit L100), enteric type III acrylic resin (such as Eudragit S100), hydroxyl Promellose phthalate, hypromellose succinate, etc., are used in an amount of 5-8% (w/v). The coating solution contains a hydrophobic substance, such as ethyl cellulose, which can be used under the trade name Aquacoat@, Asahi Kasei or Surelease ^@ , Colorcon or a trimethylammonium ethyl methacrylate-acrylate copolymer (such as Eudragit RL or Eudragit RS), the dosage is 1.5-2.5% (w/v), and the most commonly selected hydrophobic substance is ethyl cellulose. Plasticizers such as propylene glycol, polyethylene glycol, castor oil, cetyl alcohol, Tween-80, diethyl phthalate and/or triethyl citrate are added to the film coating formulation, the optimal dosage is 2 to 3% (w/v).

The tablet core of the present invention can adopt common coating methods, for example, fluidized bed coating method or pan rolling coating method, and can be coated with one or two layers of coating.

The invention relates to a pulse release system, especially an oral timed release coated drug tablet which combines the coating dissolution and burst release mechanism.

The benzodiazepine drug pulse tablet of the present invention is characterized in that, during the in vitro dissolution test, there is a time lag in the gastrointestinal fluid, and when the tablet reaches a certain position in the intestinal tract, the drug is released immediately to form a pulse blood drug concentration peak, This release rate is not affected by the pressure when the tablet is pressed.

The pulse controlled-release tablet provided by the invention does not release the drug immediately after oral administration, but releases the drug rapidly from the tablet after a certain time lag, and the blood drug concentration presents a pulse-like peak value. The advantage is that, when the patient takes the medicine before going to bed, a certain dose of medicine can be released suddenly before waking up early at night, which acts as a sedative and hypnotic, making the patient sleep again, and has the best bioavailability.

Because the pulse-controlled release tablet of the present invention has a short action time, it does not have the hysteresis drug effect of the sustained-release tablet, that is, drowsiness, and will not affect the normal work of the next day. The present invention can use the minimum dose of medicine to achieve the best effect of treating early awakening patients. In addition, if necessary, the pulse tablet of the present invention can be used in combination with ordinary tablets, so that those who have trouble falling asleep can fall asleep quickly and safely, and those who wake up early can sleep peacefully until early morning.

The preparation method of the pharmaceutical dosage form with timed release provided by the present invention proves to have good reproducibility in the implementation process, even if the pressure changes during tablet compression, it does not affect the drug release speed of the pulse preparation of the present invention; the pulse prepared by the method of the present invention The preparation can ensure accurate drug dosage; and the process is relatively simple, the production cost is low, and it is beneficial to industrial production.

Description of drawings

Figure: Diazepam Pulse Tablets and Ordinary Tablets Blood Drug Concentration Curves (n=6)

Detailed ways

Raw material sources and specifications:

Diazepam, estazolam (for medicinal use, Jiangsu Changzhou Siyao Pharmaceutical Co., Ltd.), triazolam (for medicinal use, Nhua Pharmaceutical Group, Xuzhou No. 3 Pharmaceutical Factory), and pharmaceutical excipients are all conventional.

Embodiment 1: Diazepam Pulse Tablets

Tablet core prescription: %(W/W)

Diazepam 5.3

Lactose 46.3

  Pregelatinized Starch                                            

  Sodium Carboxymethyl Starch                       6.5

Sodium Lauryl Sulfate 1.2

4% povidone 1.1

Magnesium stearate 0.8

Total 100%

Preparation Process:

According to the above prescription ratio, put diazepam and sodium lauryl sulfate in the mixer, dry mix for 8 minutes, put lactose, pregelatinized starch, carboxymethyl starch sodium in the mixer again, dry mix for 12 minutes, The binder is added to the mixture to make a soft material, sieved to make granules of uniform size, put into an oven at 55°C for 2 hours, add magnesium stearate and mix for 5 minutes, and press into tablet cores.

Coating prescription: %(W/V)

Enteric type II acrylic resin 5.4

Ethyl cellulose 1.6

Propylene Glycol 1.0

  Diethyl phthalate                                    

Add 95% ethanol to 100.0%

Preparation Process:

According to the above prescription ratio (when the volume of ethanol is milliliters, the remaining auxiliary materials are in grams, the same below), several auxiliary materials are first dispersed in ethanol to form a uniform suspension, and in a fluidized bed, use this suspension for 500g The diazepam tablet core is spray-coated, the bed temperature of the tablet core is 45°C when the tablet core is coated, and the weight gain of the coating layer is 4.5% of the weight of the tablet core.

Each pulse tablet contains 5 mg of the main drug, once a day, before going to bed.

Embodiment 2: Diazepam Pulse Tablets

Tablet core prescription %(W/W)

Diazepam 5.3

Starch 41.6

  Microcrystalline Cellulose                                                        

 Low-substituted hydroxypropyl cellulose                        

Sodium Lauryl Sulfate 1.2

4% hypromellose 1.1

  Micro-powder silica gel                              

Total 100%

Preparation Process:

According to the above prescription ratio, put diazepam and sodium lauryl sulfate in the mixer, dry mix for 5 minutes, then put microcrystalline cellulose, starch, low-substituted hydroxypropyl cellulose in the mixer, dry mix for 15 minutes Minutes, add the binder to the mixture to make a soft material, sieve to make granules of uniform size, put them in an oven for 2 hours at 53°C, add micronized silica gel and mix for 5 minutes, and press into tablet cores.

Coating prescription %(W/V)

  Hypromellose phthalate 6.0

EudragitRL 1.5

Propylene Glycol 2.0

  Triethyl citrate           3.0

Add 95% ethanol to 100.0%

Preparation Process:

Disperse the above-mentioned several auxiliary materials in ethanol to form a homogeneous substance according to the above-mentioned prescription ratio. In the coating pan, use this suspension to spray coat the 500g diazepam tablet core. During the tablet core coating, the tablet bed temperature is 40 °C until the weight gain of the coating layer is 4%.

Embodiment 3: Estazolam Pulse Tablets

Tablet core prescription %(W/W)

Estazolam 2.1

  Microcrystalline Cellulose                                                                                    

  Pregelatinized Starch                                              

Sodium Lauryl Sulfate 0.5

  Sodium Carboxymethyl Starch                                            

4% hypromellose 1.2

  Micro-powder silica gel                                

Total 100%

Preparation Process:

According to the above prescription ratio, put estazolam, microcrystalline cellulose and sodium lauryl sulfate in a mixer, dry mix for 10 minutes, then put pregelatinized starch and sodium carboxymethyl starch in a mixer, dry Mix for 10 minutes, add binder to the mixture to make a soft material, sieve to make granules with uniform size, dry in an oven at 50°C for 2.5 hours, add micronized silica gel and mix for 5 minutes, and press into tablet cores.

Coating prescription %(W/V)

Eudragit L100 8.0

Ethyl cellulose 2.3

Tween-80 1.3

  Triethyl citrate                            

Add 95% ethanol to 100.0%

Preparation Process:

Disperse the above-mentioned several auxiliary materials in ethanol to form a homogeneous substance according to the above-mentioned prescription ratio. In the coating pan, use this suspension to spray coat 500g estazolam tablet cores. When the tablet cores are coated, the tablet bed temperature is At 50°C, the weight gain of the coating layer is 3.5%.

Embodiment 4: Triazolam Pulse Tablets

Tablet core prescription %(W/W)

Triazolam 0.83

Starch 50.67

  Microcrystalline Cellulose                                                      

Sodium Lauryl Sulfate 0.1

  Croscarmellose sodium         4.3

4% povidone 1.0

Magnesium stearate 0.6

Total 100%

Preparation Process:

According to the above prescription ratio, put triazolam, microcrystalline cellulose and sodium lauryl sulfate in a mixer, dry mix for 8 minutes, then put starch, croscarmellose sodium in a mixer, and dry mix After 15 minutes, add the binder to the mixture to make a soft material, sieve to make granules of uniform size, put them in an oven and dry at 55°C for 2 hours, add magnesium stearate and mix for 6 minutes, and press into tablet cores.

Coating prescription %(W/V)

Eudragit S100 5.8

Eudragit RL100 1.7

Castor Oil 1.8

  Triethyl citrate                              

Add 95% ethanol to 100%

Preparation Process:

According to the above prescription ratio, first disperse the above several auxiliary materials in ethanol to form a homogeneous substance, and in the coating pan, use this suspension to spray coat 500g triazolam tablet core until the weight gain of the coating layer is 4.2%. .

Example 5:

Test instrument: AGILENT1100 liquid chromatograph, Hewlett-Packard Company, USA.

Diazepam pulse tablets and commercially available ordinary tablets were administered to 6 healthy volunteers in a single-dose crossover mode, and the concentration of diazepam in plasma was determined by reversed-phase HPLC. For testing methods, see: "Chinese Journal of Pharmaceutical Sciences", 1996, 3(18): 507 and "Chinese Journal of Clinical Pharmacy", 1999, 8(1): 43-44.

Six healthy volunteers were randomly given diazepam pulse tablets (once a day, 5 mg/time), commercially available diazepam ordinary tablets (once a day, 2×2.5 mg/time), each group of 3 people, crossover After taking the medicine, the blood drug concentration was measured at multiple time intervals after each dose. See accompanying drawing: Diazepam pulse tablet and ordinary tablet in vivo blood drug concentration curve (n=6).

The HPLC data show that the blood drug concentration of patients taking diazepam pulse tablets has an obvious lag peak, and the lag time is about 5 to 7 hours, which has a more obvious delayed-release pulse effect. Patients who wake up early at 4 o'clock can also be adapted to patients who wake up early at different times by adjusting different time of taking medicine before going to bed.

Claims (9)

1. A pulse tablet for treating early awakening, which contains benzodiazepine drug compound diazepam, estazolam or triazolam, characterized in that: in parts by weight, the tablet core is basically composed of benzodiazepine Composition of phenotype compound and surfactant sodium lauryl sulfate, disintegrating agent, and filler in a ratio of 1:0.1~0.3:1.0~5.5:16~113; the outer pulse coating layer is made of acrylic resin polymer, ethyl fiber Plain or trimethylammonium ethyl methacrylate-acrylic ester copolymer and plasticizer are made up with the ratio of 1:0.2～0.3:0.4～1.0, and plasticizer is selected from propylene glycol, polyethylene glycol, castor oil, cetyl alcohol, Tween-80, diethyl phthalate and/or triethyl citrate; the weight of the outer pulse coat layer is 3.5-4.5% of the weight of the tablet core. 2. The pulse tablet for treating early awakening according to claim 1, characterized in that: in the tablet core, the disintegrating agent is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, Crosslinked povidone and/or sodium starch glycolate, the filler is starch, lactose, microcrystalline cellulose and/or pregelatinized starch; in the outer impulse coating layer, the acrylic resin polymer is enteric type II Acrylic resin, enteric type III acrylic resin, hypromellose phthalate and/or hypromellose succinate. 3. According to the pulse tablet for treating early awakening according to claim 1, povidone and/or hypromellose can be added as binder in the tablet core; talcum powder, micropowder silica gel and/or magnesium stearate can also be added as lubricant. 4. The pulse tablet for treating early awakening according to any one of claims 1 to 3, characterized in that by weight ratio: the tablet core is diazepam 1: sodium lauryl sulfate 0.3: lactose and/or pregelatinized starch 12～17: Sodium carboxymethyl starch 1.0～1.5; In the external pulse coating layer, enteric type II acrylic resin 1: Ethyl cellulose 0.2～0.3: Propylene glycol and/or diethyl phthalate 0.4～0.7 . 5. The pulse tablet for treating early awakening according to any one of claims 1 to 3, characterized in that by weight ratio: the tablet core is estazolam 1: sodium lauryl sulfate 0.3: microcrystalline cellulose and/or Pregelatinized starch 36~45: sodium carboxymethyl starch 1.0~3.0; in the outer pulse coating layer, enteric-coated type II acrylic resin 1: ethyl cellulose 0.2~0.3: Tween-80 and/or tricitric acid Ethyl ester 0.4～0.5. 6. The pulsating tablet for treating early awakening according to any one of claims 1 to 3, characterized in that by weight ratio: the tablet core is triazolam 1: sodium lauryl sulfate 0.1: starch and/or microcrystalline cellulose 112-113: croscarmellose sodium 3.6~5.5; in the outer pulse coating layer, enteric type III acrylic resin 1: trimethylammonium ethyl methacrylate-acrylate copolymer 0.2~0.3: castor oil and /or triethyl citrate 0.5-0.6. 7. A method for preparing pulse tablets for treating early awakening, characterized in that: 1) Mix benzodiazepines, surfactant sodium lauryl sulfate, disintegrant, and filler in a weight ratio of 1:0.1-0.3:1.0-5.5:16-113, and press to form a tablet core; 2) A suspension composed of acrylic resin polymer, ethyl cellulose or trimethylammonium ethyl methacrylate-acrylic acid ester copolymer and plasticizer dispersed in ethanol, acrylic resin polymer, ethyl cellulose or methyl cellulose The weight/volume ratio of trimethylammonium ethyl acrylate-acrylate copolymer, plasticizer and 95% ethanol is 1: 0.2～0.3: 0.4～1.0: 10.0～20.0, plasticizer is selected from propylene glycol, polyethylene glycol , castor oil, cetyl alcohol, Tween-80, diethyl phthalate and/or triethyl citrate; 3) Coating the tablet core 1) with the suspension 2) in a fluidized bed or a coating pan until the weight gain of the coating layer is 3.5-4.5% of the weight of the tablet core. 8. The method for preparing the pulse sheet according to claim 7, characterized in that: 1) The preparation of the tablet core, after dry mixing the benzodiazepine compound and the surfactant sodium lauryl sulfate, the disintegrating agent added is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked Sodium carboxymethylcellulose, crospovidone and/or sodium starch glycolate; added fillers are starch, lactose, microcrystalline cellulose and/or pregelatinized starch; compressed into tablet cores; 2) Preparation of pulse coating suspension, acrylic resin polymer is enteric type II acrylic resin, enteric type III acrylic resin, hypromellose phthalate and/or hypromellose succinate Ethyl cellulose or trimethylammonium ethyl methacrylate-acrylate copolymer; plasticizers are propylene glycol, polyethylene glycol, castor oil, cetyl alcohol, Tween-80, diethyl phthalate esters and/or triethyl citrate; dispersed in 95% ethanol, 3) The tablet core 1) is coated with the suspension 2). 9. The preparation method of the pulsating tablet according to claim 8, characterized in that: an appropriate amount of povidone and/or hypromellose is added to the tablet core as a binder; an appropriate amount of talcum powder and micropowdered silica gel can also be added. And/or magnesium stearate as a lubricant; it can be compressed into tablets after granulation, the drying temperature of the tablet core wet granules is 50-60°C, and the drying time is 1-3 hours.

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