An estazolam tablet and a preparation method thereof

Abstract

The application discloses eszopiclone tablets and a preparation method thereof, and the preparation method comprises the following steps: S1. eszopiclone, corn starch, low-substitution hydroxypropyl cellulose, magnesium stearate are mixed and then screened through a 100-mesh sieve; S2. the screened material in step S1 is sprayed with water in a balling machine and then balling is performed, and then the material is screened through a 30-mesh sieve; S3. calcium hydrogen phosphate is added into the balling machine, and the screened material in step S2 is sprayed and balling is performed again until the particle size reaches 1.6-2 mm; a slurry containing corn starch and mannitol is used for spraying; S4. the material balling in step S3 is dried and granulated to obtain 1.5-mm granules, and then the granules are mixed and compressed to obtain eszopiclone tablets; the preparation method can effectively avoid the generation of drug dust, improve the disintegration rate, is stable in quality and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine tablet preparation, and more particularly to an estazolam tablet and a preparation method thereof. BACKGROUND

[0002] Estazolam, chemical formula is C 16 H 11 ClN4, the Chinese name is 6-phenyl-8-chloro-4h-[1,2,4] triazol [4,3a] [1,4] benzodiazepine, has strong sedative, hypnotic, anticonvulsant, anxiolytic effect, and weak central skeletal muscle relaxation effect. It is suitable for insomnia, convulsion, anxiety, tension, fear and epilepsy attack and the like.

[0003] The main mechanism of action of estazolam is to strengthen the inhibitory neurotransmitter in the brain, that is, gamma-aminobutyric acid, and with the increase of the dose, it has the effects of anxiolytic, sedative hypnotic, amnesia, anticonvulsant and skeletal muscle relaxation, so it is widely used in clinical anxiolytic, insomnia, also used in tension, fear, relieving preoperative tension, anxiety, and antiepileptic, anticonvulsant and the like, and can also be used for muscle tension headache.

[0004] The existing tablet preparation method generally adopts the most widely used wet granulation compression tablet and / or dry tablet method; the wet granulation method includes screening granulation, fluidized boiling granulation method, spray drying granulation method and high-speed stirring granulation method. The dry tablet method generally includes crystallization compression tablet method, dry granulation compression tablet method and powder direct compression tablet method.

[0005] In the production process of estazolam, due to the fine material, and the mechanical extrusion or strong oscillation effect existing in the granulation and compression process, especially in the whole mixing process, a large amount of drug dust is generated, the drug dust pollutes the preparation workshop, and may cause occupational diseases, and estazolam itself can strengthen the inhibitory neurotransmitter in the brain, and long-term contact has great harm to the healthy human body. On the other hand, due to the need for tablet disintegration, a proper amount of disintegrant must be added, and to a certain extent, the disintegration speed is positively correlated with the generation of drug dust. Therefore, how to reduce the amount of dust while improving the disintegration speed has become a big problem in the production process of estazolam tablets.

[0006] Therefore, it is necessary to provide a preparation method of estazolam tablet to solve the defects of large amount of drug dust and slow disintegration speed in the use process of the tablet in the production process of the prior art. SUMMARY

[0007] In view of this, the present application provides a preparation method of estazolam tablet to solve the defect of serious drug dust in the production process of the prior art.

[0008] Based on this, the technical scheme of the present application is as follows:

[0009] A preparation method of estazolam tablets, comprising the following steps:

[0010] S1. According to the prescription, estazolam, corn starch and low-substituted hydroxypropyl cellulose are prepared and mixed, and then sieved through a 100-mesh sieve for use;

[0011] S2. The sieved material in step S1 is sprayed with water in a balling machine and then balling is performed, and then sieved through a 30-mesh sieve;

[0012] S3. Calcium hydrogen phosphate is added to the balling machine, and the sieved material in step S2 is sprayed and balling is performed again until the particle size reaches 1.6-2 mm; the spraying uses a slurry containing corn starch and mannitol;

[0013] S4. The material balling in step S3 is dried, magnesium stearate is added for granulation to obtain 1.5 mm particles, and then total mixing is performed to obtain estazolam tablets.

[0014] Further, the raw material components are as follows in terms of weight parts: 1 part of estazolam, 5-10 parts of corn starch, 5-12 parts of low-substituted hydroxypropyl cellulose, 40-55 parts of calcium hydrogen phosphate, and 3-6 parts of magnesium stearate.

[0015] Further, the raw material components are as follows in terms of weight parts: 1 part of estazolam, 5-10 parts of corn starch, 5-12 parts of low-substituted hydroxypropyl cellulose, 40-55 parts of calcium hydrogen phosphate, and 3-6 parts of magnesium stearate.

[0016] Further, the amount of water sprayed in step S2 is 3-10 wt%, the rotation speed of the balling machine is 1-5 revolutions per second, the time per cycle is 5-15 seconds, and the spraying frequency is 1-2 times per minute.

[0017] Further, the rotation speed of the balling machine in step S3 is 1-5 revolutions per second, the time per cycle is 5-15 seconds, and the spraying frequency is 1 time per 1 minute.

[0018] Further, the spraying material in step S4 is a slurry containing 5 wt% of corn starch and 5 wt% of mannitol, and the spraying amount is 6. After adding calcium hydrogen phosphate, the spraying amount of the obtained powder is 30 wt%.

[0019] Further, the drying in step S4 is performed by microwave dehydration, and the process control temperature is 100-150℃, and the time is 30-120 minutes.

[0020] Further, the microwave dehydration process controls the heating rate to be 3-10℃ / minute.

[0021] Another object of the present application is to provide estazolam tablets obtained by the above preparation method, which have a disintegration time of less than 40 seconds in the oral cavity.

[0022] The beneficial effects of the present application are:

[0023] 1. The preparation method of the present application coats the disintegrant calcium hydrogen phosphate on the surface of the microspheres through multiple balling, and then uses the slurry wrapped with corn starch and mannitol to effectively avoid the generation of drug dust and improve the disintegration rate of estazolam tablets, which is suitable for industrial production.

[0024] 2. The estazolam tablets obtained by the preparation method of the present application have stable quality, which provides a new direction for the industrialized production of estazolam tablet preparations. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of the present application.

[0026] In one embodiment of the present application, a preparation method of estazolam tablets is provided, which comprises the following steps:

[0027] S1. Prepare estazolam, corn starch and low-substituted hydroxypropyl cellulose according to the prescription, mix them and pass them through a 100-mesh sieve for use;

[0028] S2. Spray water on the sieved material in step S1 in a balling machine and ball it, and pass it through a 30-mesh sieve;

[0029] S3. Add calcium hydrogen phosphate to the balling machine, spray and ball the sieved material in step S2 again to reach a particle size of 1.6-2 mm; spray a slurry containing corn starch and mannitol;

[0030] S4. Dry the material formed in step S3, add magnesium stearate to granulate to obtain 1.5-mm granules, and then mix them and press them to obtain estazolam tablets.

[0031] The above preparation method coats the surface of estazolam with the ingredients through the first balling, coats the disintegrant calcium hydrogen phosphate on the surface of the microspheres in the second balling, and then uses the slurry wrapped with corn starch and mannitol to form a hydrophilic layer with large molecules combined with small molecules on the outside, and the mannitol can form hydrogen bonds with the corn starch in the outer and inner layers, which can reduce the generation of dust after drying and pressing, and can form large disintegration and improve the disintegration rate when absorbing water.

[0032] In the preferred embodiment, the raw materials used in the above preparation process of estazolam are configured according to the prescription requirements, and the raw material components are 1 part of estazolam, 5-10 parts of corn starch, 5-12 parts of low-substituted hydroxypropyl cellulose, 40-55 parts of calcium hydrogen phosphate, and 3-6 parts of magnesium stearate, by weight. More preferably, the raw material components are 1 part of estazolam, 6 parts of corn starch, 10 parts of low-substituted hydroxypropyl cellulose, 52 parts of calcium hydrogen phosphate, and 4 parts of magnesium stearate, by mass.

[0033] In the preferred embodiment, the amount of water sprayed in step S2 is 3-10 wt%, the rotation speed of the balling machine is 1-5 revolutions per second, and the spraying frequency is 1-2 times per minute, 5-15 seconds per time. In step S3, the rotation speed of the balling machine is 1-5 revolutions per second, the spraying frequency is 1 time per 1 minute, and the spraying time is 5-15 seconds per time.

[0034] In the preferred embodiment, the spraying material in step S4 is a slurry containing 5 wt% of corn starch and 5 wt% of mannitol, and the spraying amount is 30 wt% of the resulting powder after the addition of calcium hydrogen phosphate, which facilitates the formation of a more stable coating structure, reduces the amount of dust in the later stage, and increases the disintegration speed.

[0035] In the preferred embodiment, the drying in step S4 is performed by microwave dehydration, the process control temperature is 100-150°C, the time is 30-120 minutes, the microwave dehydration process control temperature rising rate is 3-10°C / min, and the water content of the particles is less than 3.0%. The use of microwave dehydration can further reduce the amount of dust generated.

[0036] In this scheme, the balling machine used is a common balling machine or a circular pan granulator, and the spraying is from the circular pan opening, which further suppresses the escape of dust.

[0037] In this scheme, the final product of the estazolam tablet refers to a standard tablet containing 1 mg of estazolam, and the output can be determined according to the input weight of estazolam to produce the number of tablets, for example, 1 kg of estazolam can produce 1 million tablets. The estazolam tablet obtained by the above preparation method has an oral disintegration time of less than 40 seconds, solving the problem of reducing the amount of dust while increasing the disintegration speed in the production process of estazolam tablets.

[0038] In this scheme, dust refers to, but is not limited to, PM 2.5 and PM 10 and other solid particulate matter, and the suppression of dust refers to a decrease in the content of particulate matter when this parameter is used as a reference index; oral disintegration refers to the complete dissolution of the tablet in the oral cavity as determined in random volunteers, and in vitro disintegration refers to the complete disintegration of the tablet as determined by a disintegration instrument, and the disintegration time of both is used as a reference for the disintegration efficiency of the tablet.

[0039] Example 1

[0040] Formulation: Eszopiclone 1 part, corn starch 6 parts, low-substituted hydroxypropyl cellulose 10 parts, calcium hydrogen phosphate 52 parts, magnesium stearate 4 parts, slurry containing 5 wt% corn starch and 5 wt% mannitol 22 parts.

[0041] 1) Mix eszopiclone, corn starch and low-substituted hydroxypropyl cellulose and sieve through a 100-mesh sieve;

[0042] 2) Spray the sieved material in step 1) with 3 parts of water in a balling machine at a rotation speed of 2 revolutions per second and a spraying frequency of 2 times per minute, 10 seconds per time, and then sieve through a 30-mesh sieve;

[0043] 3) Add calcium hydrogen phosphate to the balling machine, and spray the sieved material in step 2) with the slurry containing corn starch and mannitol to form balls with a particle size of 1.6-2 mm; the rotation speed of the balling machine is 2 revolutions per second, and the spraying frequency is 1 time per minute, 10 seconds per time;

[0044] 4) Dry the formed material in step 3), add magnesium stearate to granulate to obtain 1.5-mm granules, and then compress the granules to obtain eszopiclone tablets containing 1 mg after general mixing.

[0045] Example 2

[0046] Formulation: Eszopiclone 1 part, corn starch 10 parts, low-substituted hydroxypropyl cellulose 6 parts, calcium hydrogen phosphate 50 parts, magnesium stearate 6 parts, slurry containing 5 wt% corn starch and 5 wt% mannitol 22 parts.

[0047] 1) Mix eszopiclone, corn starch and low-substituted hydroxypropyl cellulose and sieve through a 100-mesh sieve;

[0048] 2) Spray the sieved material in step 1) with 6 parts of water in a balling machine at a rotation speed of 5 revolutions per second and a spraying frequency of 1 time per minute, 5 seconds per time, and then sieve through a 30-mesh sieve;

[0049] 3) Add calcium hydrogen phosphate to the balling machine, and spray the sieved material in step 2) with the slurry containing corn starch and mannitol to form balls with a particle size of 1.6-2 mm; the rotation speed of the balling machine is 5 revolutions per second, and the spraying frequency is 1 time per minute, 5 seconds per time;

[0050] 4) Dry the formed material in step 3), add magnesium stearate to granulate to obtain 1.5-mm granules, and then compress the granules to obtain eszopiclone tablets containing 1 mg after general mixing.

[0051] Example 3

[0052] Formulation: Eszopiclone 1 part, corn starch 6 parts, low-substituted hydroxypropyl cellulose 12 parts, calcium hydrogen phosphate 48 parts, magnesium stearate 6 parts, slurry containing 5 wt% corn starch and 5 wt% mannitol 22 parts.

[0053] 1) Mix eszopiclone, corn starch, low-substituted hydroxypropyl cellulose and sieve through 100 mesh sieve for use;

[0054] 2) Spray the sieved material in step 1) with 4 parts of water in a balling machine at a rotation speed of 3 revolutions per second and a spraying frequency of 1 time per minute and 8 seconds per time, and then sieve through a 30 mesh sieve;

[0055] 3) Add calcium hydrogen phosphate to the balling machine, and spray the sieved material in step 2) with a slurry containing corn starch and mannitol to form granules with a particle size of 1.6-2 mm; the rotation speed of the balling machine is 3 revolutions per second, and the spraying frequency is 1 time per minute and 7 seconds per time;

[0056] 4) Dry the granules formed in step 3), add magnesium stearate to size the granules to 1.5 mm, and then mix all the ingredients together and press into tablets to obtain eszopiclone tablets containing 1 mg.

[0057] Comparative Example 1

[0058] The slurry used in Example 1 is replaced with 10 wt% corn starch, and the other formulations and preparation processes are the same as in Example 1.

[0059] Comparative Example 2

[0060] The calcium hydrogen phosphate in step 3) is added to step 2), and the formulation and other steps are the same as in Example 1.

[0061] Comparative Example 3

[0062] The formulation is the same as in Example 1, and a conventional wet granulation method is used. All the ingredients are dry mixed and then added to a slurry containing corn starch and mannitol. A fluidized bed dryer is then used to control the moisture content to be less than 3.0% at an inlet temperature of 85°C and a product temperature of 45°C. The granules are then sized and pressed into tablets.

[0063] Experimental Example

[0064] Dust testing and disintegration rate testing are performed on Examples 1-3 and Comparative Examples 1-3 above. The dust testing involves collecting the gas during the mixing process, and testing the content of PM 2.5 and PM 10. The lower the content, the better the dust suppression effect. The disintegration rate testing includes oral disintegration testing and in-vitro disintegration testing. The oral disintegration testing involves selecting a number of healthy volunteers or patients with normal oral function, and the in-vitro disintegration testing involves using a ZBS intelligent disintegration instrument to test the time required for complete disintegration, thereby comparing the speed of disintegration.

[0065] The results are shown in Table 1.

[0066] Table 1:

[0067]

[0068] As can be seen from Table 1, the scheme of Examples 1-3 has obvious effect on the inhibition of dust and the improvement of disintegration rate. The comparative example 1 does not use mannitol, the comparative example 2 directly dry-mixes the disintegrant, and the disintegration rate and dust inhibition rate of the comparative example 3 are both decreased, which may be due to the fact that mannitol, calcium hydrogen phosphate and corn starch have a synergistic effect on the binding force when forming the wrapping system, which can avoid disintegration in a dry environment, but can accelerate the disintegration rate in water.

[0069] Finally, it should be pointed out that although the present application has been described in detail above with general description and specific examples, the above examples are only used to illustrate the technical solutions of the present application, and not to limit it; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that the technical solutions recorded in the foregoing examples can still be modified, or some or all of the technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing estazolam tablets, characterized in that, Includes the following steps: S1. Prepare estazolam, corn starch, and low-substituted hydroxypropyl cellulose according to the prescription, mix them, and pass them through a 100-mesh sieve for later use; S2. In step S1, the sieved material is sprayed with water and granulated in a pelletizing machine, then passed through a 30-mesh sieve. S3. Add dicalcium phosphate to the pelletizer, and spray the sieved material from step S2 again to form pellets until the particle size reaches 1.6-2 mm; the spraying uses a slurry containing corn starch and mannitol, wherein the slurry contains 5 wt% corn starch and 5 wt% mannitol, and the spraying volume is 30 wt% of the powder obtained after adding dicalcium phosphate; S4. The agglomerated material in step S3 is dried by microwave dehydration, with the process temperature controlled at 100-150℃ and the time at 30-120 minutes; then magnesium stearate is added to granulate the material to obtain 1.5mm particles, which are then mixed and compressed into tablets to obtain estazolam tablets. The components of the prescription, by weight, are: 1 part estazolam, 5-10 parts corn starch, 5-12 parts low-substituted hydroxypropyl cellulose, 40-55 parts dicalcium phosphate, and 3-6 parts magnesium stearate.

2. The preparation method according to claim 1, characterized in that, The prescription components, by weight, are: 1 part estazolam, 6 parts corn starch, 10 parts low-substituted hydroxypropyl cellulose, 52 parts dicalcium phosphate, and 4 parts magnesium stearate.

3. The preparation method according to claim 1, characterized in that, In step S2, the amount of water added to the spray is 3-10 wt%, the speed of the baller is 1-5 revolutions / second, the spraying time is 5-15 seconds / time, and the spraying frequency is 1-2 times / minute.

4. The preparation method according to claim 1, characterized in that, The baller speed in step S3 is 1-5 revolutions per second, 5-15 seconds per spray, and the spray frequency is 1 spray per minute.

5. The preparation method according to claim 1, characterized in that, The microwave dehydration process controls the heating rate to be 3-10℃ / minute.

6. The preparation method of claim 1 yields estazolam tablets, characterized in that, It disintegrates in the oral cavity in less than 40 seconds.

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