CN115770227A - Estazolam tablet and preparation method thereof - Google Patents
Estazolam tablet and preparation method thereof Download PDFInfo
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- CN115770227A CN115770227A CN202211626179.2A CN202211626179A CN115770227A CN 115770227 A CN115770227 A CN 115770227A CN 202211626179 A CN202211626179 A CN 202211626179A CN 115770227 A CN115770227 A CN 115770227A
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Abstract
The invention discloses an estazolam tablet and a preparation method thereof, wherein the preparation method comprises the following steps: s1, preparing estazolam, corn starch, low-substituted hydroxypropyl cellulose and magnesium stearate, mixing, and sieving by a 100-mesh sieve for later use; s2, spraying water and balling the sieved materials in a balling machine in the step S1, and sieving by a 30-mesh sieve; s3, adding calcium hydrophosphate into the pelletizing machine, and spraying the sieved substances obtained in the step S2 again to form pellets until the particle size reaches 1.6-2mm; spraying slurry containing corn starch and mannitol; s4, drying and finishing the agglomerated materials in the step S3 to obtain particles with the particle size of 1.5mm, and tabletting to obtain the estazolam tablets after total mixing; the preparation method can effectively avoid the generation of drug dust, improves the disintegration speed, has stable quality, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of pharmaceutical tablets, in particular to an estazolam tablet and a preparation method thereof.
Background
Estazolam (estazolam), formula C 16 H 11 ClN 4 The Chinese cultural name is 6-phenyl-8-chloro-4 h- [1,2,4]Triazolo [4,3a][1,4]Benzodiazepines have strong sedative, hypnotic, anticonvulsant, anxiolytic effects, and weak central skeletal muscle relaxant effects. It is suitable for treating insomnia, convulsion, anxiety, stress, fear, and epileptic seizure.
The main action mechanism of the estazolam is to exert the effect by strengthening inhibitory neurotransmitter in brain, namely gamma-aminobutyric acid, and the estavel has the effects of antianxiety, sedation hypnosis, amnesia, anticonvulsant and skeletal muscle relaxation along with the increase of the dosage, so the estavel-based eszolam is widely used for the aspects of antianxiety and insomnia, tension, fear, alleviation of tension and anxiety before operation, antiepileptic and anticonvulsant and can also be used for muscle tension headache.
The existing tabletting method generally adopts the most extensive wet granulation tabletting and/or dry tabletting method; the wet granulation method includes sieving granulation, fluidized boiling granulation, spray drying granulation, and high speed stirring granulation. Dry tabletting: generally comprises a crystallization tabletting method, a dry granulation tabletting method and a powder direct tabletting method.
In the production process of the estazolam, due to the fact that materials are fine, and a large amount of medicine dust is caused by mechanical extrusion or strong oscillation action in the granulating and tabletting process, particularly in the granulating and total mixing process, the medicine dust pollutes a preparation workshop and possibly causes occupational diseases, and the estazolam can strengthen inhibitory neurotransmitters in brain, so that the long-term contact has great harm to healthy human bodies. On the other hand, due to the requirement of the tablet to disintegrate, a proper amount of disintegrant must be added, and the disintegration speed is in direct correlation with the generation of drug dust to some extent. Therefore, how to increase the disintegration rate while reducing the amount of dust becomes a big problem in the production process of the estazolam tablet.
Therefore, a preparation method of the estazolam tablet is needed to be provided, and the defects that the amount of medicinal dust is large and the disintegration speed of the tablet in the using process is low in the production process in the prior art are overcome.
Disclosure of Invention
In view of this, the invention provides a preparation method of estazolam tablets, which solves the defect of serious drug dust in the production process in the prior art.
Based on the technical scheme, the invention comprises the following steps:
a preparation method of estazolam tablets comprises the following steps:
s1, preparing estazolam, corn starch and low-substituted hydroxypropyl cellulose according to a prescription, mixing, and sieving by a 100-mesh sieve for later use;
s2, spraying water and pelletizing the screened material in a pelletizing machine in the step S1, and screening by a 30-mesh sieve;
s3, adding calcium hydrophosphate into the pelletizing machine, and spraying the sieved substances obtained in the step S2 again to form pellets until the particle size reaches 1.6-2mm; spraying slurry containing corn starch and mannitol;
and S4, drying the agglomerated material in the step S3, adding magnesium stearate to complete granules to obtain granules with the diameter of 1.5mm, and tabletting to obtain the estazolam tablets after total mixing.
Further, the raw material components comprise, by weight, 1 part of estazolam, 5-10 parts of corn starch, 5-12 parts of low-substituted hydroxypropyl cellulose, 40-55 parts of calcium hydrophosphate and 3-6 parts of magnesium stearate.
Further, the raw material components comprise, by mass, 1 part of estazolam, 6 parts of corn starch, 10 parts of low-substituted hydroxypropylcellulose, 52 parts of calcium hydrophosphate and 4 parts of magnesium stearate.
Furthermore, the amount of the water added in the spraying in the step S2 is 3-10wt%, the rotating speed of the ball forming machine is 1-5 revolutions per second and 5-15 seconds per time, and the spraying frequency is 1-2 times per minute.
Further, in the step S3, the rotating speed of the ball machine is 1-5 revolutions per second and 5-15 seconds per time, and the spraying frequency is 1 time per 1 minute.
Further, the spray material in step S4 is slurry containing 5wt% of corn starch and 5wt% of mannitol, the spraying amount is 6, and 30wt% of the powder obtained after calcium hydrogen phosphate is added.
Further, in the step S4, microwave dehydration is adopted for drying, the temperature is controlled to be 100-150 ℃, and the time is 30-120 minutes.
Further, the temperature rise rate is controlled to be 3-10 ℃/min in the microwave dehydration process.
Another object of the present invention is to provide the estazolam tablets obtained by the above preparation method, which have a disintegration time in the oral cavity of less than 40 seconds.
The invention has the beneficial effects that:
1. according to the preparation method, through repeated ball forming, the calcium hydrogen phosphate as a disintegrating agent is coated on the surfaces of the microspheres, and then the slurry coated with corn starch and mannitol is used, so that the generation of medicine dust can be effectively avoided, the disintegration speed of the estazolam tablet is improved, and the preparation method is suitable for industrial production.
2. The estazolam tablet prepared by the preparation method provided by the invention has stable quality, and provides a new direction for industrial production of the estazolam tablet preparation.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
In one embodiment of the invention, a preparation method of the estazolam tablet is provided, which comprises the following steps:
s1, preparing estazolam, corn starch and low-substituted hydroxypropyl cellulose according to a prescription, mixing, and sieving by a 100-mesh sieve for later use;
s2, spraying water and pelletizing the screened material in a pelletizing machine in the step S1, and screening by a 30-mesh sieve;
s3, adding calcium hydrophosphate into the pelletizing machine, and spraying the sieved substances obtained in the step S2 again to form pellets until the particle size reaches 1.6-2mm; spraying slurry containing corn starch and mannitol;
and S4, drying the agglomerated material obtained in the step S3, adding magnesium stearate to complete granules to obtain granules with the diameter of 1.5mm, and tabletting after total mixing to obtain the eszolam tablets.
According to the preparation method, the surface of the estazolam is wrapped by ingredients through first pelletizing, the disintegrant calcium hydrogen phosphate is coated on the surface of the microsphere during second pelletizing, and then the slurry wrapping corn starch and mannitol is used for forming the hydrophilic layer with the outer part provided with macromolecule combined micromolecules, and the mannitol can be in hydrogen bond combination with the corn starch of the outer layer and the inner layer, so that the generation of dust after drying and tabletting can be reduced, and the large block can be formed for disintegration during water absorption, and the disintegration speed is increased.
In a preferred embodiment, in the above preparation process of estazolam, the used raw materials are configured according to the prescription requirements, and optionally, the raw material components comprise, by weight, 1 part of estazolam, 5-10 parts of corn starch, 5-12 parts of low-substituted hydroxypropylcellulose, 40-55 parts of calcium hydrophosphate and 3-6 parts of magnesium stearate. More preferably, the raw material components comprise, by mass, 1 part of estazolam, 6 parts of corn starch, 10 parts of low-substituted hydroxypropylcellulose, 52 parts of calcium hydrophosphate and 4 parts of magnesium stearate.
In a preferred embodiment, the amount of water added in step S2 is 3-10wt%, the rotation speed of the ball forming mill is 1-5 r/S, and the spraying frequency is 1-2 times/min and 5-15S/S. In the step S3, the rotating speed of the ball machine is 1-5 revolutions per second, the spraying frequency is 1 time per 1 minute, and 5-15 seconds per time.
In a preferred embodiment, the spray material in step S4 is slurry containing 5wt% of corn starch and 5wt% of mannitol, and the spray amount is 30wt% of the powder obtained after adding calcium hydrogen phosphate, so that a more stable coating structure is formed, the dust amount in the later period is reduced, and the disintegration speed is increased.
In a preferred embodiment, in the step S4, microwave dehydration is adopted for drying, the process control temperature is 100-150 ℃, the time is 30-120 minutes, and the microwave dehydration process control heating rate is 3-10 ℃/minute until the moisture of the particles is lower than 3.0%. The process of dehydration using microwaves can further reduce the amount of dust generated.
In this scheme, the ball machine of adoption is common ball machine or round pot granulator, and the spraying gets into from circular pot mouth, further inhibits the effusion of dust.
In the scheme, the final finished product of the estazolam tablet is an estazolam standard tablet containing 1mg, the yield can be the number of the finally generated tablets according to the input weight of the estazolam, and 100 ten thousand tablets can be prepared if the input amount of the estazolam is 1 kg. The obtained estazolam tablet by the preparation method has disintegration time of less than 40 seconds in the oral cavity, and the problem that the disintegration speed is increased while the dust amount is reduced in the production process of the estazolam tablet is solved.
In the scheme, the dust refers to solid particulate matters including but not limited to PM 2.5, PM 10 and the like, and the dust inhibition effect refers to that the content of the particulate matters is reduced when the parameter is taken as a reference index; oral disintegration means that tablets measured in random volunteers are completely dissolved in the oral cavity, in vitro disintegration means that tablets measured by a disintegration apparatus are completely disintegrated, and disintegration time of both is used as a reference for disintegration efficiency of tablets.
Example 1
The formula is as follows: 1 part of estazolam, 6 parts of corn starch, 10 parts of low-substituted hydroxypropyl cellulose, 52 parts of calcium hydrophosphate, 4 parts of magnesium stearate, and 22 parts of slurry containing 5wt% of corn starch and 5wt% of mannitol.
1) Mixing the estazolam, the corn starch and the low-substituted hydroxypropyl cellulose, and then sieving the mixture by a 100-mesh sieve for later use;
2) Step 1) spraying 3 parts of water into the sieved materials in a ball machine, and pelletizing, wherein the rotating speed of the ball machine is 2 revolutions per second, and the spraying frequency is 2 times per minute and 10 seconds per time; then sieving the mixture by a 30-mesh sieve;
3) Adding calcium hydrogen phosphate into the pelletizing machine, and spraying slurry containing corn starch and mannitol to the sieved material in the step 2) to form pellets until the particle size reaches 1.6-2mm; the rotating speed of the ball machine is 2 revolutions per second, the spraying frequency is 1 time per minute and 10 seconds per time;
4) Drying the agglomerated material in the step 3), adding magnesium stearate, granulating to obtain granules with the diameter of 1.5mm, totally mixing, and tabletting to obtain 1mg of the estazolam tablets.
Example 2
The formula is as follows: 1 part of estazolam, 10 parts of corn starch, 6 parts of low-substituted hydroxypropyl cellulose, 50 parts of calcium hydrophosphate, 6 parts of magnesium stearate, and 22 parts of slurry containing 5wt% of corn starch and 5wt% of mannitol.
1) Mixing the estazolam, the corn starch and the low-substituted hydroxypropyl cellulose, and sieving the mixture by a 100-mesh sieve for later use;
2) Step 1) spraying 6 parts of water into the sieved material in a ball machine, and pelletizing, wherein the rotating speed of the ball machine is 5 revolutions per second, and the spraying frequency is 1 time per minute and 5 seconds per time; then sieving the mixture by a 30-mesh sieve;
3) Adding calcium hydrogen phosphate into a ball-making machine, and spraying the screened substance obtained in the step 2) with slurry containing corn starch and mannitol to make balls until the particle size reaches 1.6-2mm; the rotating speed of the ball machine is 5 revolutions per second, the spraying frequency is 1 time per minute and 5 seconds per time;
4) Drying the agglomerated material in the step 3), adding magnesium stearate to complete granules to obtain 1.5mm granules, and tabletting after total mixing to obtain 1mg of estazolam tablets.
Example 3
The formula is as follows: 1 part of estazolam, 6 parts of corn starch, 12 parts of low-substituted hydroxypropyl cellulose, 48 parts of calcium hydrophosphate, 6 parts of magnesium stearate, and 22 parts of slurry containing 5wt% of corn starch and 5wt% of mannitol.
1) Mixing the estazolam, the corn starch and the low-substituted hydroxypropyl cellulose, and sieving the mixture by a 100-mesh sieve for later use;
2) Step 1) spraying and adding 4 parts of water into the sieved material in a ball machine, and carrying out ball-mixing, wherein the rotating speed of the ball machine is 3 revolutions per second, and the spraying frequency is 1 time/minute and 8 seconds per time; then sieving the mixture by a 30-mesh sieve;
3) Adding calcium hydrogen phosphate into the pelletizing machine, and spraying slurry containing corn starch and mannitol to the sieved material in the step 2) to form pellets until the particle size reaches 1.6-2mm; the rotating speed of the ball machine is 3 revolutions per second, the spraying frequency is 1 time per minute and 7 seconds per time;
4) Drying the agglomerated material in the step 3), adding magnesium stearate to complete granules to obtain 1.5mm granules, and tabletting after total mixing to obtain 1mg of estazolam tablets.
Comparative example 1
The slurry used in example 1 was changed to 10wt% corn starch and the other formulation and preparation were the same as in example 1.
Comparative example 2
Adding the calcium hydrophosphate obtained in the step 3) into the step 2), and the formula and other steps are the same as those in the example 1.
Comparative example 3
The formula is the same as that of example 1, a traditional wet granulation mode is adopted, all the components are dry-mixed and then added into the slurry of corn starch and mannitol, then a boiling dryer is adopted, the air inlet temperature is 85 ℃, and the product temperature is 45 ℃ and the moisture content is controlled to be lower than 3.0%. And then granulating and tabletting.
Examples of the experiments
The above examples 1 to 3 and comparative examples 1 to 3 were subjected to a dust test for collecting gas during the total mixing and a disintegration rate test for measuring the content of PM 2.5 and PM 10, and a relatively low one was considered to exert an inhibiting effect on dust. The disintegration speed test comprises an oral disintegration test and an external disintegration test, a plurality of healthy volunteers or patients with normal oral functions are selected in the oral disintegration test, a ZBS intelligent disintegration instrument tester is adopted for external disintegration, and the disintegration speed is compared through the complete disintegration time.
The results are shown in Table 1.
Table 1:
as can be seen from Table 1, the use of the solutions of examples 1-3 has a significant effect on the suppression of dust and the increase in the disintegration rate. Comparative example 1 does not use mannitol, comparative example 2 dry-mixes the disintegrant directly and comparative example 3 shows a decrease in disintegration rate and dust suppression rate, probably because mannitol, calcium hydrogen phosphate and corn starch produce a synergistic effect of binding force when forming a coating system, which can prevent disintegration in a dry environment, but can accelerate the disintegration rate in water.
Finally, although the present invention has been described in detail by way of general description and specific examples, the above examples are only intended to illustrate the technical solutions of the present invention, but not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (9)
1. The preparation method of the estazolam tablet is characterized by comprising the following steps:
s1, preparing estazolam, corn starch and low-substituted hydroxypropyl cellulose according to a prescription, mixing, and sieving by a 100-mesh sieve for later use;
s2, spraying water and balling the sieved materials in a balling machine in the step S1, and sieving by a 30-mesh sieve;
s3, adding calcium hydrophosphate into the pelletizing machine, and spraying the sieved substances obtained in the step S2 again to form pellets until the particle size reaches 1.6-2mm; spraying slurry containing corn starch and mannitol;
and S4, drying the agglomerated material in the step S3, adding magnesium stearate to complete granules to obtain granules with the diameter of 1.5mm, and tabletting to obtain the estazolam tablets after total mixing.
2. The preparation method according to claim 1, characterized in that the raw material components comprise, by weight, 1 part of estazolam, 5-10 parts of corn starch, 5-12 parts of low-substituted hydroxypropylcellulose, 40-55 parts of calcium hydrogen phosphate and 3-6 parts of magnesium stearate.
3. A preparation method according to claim 1, wherein the raw material components comprise, by mass, 1 part of estazolam, 6 parts of corn starch, 10 parts of low-substituted hydroxypropylcellulose, 52 parts of calcium hydrophosphate and 4 parts of magnesium stearate.
4. The method of claim 1, wherein the amount of water added for spraying in step S2 is 3 to 10wt%, the rotation speed of the ball mill is 1 to 5 rpm, 5 to 15 sec/min, and the frequency of spraying is 1 to 2 rpm.
5. The method according to claim 1, wherein the speed of the ball machine in step S3 is 1 to 5 rpm/sec, 5 to 15 sec/min, and the frequency of spraying is 1 rpm/1 min.
6. The method of claim 1, wherein the spray material in step S4 is a slurry containing 5wt% of corn starch and 5wt% of mannitol, and the spray amount is 30wt% of the powder obtained after adding calcium hydrogen phosphate.
7. The method according to claim 1, wherein the drying step S4 is performed by microwave dehydration at a temperature of 100-150 ℃ for 30-120 minutes.
8. The preparation process according to claim 5, wherein the microwave dehydration process controls the temperature rise rate to be 3-10 ℃/min.
9. The process of claim 1 to obtain estazolam tablets wherein the disintegration time in the oral cavity is less than 40 seconds.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211626179.2A CN115770227A (en) | 2022-12-15 | 2022-12-15 | Estazolam tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211626179.2A CN115770227A (en) | 2022-12-15 | 2022-12-15 | Estazolam tablet and preparation method thereof |
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| CN115770227A true CN115770227A (en) | 2023-03-10 |
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| CN202211626179.2A Pending CN115770227A (en) | 2022-12-15 | 2022-12-15 | Estazolam tablet and preparation method thereof |
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