CN114748435B

CN114748435B - Donepezil hydrochloride orally disintegrating tablet and preparation method thereof

Info

Publication number: CN114748435B
Application number: CN202210548214.7A
Authority: CN
Inventors: 程亮; 姚欣; 杨强; 肖华冀; 蒲虹橙; 武刚; 李�杰
Original assignee: Sichuan Shenghe Pharmaceutical Co Ltd
Current assignee: Sichuan Shenghe Pharmaceutical Co Ltd
Priority date: 2022-05-18
Filing date: 2022-05-18
Publication date: 2023-06-23
Anticipated expiration: 2042-05-18
Also published as: CN114748435A

Abstract

The invention discloses a donepezil hydrochloride orally disintegrating tablet which comprises the following raw materials in parts by weight: 5 parts of donepezil hydrochloride, 100-130 parts of mannitol, 30-50 parts of microcrystalline cellulose, 4-7 parts of crospovidone, 1-3 parts of silicon dioxide and 1-2.5 parts of magnesium stearate. The invention also discloses a preparation method of the donepezil hydrochloride orally disintegrating tablet, which comprises the following steps: (1) weighing the raw materials; (2) sieving respectively for standby; (3) Mixing donepezil hydrochloride, mannitol, microcrystalline cellulose and crospovidone for four times; (4) Mixing the fourth mixed material, silicon dioxide and magnesium stearate three times; (5) selecting a 8mm shallow arc stamping die for stamping according to the stamping die specification; and (6) controlling the heat sealing temperature, and packaging. Compared with a reference preparation, the preparation process of the invention is simpler and more feasible, and is stable and controllable.

Description

Donepezil hydrochloride orally disintegrating tablet and preparation method thereof

Technical Field

The invention relates to the technical field of medicine preparation, in particular to a donepezil hydrochloride orally disintegrating tablet and a preparation method thereof.

Background

Donepezil hydrochloride (Donepezil hydrochloride, i) is a second generation reversible acetylcholinesterase inhibitor (AchEI) developed by japan kava in the late eighties, and increases the concentration of acetylcholine, an important neurotransmitter, mainly by specifically inhibiting the activity of acetylcholinesterase in the brain. Can be used for treating mild, moderate and severe Alzheimer's Disease (AD), delaying memory decline of AD patients, improving cognitive function, and improving life self-care ability of patients.

Donepezil hydrochloride film coated tablets (trade name: aricept) were approved by the FDA in the United states at month 11 in 1996, and were first marketed in the United states at 1 in 1997 in specifications of 3mg, 5mg, 10mg; donepezil hydrochloride orally disintegrating tablets were first marketed in japan in 6 months 2004 and in the united states in 10 months 2004, with both 5mg and 10mg specifications.

The reference preparation of the donepezil hydrochloride orally disintegrating tablet is prepared by a wet granulation tabletting method. In order to ensure that the medicine is uniformly distributed in the bitter masking agent carrageenan, the main medicine, the carrageenan and part of excipient (D-mannitol) are uniformly mixed, then polyvinyl alcohol solution is used for preparing medicine-containing particles, and the medicine-containing particles are uniformly mixed with the auxiliary materials such as D-mannitol and the like for tabletting after drying/granulating. Reference preparation donepezil hydrochloride orally disintegrating tablet

D) Prescriptions in Japanese specification: each tablet contains donepezil hydrochloride with the specification of 3mg, 5mg and 10mg, and the weight of each tablet is 168 mg/tablet. The inactive ingredients are carrageenan, mannitol, silicon dioxide, polyvinyl alcohol solution and purified water.

In European patent (EP 2 826 465 A1) donepezil hydrochloride orally disintegrating tablets are mainly prepared by wet granulation, drying and tabletting. Key parameters: the drying temperature is 60-70 ℃, and the hardness of the tablet is controlled between 20N and 30N/mm ² The disintegration time is not more than 60 seconds, preferably not more than 30 seconds.

In European patent EP1513528B1, the preparation of the conventional donepezil hydrochloride tablet mainly adopts wet granulation, drying and tabletting. The key steps are as follows: 10g of donepezil hydrochloride was dissolved in 120mL of purified water, and 2mL of concentrated hydrochloric acid was added to prepare a solution, which was wet granulated by a fluidized bed, and the raw material solution was sprayed into a part of the filler and the disintegrant.

Disclosure of Invention

In view of the above, the present invention aims to provide a donepezil hydrochloride orally disintegrating tablet and a preparation method thereof, which solve the defects in the prior art.

In order to achieve the above purpose, the present invention adopts the following technical scheme:

the donepezil hydrochloride orally disintegrating tablet comprises the following raw materials in parts by weight: 5 parts of donepezil hydrochloride, 100-130 parts of mannitol, 30-50 parts of microcrystalline cellulose, 4-7 parts of crospovidone, 1-3 parts of silicon dioxide and 1-2.5 parts of magnesium stearate;

preferably, it is: 5 parts of donepezil hydrochloride, 110-120 parts of mannitol, 35-45 parts of microcrystalline cellulose, 4.5-5.5 parts of crospovidone, 1.5-2.5 parts of silicon dioxide and 1-2 parts of magnesium stearate;

in the invention, the following components are added:

mannitol has no hygroscopicity, quick drying, good chemical stability, good taste, good granulation, and the like, and can serve as a filler and simultaneously have the function of flavoring.

Microcrystalline cellulose has excellent flowability and is a relatively non-toxic and non-irritating substance as a filler; and is not absorbed after oral administration, and has almost no potential toxicity.

The crospovidone is used as a disintegrating agent, and the tablet obtained after the tablet is pressed into a tablet has high hardness, short disintegration time and high dissolution rate; and the stability is strong, and the time does not change.

The silicon dioxide is mainly used as an anti-adhesive agent and a glidant, can greatly improve the fluidity of particles, increase the bulk density, increase the hardness of the prepared tablet, shorten the disintegration time and increase the dissolution speed of the medicine.

Magnesium stearate is mainly used as a lubricant, an anti-sticking agent, and a glidant.

The preparation method of the donepezil hydrochloride orally disintegrating tablet specifically comprises the following steps:

(1) Weighing the raw materials according to the weight parts of the donepezil hydrochloride orally disintegrating tablet;

(2) Sieving donepezil hydrochloride, mannitol, microcrystalline cellulose, crospovidone, silicon dioxide and magnesium stearate respectively for standby;

(3) Mixing donepezil hydrochloride, mannitol, microcrystalline cellulose and crospovidone for four times;

mixing for the first time: adding donepezil hydrochloride and crospovidone into a three-dimensional motion mixer to be uniformly mixed to obtain a first mixed material;

mixing for the second time: adding microcrystalline cellulose into a three-dimensional motion mixer, and uniformly mixing the microcrystalline cellulose with the first mixed material to obtain a second mixed material;

third mixing: adding mannitol which is equal to the second mixed material into the three-dimensional motion mixer, and uniformly mixing the mannitol with the second mixed material to obtain a third mixed material;

fourth mixing: adding all the rest mannitol into a three-dimensional motion mixer, and uniformly mixing with the third mixed material to obtain a fourth mixed material;

(4) Mixing the fourth mixed material, silicon dioxide and magnesium stearate three times;

fifth mixing: adding silicon dioxide and magnesium stearate into a three-dimensional motion mixer, and uniformly mixing to obtain a fifth mixed material;

sixth mixing: adding the fourth mixed material which is equal to the fifth mixed material into the three-dimensional motion mixer, and uniformly mixing with the fifth mixed material to obtain a sixth mixed material;

seventh mixing: adding all the rest fourth mixed materials into a three-dimensional motion mixer to be uniformly mixed with the sixth mixed materials, so as to obtain a seventh mixed material;

(5) Tabletting: the specification of the stamping die is that an 8mm shallow arc stamping die is selected for tabletting;

(6) And (3) packaging: and controlling the heat sealing temperature, and packaging.

Further, in the step (2), the specific sieving operation is as follows: donepezil hydrochloride, mannitol and microcrystalline cellulose were sieved through a 50 mesh sieve, and crospovidone, silicon dioxide and magnesium stearate were sieved through an 80 mesh sieve. Still further, the apparatus for sieving is a vortex oscillating screen.

The technical scheme has the advantages that the method is determined according to the process verification results of commercial mass production after small-scale test, pilot-scale test and equipment change according to the influence of the particle size of the materials on the mixing uniformity and the appearance of the finished product, and meets the operability of mass production.

Further, in the step (3), the frequency of the first mixing is 40-60Hz, and the time is 20min; the frequency of the second mixing is 40-60Hz, and the time is 20min; the frequency of the third mixing is 40-60Hz, and the time is 10min; the fourth mixing frequency is 40-60Hz, and the time is 10min.

The technical scheme has the advantages that the technical scheme is determined according to the technological parameters of small-scale test raw and auxiliary material treatment and the technological verification results of commercial mass production after pilot scale test and equipment change, and accords with the operability of mass production.

Further, in the step (4), the frequency of the fifth mixing is 40-60Hz, and the time is 10min; the frequency of the sixth mixing is 40-60Hz, and the time is 10min; the seventh mixing frequency is 40-60Hz, and the time is 50min. Still further, the above-described mixing apparatus is a three-dimensional motion mixer.

The technical scheme has the advantages that the technical scheme is determined according to the technological parameter research of the pilot scale total mixing and the technological verification result after the pilot scale equipment and the commercial batch equipment are changed, and meets the operability of mass production.

Further, in the step (5), the tabletting equipment is a high-speed rotary tablet press.

The technical scheme has the advantages that the technical scheme is determined according to the process parameter research of the small test piece and the process verification result after the pilot test and commercial batch equipment are changed, and meets the operability of mass production.

Further, in the step (6), the packaging device is an aluminum plastic blister packaging machine.

The technical scheme has the beneficial effects that the condition of pilot scale test and commercial batch equipment is combined, and the method accords with the operability of mass production.

Compared with the prior art, the invention has the following beneficial effects:

the invention refers to the original drug-grinding instruction book, japanese standard commodity classification number 87119, revised 7 (29 th edition) in 2015, raw and auxiliary material compatibility test conditions, related production experience and the like, determines the types and dosage ranges of auxiliary materials, adopts moisture, hardness, disintegration time limit, dissolution rate and dissolution curve as indexes, adopts a single factor experiment to compare and screen the types and dosage of filling agent, disintegrating agent and lubricant in a prescription, and finally determines that the preparation process of the donepezil hydrochloride orally disintegrating tablet adopts a powder direct tabletting method.

Sieving raw materials and auxiliary materials (donepezil hydrochloride, mannitol and microcrystalline cellulose are sieved by a vortex oscillating sieve with a mesh size of 50, cross-linked povidone, magnesium stearate and silicon dioxide are sieved by a vortex oscillating sieve with a mesh size of 80 for standby), then uniformly mixing part of raw materials and auxiliary materials (donepezil hydrochloride, cross-linked povidone, microcrystalline cellulose and mannitol) by an equivalent increasing method, finally adding silicon dioxide and magnesium stearate for total mixing, and tabletting and packaging after intermediate control detection is qualified.

Compared with a reference preparation, the preparation process of the invention is simpler and more feasible, and is stable and controllable.

Detailed Description

The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1

The donepezil hydrochloride orally disintegrating tablet comprises the following raw materials in parts by weight: donepezil hydrochloride 0.5kg, mannitol 11kg, microcrystalline cellulose 4.5kg, crospovidone 0.5kg, silicon dioxide 0.2kg and magnesium stearate 0.2kg;

(1) Weighing the raw materials according to the weight;

(2) Adding donepezil hydrochloride, mannitol and microcrystalline cellulose into a vortex oscillating screen to pass through 50 meshes, and passing the cross-linked povidone, silicon dioxide and magnesium stearate through 80 meshes for later use;

mixing for the first time: adding donepezil hydrochloride and crospovidone into a three-dimensional motion mixer, and uniformly mixing at a frequency of 55Hz for 20min to obtain a first mixed material;

mixing for the second time: adding microcrystalline cellulose into a three-dimensional motion mixer, and uniformly mixing with the first mixed material, wherein the mixing frequency is 50Hz, and the mixing time is 20min, so as to obtain a second mixed material;

third mixing: adding mannitol which is equal to the second mixed material into a three-dimensional motion mixer, uniformly mixing the mannitol with the second mixed material, wherein the mixing frequency is 55Hz, and the mixing time is 10min, so as to obtain a third mixed material;

fourth mixing: adding all the rest mannitol into a three-dimensional motion mixer, and uniformly mixing with the third mixed material, wherein the mixing frequency is 55Hz, and the mixing time is 10min, so as to obtain a fourth mixed material;

fifth mixing: adding silicon dioxide and magnesium stearate into a three-dimensional motion mixer, and uniformly mixing at a frequency of 55Hz for 10min to obtain a fifth mixed material;

sixth mixing: adding the fourth mixed material which is equal to the fifth mixed material into a three-dimensional motion mixer, and uniformly mixing with the fifth mixed material, wherein the mixing frequency is 55Hz, and the mixing time is 10min, so as to obtain a sixth mixed material;

seventh mixing: adding all the rest fourth mixed materials into a three-dimensional motion mixer to be uniformly mixed with the sixth mixed materials, wherein the mixing frequency is 55Hz, and the mixing time is 50min, so as to obtain a seventh mixed material;

(5) Tabletting: selecting a high-speed rotary tablet press, and selecting a 8mm shallow arc die for die specification to perform tablet pressing;

(6) And (3) packaging: and (5) selecting an aluminum-plastic blister packaging machine, controlling the heat sealing temperature, and packaging.

Performance testing

1. Prescription screening of reference formulations

Table 1 process screening against reference formulation recipe

Prescription 1, dissolving the main medicine in hydrochloric acid solution, mixing with carrageenan, granulating, drying at 60 ℃, granulating, mixing with mannitol uniformly, granulating with polyvinyl alcohol solution, drying at 60 ℃, granulating, mixing with silicon dioxide, and tabletting. Poor compressibility, sticking, degradation reaction of carrageenan after meeting acid, obvious peculiar smell, and need to adjust the adding sequence of the main medicine hydrochloric acid solution.

Prescription 2, the main medicine is dissolved in hydrochloric acid solution, and then mixed with mannitol for granulation is difficult, the material caking is serious, and the main medicine hydrochloric acid solution is adopted for granulation, so that the prescription is not suitable for the prescription.

Prescription 3, after the main medicine and mannitol are uniformly mixed, granulating by using 1% polyvinyl alcohol solution, drying, after granulating, uniformly mixing with carrageenan and silicon dioxide, tabletting, poor compressibility, tablet dispersion and astringent flushing.

Prescription 4, after the main medicine is uniformly mixed with mannitol and carrageenan, granulating by using 1% polyvinyl alcohol solution, drying, after granulating, uniformly mixing with silicon dioxide, tabletting, poor compressibility, tablet dispersion and astringent flushing. The recipe was modified as recipe 5, the lubricant magnesium stearate was added, and carrageenan was removed.

Prescription 5, the main medicine and mannitol are mixed uniformly, then are granulated by using 2% polyvinyl alcohol solution, dried, granulated, mixed uniformly with silicon dioxide, and then pressed into tablets, wherein the tablets have poor compressibility, and are scattered and flushable.

The above 5 prescriptions use adhesives with different concentrations and lubricant is added, so that sticky and astringent rushes occur, and the compressibility is poor.

2. Prescription screening with reference to original prescription, european patent prescription and reference prescription

TABLE 2 screening results for original prescriptions, european patent prescriptions, reference prescriptions

Prescription 1 and 2, adding microcrystalline cellulose, low-substituted hydroxypropyl cellulose and menthol, granulating with 5% povidone K30 ethanol solution, mixing with lubricant silicon dioxide, and tabletting. Prescription 1 has poor compressibility and astringency. After the sodium carboxymethyl starch serving as a disintegrating agent is added in the prescription 2, the compressibility is good, when the hardness is 3kg, the disintegration time limit is 50S, the hardness of a reference preparation is 5-6kg, the disintegration is about 30S, the difference is large, and the dosage of the adhesive needs to be adjusted. The disintegration time of the tablet is not significantly improved after the addition of the disintegrant.

The solution is as follows: the disintegrants were changed to crospovidone of formulations 5, 6 and the effect of the binder was investigated in comparison.

Prescription 3 and 4 refer to European patent prescription screening, have good compressibility, have large influence on the disintegration time limit due to hardness, and the addition of the disintegrant sodium carboxymethyl starch has no obvious improvement on the disintegration time limit.

The solution is as follows: the method combines the approved prescription production condition and the European patent prescription test result, uses the adhesive for granulating, can improve the material compressibility to a certain extent, but can obviously influence the tablet disintegration time limit, and adopts direct compression and wet granulation tabletting respectively when the prescriptions 5 and 6 replace the disintegrating agent to be the crosslinked povidone.

In the prescription 5, the cross-linked povidone of the disintegrating agent is added, the powder is adopted for direct compression, the small test compressibility is good, the indexes such as hardness and disintegration time limit are close to those of a reference preparation, small bumps appearing on the appearance of the tablet are CL-shaped cross-linked povidone with larger particle size used in experiments, and the later research can be improved by adjusting the model of auxiliary materials or adding the pretreatment procedure of the auxiliary materials.

Prescription 6, adding disintegrating agent crosslinked povidone, adopting wet granulation and tabletting, and having good compression resistance, lower hardness than reference, and prolonged disintegration time.

The above prescription screening can determine that the disintegrating agent is needed to be added into the prescription for crosslinking povidone. The preparation method comprises the steps of preparing the raw materials and the auxiliary materials in the prescription, uniformly mixing, directly carrying out powder direct compression, and ensuring that the quality indexes such as the compressibility is good, the hardness, the disintegration time limit, the dissolution curve and the like can be consistent with those of a reference preparation, and the preparation method is more suitable for the prescription than a wet granulation process, so that the process is determined as powder direct compression.

3. Screening of the amount of crospovidone

TABLE 3 screening results for amount of crospovidone

As the early-stage prescription research shows that the volume of the low-generation hydroxypropyl cellulose rapidly expands after absorbing water, the tablet disintegrates to form swelling type, the disintegration phenomenon of the tablet is greatly different from that of the reference erosion type, the disintegration time limit is obviously improved after the disintegrant crospovidone is added into the current prescription, and the low-generation hydroxypropyl cellulose is not added into the prescription as the disintegrant. Only the dosage of the disintegrant crospovidone is examined in the prescriptions 2, 3 and 4, and when the dosage is in the prescription 3, the appearance of the tablet is superior to the prescription 2, no obvious difference exists between the tablet and the prescription 4, and the disintegration time limit is close to that of a reference.

4. Microcrystalline cellulose dosage screening

TABLE 4 microcrystalline cellulose dosage screening study results

In the prescription 1, powder is directly pressed after the main medicine is added, and the main medicine has larger electrostatic adsorption, so that the compressibility of materials is reduced, phenomena of cracking, astringent flushing and the like occur, and the moisture of the powder is lower. The solution is as follows: proper amount of microcrystalline cellulose is added in the prescription, so that the compressibility of the material is improved.

The dosage of microcrystalline cellulose is screened by the prescription 2, 3 and 4, and the pressure test result shows that the prescription 4 has good compressibility, and the indexes such as hardness, disintegration time limit and the like are similar to those of the reference preparation.

5. Cross-linked povidone model screening

In table 4, prescriptions 5, 6, and 7 were used to solve the problem that small bumps were present on one surface, and the influence of different types of crosslinked povidone, pulverized and 80 mesh-sieved on the compressibility, content uniformity and appearance of tablets was examined. Experimental results show that XL-10 and CL-F types are not selected because of small particle size and are easy to delaminate when mixed with other auxiliary materials, and the uniformity of the materials is affected. The original CL type powder is crushed and sieved for use, the appearance of the tablet is obviously improved, and small bumps are few. The prescription is determined as CL type and is used after being crushed and sieved by a 80-mesh sieve.

6. Batch post-magnification prescription study

Table 5 results of batch post-magnification prescription study

Prescription 1 is verified after three determined batches are amplified in a small test, and the test finds that the sticking and astringent conditions occur when the batch is pressed to 2/3 of the batch, the sheet weight difference is large, and the flowability of the material is poor. The solution is to adjust the dosage of the lubricant silicon dioxide and screen out the proper prescription dosage.

Prescriptions 2, 3: the compressibility of the formulation and other evaluation criteria were examined when the amount of silica was increased to 2g/1000 tablets. The phenomenon of poor viscosity, astringency and fluidity can be effectively improved after the dosage is increased.

Prescription 4: the prescription is continuously amplified to 5000 pieces/batch, the laboratory pressure test is carried out, the whole batch has good compressibility, no sticking and flushing phenomenon occurs, and the other evaluation indexes all meet the requirements.

Prescriptions 5, 6: and (3) continuing two-batch amplification batch (5000 tablets/batch) verification, which is mainly used for examining the stability of a prescription and the process adaptability of tabletting. The three batches of prescriptions are confirmed and the batch is amplified to 5000 tablets for pressure test, the compressibility of materials, the appearance of tablets, the hardness of tablets and the like are all good, and the detection of the weight detection indexes (disintegration time limit, moisture, content uniformity and dissolution) meets the requirements.

7. Prescription determination

Table 6 recipe validation 3 Key index measurement results

	Prescription 1	Prescription 2	Prescription 3
				Tablet appearance	Qualified product	Qualified product	Qualified product
Tablet hardness (N)	4～5	2.8～3.1	3.4～3.6
				Disintegration time(s)	＜1min	＜1min	＜1min
Dissolution rate%	95.81	100.13	100.31
				Content%	96.81	98.12	98.88
Content uniformity (less than or equal to 15)	8.54	9.47	9.22

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. The preparation method of the donepezil hydrochloride orally disintegrating tablet specifically comprises the following steps:

(1) Weighing 0.5kg of donepezil hydrochloride, 11kg of mannitol, 4.5kg of microcrystalline cellulose, 0.5kg of crospovidone, 0.2kg of silicon dioxide and 0.2kg of magnesium stearate;