A pharmaceutical composition of donepezil hydrochloride

Abstract

The application provides a donepezil hydrochloride orally disintegrating tablet pharmaceutical composition and a preparation method thereof, and belongs to the technical field of medicines.The technical scheme of the application is as follows: a donepezil hydrochloride composition, characterized in that the composition contains donepezil hydrochloride 6.25%, porous silicon carrier 2-6%, fumaric acid 1-3%, sodium carboxymethyl cellulose 0.7%, mannitol 53.05-79.05%, soluble starch 10-30%, and sodium stearyl fumarate 1%.The application provides a donepezil hydrochloride orally disintegrating tablet prescription process which is fast in disintegration, good in taste, high in safety, and feasible in large-scale production, is more suitable for the oral cavity characteristics of the elderly, and improves the compliance of patients in taking medicine.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to donepezil hydrochloride orally disintegrating tablets and their preparation method. Background Technology

[0002] Alzheimer's disease (AD), also known as senile dementia, is a degenerative disease of the central nervous system. It has an insidious onset and a chronic, progressive course, and is the most common type of dementia in the elderly. Its main manifestations include progressive memory impairment, cognitive dysfunction, personality changes, and language disorders, severely affecting social, occupational, and daily life functions. Clinical treatment still faces significant challenges. With the increasingly serious aging of my country's population, Alzheimer's disease has become a serious public health problem, placing a heavy burden on society and families.

[0003] Donepezil hydrochloride is a second-generation cholinesterase inhibitor (AChEI) for the treatment of Alzheimer's disease. It has a high selectivity for neuronal acetylcholinesterase. It increases the content of acetylcholine in the animal brain by inhibiting acetylcholinesterase, thereby increasing the content of acetylcholine in the synaptic spaces that are directly involved in nerve transmission, thus producing a therapeutic effect. It can improve learning disabilities. It has almost no inhibitory effect on acetylcholinesterase in the heart and intestines. Therefore, it has the characteristics of high selectivity, long duration of action, few side effects, and no liver toxicity, making it an ideal drug for the treatment of early-onset Alzheimer's disease.

[0004] Orally disintegrating tablets are tablets that rapidly disintegrate or dissolve in saliva in the mouth. They are often used for patients who have difficulty swallowing or are uncooperative with taking medication, such as the elderly, children, and patients in special circumstances. Compared with ordinary preparations, they have advantages such as convenient administration, rapid absorption, high bioavailability, and less irritation to the digestive tract mucosa, and have received widespread attention.

[0005] The original formulation of donepezil hydrochloride orally disintegrating tablets used a wet granulation molding method, in which carrageenan and mannitol were wet granulated, dried, and then wet granulated again. The wet soft material was then molded and dried. The resulting product has a good taste and disintegrates through the dissolution of mannitol. However, this technology has a complex preparation process and requires high-end equipment, making it difficult to industrialize in China at present.

[0006] Chinese patent CN114748435B discloses a donepezil hydrochloride orally disintegrating tablet, comprising the following raw materials in parts by weight: 5 parts donepezil hydrochloride, 100-130 parts mannitol, 30-50 parts microcrystalline cellulose, 4-7 parts crospovidone, 1-3 parts silica, and 1-2.5 parts magnesium stearate. This formulation uses a relatively large amount of microcrystalline cellulose and crospovidone. Although these can improve disintegration in vitro, the addition of a large amount of disintegrant will rapidly absorb a large amount of water in the oral cavity. Since elderly people have reduced saliva secretion, this affects the disintegration and taste of the donepezil hydrochloride orally disintegrating tablet in the oral cavity, resulting in poor medication compliance in Alzheimer's patients.

[0007] Chinese patent CN107789328B discloses a donepezil hydrochloride orally disintegrating tablet and its preparation method. In order to achieve the effect of masking the taste, the patent adds a mixture of aspartame and citric acid or sodium citrate as a masking agent in the prescription. Aspartame has been listed by the World Health Organization as a possible carcinogen, and long-term use may pose risks.

[0008] Chinese patent CN102038653A discloses donepezil hydrochloride orally disintegrating tablets and their preparation method. To address the disintegration time issue, this patent incorporates both a disintegrant and an effervescent agent. While this improves disintegration efficiency, the disintegration time still exceeds 30 seconds, with some formulations requiring up to 50 seconds to disintegrate.

[0009] Therefore, developing donepezil hydrochloride orally disintegrating tablets that are suitable for the oral characteristics of the elderly, disintegrate rapidly, have a good taste, are highly safe, and are feasible for large-scale production is of great significance for fully leveraging the dosage form advantages of orally disintegrating tablets, improving patient compliance, and enabling the drug to serve more patients. Summary of the Invention

[0010] Purpose of the invention: To provide a donepezil hydrochloride pharmaceutical composition that can achieve rapid disintegration with only a small amount of water, has a good taste, high safety, and good stability.

[0011] The applicant discovered that dissolving donepezil hydrochloride in water, adding a porous silica carrier (Parteck® SLC), and then ultrasonically vibrating to form a suspension, followed by adding sodium carboxymethyl cellulose and fumaric acid to the suspension and stirring to dissolve them as a binder, then spraying the binder into a material containing mannitol and soluble starch for granulation, drying, adding a lubricant, and tableting, can significantly promote the disintegration of donepezil hydrochloride tablets in a low-water environment, and the tablets have a sweet taste without the need for other flavor masking agents or taste-correcting agents; the fluidized bed granulation process used is suitable for industrial production.

[0012] Artificial saliva tests simulating an oral environment in vitro confirmed that the addition of porous silica carrier and fumaric acid can significantly accelerate the disintegration rate of tablets; taste tests confirmed that the addition of porous silica carrier, fumaric acid, and soluble starch can significantly improve the taste; and accelerated stability tests confirmed that the addition of fumaric acid can significantly improve the stability of the drug.

[0013] The underlying mechanism is likely as follows: The porous silica carrier, acting as an adsorbent, possesses a loose, porous structure that allows donepezil hydrochloride to penetrate the pores, masking the drug's unpleasant odor and significantly improving its taste. Furthermore, the porous silica carrier's excellent hydrophilicity allows water to rapidly enter the tablet, promoting disintegration in the oral cavity. The soluble starch in the formulation reacts with salivary amylase in the mouth to produce sweet maltose, further improving the taste. No additional disintegrants are added to the formulation, eliminating the need for large amounts of water absorption for complete tablet disintegration. Fumaric acid, a weak acid, maintains the slightly acidic environment of the tablet, contrasting with the alkaline environment of the oral cavity, thus improving the stability of donepezil hydrochloride while also promoting tablet disintegration.

[0014] The technical solution of the present invention is: a donepezil hydrochloride composition containing 6.25% donepezil hydrochloride, 2-6% porous silica support, 1-3% fumaric acid, 0.7% sodium carboxymethyl cellulose, 53.05-79.05% mannitol, 10-30% soluble starch, and 1% sodium stearate fumarate.

[0015] The porous silicon carrier used in this invention is provided by Merck and is marketed under the trade name Parteck® SLC.

[0016] Purified water is used as a solvent in this invention. It is removed during the process and is not included in the composition percentage.

[0017] Preferably, the donepezil hydrochloride composition of the present invention contains 6.25% donepezil hydrochloride, 3-5% porous silica carrier, 2% fumaric acid, 0.7% sodium carboxymethyl cellulose, 65.05-67.05% mannitol, 20% soluble starch, and 1% sodium stearate fumarate.

[0018] Preferably, the donepezil hydrochloride composition of the present invention contains 6.25% donepezil hydrochloride, 4% porous silica carrier, 2% fumaric acid, 0.7% sodium carboxymethyl cellulose, 66.05% mannitol, 20% soluble starch, and 1% sodium stearate fumarate.

[0019] The preparation method of the donepezil hydrochloride composition of the present invention includes the following steps:

[0020] Step 1: Dissolve donepezil hydrochloride in purified water, add porous silica support, and sonicate for 20 minutes to form a suspension;

[0021] Step 2: Add sodium carboxymethyl cellulose and fumaric acid to the above suspension and stir to dissolve, as a binder;

[0022] Step 3: Add mannitol and soluble starch to a fluidized bed granulator (manufacturer: Chongqing Yingge, model: WBF-2G), set the inlet air temperature to 55℃, air volume to 40m³ / h, atomization pressure to 1.2MPa, and liquid feed rate to 10rpm. Spray the binder from step 2 into the fluidized bed granulator to obtain granules with a moisture content ≤1.0%.

[0023] Step 4: Granulate the particles using a 1.0mm mesh screen;

[0024] Step 5: Add sodium stearate fumarate to the granulated granules and mix thoroughly using a three-dimensional motion mixer;

[0025] Step 6: Compress the granules into tablets using a 7.5mm shallow concave die, with a tablet hardness of 40-60N. Detailed Implementation

[0026] Example

[0027]

[0028] Prepare 1000 tablets according to the preparation method described in the technical solution.

[0029] Example 2

[0030]

[0031] Prepare 1000 tablets according to the preparation method described in the technical solution.

[0032] Example 3

[0033]

[0034] Prepare 1000 tablets according to the preparation method described in the technical solution.

[0035] Example 4

[0036]

[0037] Prepare 1000 tablets according to the preparation method described in the technical solution.

[0038] Comparative Example 1: The formulation contained no porous silicon carrier.

[0039]

[0040] Prepare 1000 tablets according to the preparation method described below.

[0041] Step 1: Dissolve donepezil hydrochloride in purified water to form a solution;

[0042] Step 2: Add sodium carboxymethyl cellulose and fumaric acid to the above solution and stir to dissolve, as a binder;

[0043] Step 3: Add mannitol and soluble starch to a fluidized bed granulator (manufacturer: Chongqing Yingge, model: WBF-2G), set the inlet air temperature to 55℃, air volume to 40m³ / h, atomization pressure to 1.2MPa, and liquid feed rate to 10rpm. Spray the binder from step 2 into the fluidized bed granulator to obtain granules with a moisture content ≤1.0%.

[0044] Step 4: Granulate the particles using a 1.0mm mesh screen;

[0045] Step 5: Add sodium stearate fumarate to the granulated granules and mix thoroughly using a three-dimensional motion mixer;

[0046] Step 6: Compress the granules into tablets using a 7.5mm shallow concave die, with a tablet hardness of 40-60N.

[0047] Comparative Example 2: The prescription did not contain fumaric acid.

[0048]

[0049] Prepare 1000 tablets according to the preparation method described below.

[0050] Step 1: Dissolve donepezil hydrochloride in purified water, add porous silica support, and sonicate for 20 minutes to form a suspension;

[0051] Step 2: Add sodium carboxymethyl cellulose to the above suspension and stir to dissolve, as a binder;

[0052] Step 3: Add mannitol and soluble starch to a fluidized bed granulator (manufacturer: Chongqing Yingge, model: WBF-2G), set the inlet air temperature to 55℃, air volume to 40m³ / h, atomization pressure to 1.2MPa, and liquid feed rate to 10rpm. Spray the binder from step 2 into the fluidized bed granulator to obtain granules with a moisture content ≤1.0%.

[0053] Step 4: Granulate the particles using a 1.0mm mesh screen;

[0054] Step 5: Add sodium stearate fumarate to the granulated granules and mix thoroughly using a three-dimensional motion mixer;

[0055] Step 6: Compress the granules into tablets using a 7.5mm shallow concave die, with a tablet hardness of 40-60N.

[0056] Comparative Example 3: The prescription contained no soluble starch.

[0057]

[0058] Prepare 1000 tablets according to the preparation method described below.

[0059] Step 1: Dissolve donepezil hydrochloride in purified water, add porous silica support, and sonicate for 20 minutes to form a suspension;

[0060] Step 2: Add sodium carboxymethyl cellulose and fumaric acid to the above suspension and stir to dissolve, as a binder;

[0061] Step 3: Add mannitol to the fluidized bed granulator (manufacturer: Chongqing Yingge, model: WBF-2G), set the inlet air temperature to 55℃, air volume to 40m³ / h, atomization pressure to 1.2MPa, and liquid feed rate to 10rpm. Spray the binder from step 2 into the fluidized bed granulator to obtain granules with a moisture content ≤1.0%.

[0062] Step 4: Granulate the particles using a 1.0mm mesh screen;

[0063] Step 5: Add sodium stearate fumarate to the granulated granules and mix thoroughly using a three-dimensional motion mixer;

[0064] Step 6: Compress the granules into tablets using a 7.5mm shallow concave die, with a tablet hardness of 40-60N.

[0065] Comparative Example 4:

[0066]

[0067] Prepare 1000 tablets according to the preparation method described in the technical solution.

[0068] Comparative Example 5:

[0069]

[0070] Prepare 1000 tablets according to the preparation method described in the technical solution.

[0071] Experimental Example 1. Disintegration Time Determination

[0072] Using an orally disintegrating tablet disintegration tester, the time it took for the products of Examples 1-4 and Comparative Examples 1-5 to completely pass through the sieve was measured at a water temperature of 37°C. The results are as follows.

[0073] Table 1. Results of disintegration time test for products from Examples 1-4 and Comparative Examples 1-5

[0074]

[0075] Table 1 shows that the donepezil hydrochloride orally disintegrating tablets of Examples 1-4 and Comparative Examples 3 and 5 prepared using the technical solution of this invention all disintegrated rapidly within 30 seconds, indicating that the addition of porous silica carrier and fumaric acid in this technical solution can significantly promote the disintegration of tablets and achieve the purpose of rapid disintegration in the oral cavity.

[0076] Experimental Example 2. Simulated Oral Environment Disintegration Test

[0077] Take one sample and place it in a petri dish (5 cm in diameter). Use a pipette to add 2 ml of artificial saliva to the petri dish. Incubate in a 37°C water bath for 3 minutes. Observe the state of the disintegrated clumps and whether there is a hard core. The samples of Examples 1-4 and Comparative Examples 1-5 were tested according to this method. The results are as follows:

[0078] Table 2 Results of simulated oral environment disintegration tests in Examples 1-4 and Comparative Examples 1-5

[0079]

[0080] Table 2 data explanation: The donepezil hydrochloride orally disintegrating tablets of Examples 1-4 and Comparative Example 5 prepared using the technical solution of this invention can completely disintegrate in a short time under the condition of a small amount of artificial saliva, and the clumps have no hard core. This indicates that the addition of 2-6% porous silica carrier, 1-3% fumaric acid, and 10-20% soluble starch in this technical solution can significantly accelerate the disintegration speed of the tablets in the oral cavity, which is more suitable for the oral characteristics of the elderly.

[0081] Experimental Example 3. Taste Test

[0082] Take one sample tablet, place it in your mouth, taste it, spit it out, and rinse your mouth. Record the taste of Examples 1-4 and Comparative Examples 1-5 according to this method. The results are as follows:

[0083] Table 3. Taste test results of products from Examples 1-4 and Comparative Examples 1-5

[0084]

[0085] Table 3 data explanation: The donepezil hydrochloride orally disintegrating tablets of Examples 1-4 prepared using the technical solution of this invention have a sweet taste, disintegrate rapidly, and have no gritty feeling. The taste of the sample of Comparative Example 5 has a sour taste and a gritty feeling, which may be related to the large amount of fumaric acid and porous silica added. This indicates that the addition of 2-6% porous silica carrier, 1-3% fumaric acid, and 10-20% soluble starch in this technical solution can significantly improve the taste of donepezil hydrochloride orally disintegrating tablets and improve patient medication compliance.

[0086] Experimental Example 4. Stability Study

[0087] The products of Examples 1-4 and Comparative Examples 1-5 were packaged in aluminum-plastic composites, with 10 aluminum-plastic composite plates per sample, and 12 plates per plate. The samples were then repackaged. They were placed in an accelerated stability testing chamber under the conditions of 40°C and 75% humidity. Samples were taken at the end of months 1, 2, 3, and 6, with 2 plates taken at each time point. Related substances were measured, and the results are shown in Table 4.

[0088] Table 4. Results of related substance determination in stability tests of products from Examples 1-4 and Comparative Examples 1-5.

[0089]

[0090] Table 4 data explanation: In the accelerated stability test, the growth rate of related substances in the products of Examples 1-4 and Comparative Examples 1, 3, and 5 prepared using the technical solution of this invention was significantly slower than that in Comparative Examples 2 and 4. That is, the stability of the products of Examples 1-4 and Comparative Examples 1, 3, and 5 was significantly better than that of Comparative Examples 2 and 4. This indicates that the addition of fumaric acid in the dosage range of 1-3% in this technical solution can significantly improve the stability of donepezil hydrochloride orally disintegrating tablets and reduce the adverse effects of impurities generated by drug degradation on the health of patients.

Claims

1. A donepezil hydrochloride composition, wherein the composition is an orally disintegrating tablet, characterized in that, The composition contains 6.25% donepezil hydrochloride, 2-6% porous silica support, 1-3% fumaric acid, 0.7% sodium carboxymethyl cellulose, 53.05-79.05% mannitol, 10-30% soluble starch, and 1% sodium stearate fumarate. The preparation method of the composition is as follows: Step 1: Dissolve donepezil hydrochloride in purified water, add porous silica support, and then sonicate to form a suspension; Step 2: Add sodium carboxymethyl cellulose and fumaric acid to the above suspension and stir to dissolve, as a binder; Step 3: Add mannitol and soluble starch to the fluidized bed granulator, and spray the binder from step 2 into the fluidized bed granulator to obtain granules; Step 4: Granulation using a granule screen; Step 5: Add sodium stearate fumarate to the granulated granules and mix well; Step 6: Compress the granules into tablets.

2. The donepezil hydrochloride composition according to claim 1, characterized in that, It contains 6.25% donepezil hydrochloride, 3-5% porous silica carrier, 2% fumaric acid, 0.7% sodium carboxymethyl cellulose, 65.05-67.05% mannitol, 20% soluble starch, and 1% sodium stearate fumarate.

3. The donepezil hydrochloride composition according to claim 1, characterized in that, It contains 6.25% donepezil hydrochloride, 4% porous silica carrier, 2% fumaric acid, 0.7% sodium carboxymethyl cellulose, 66.05% mannitol, 20% soluble starch, and 1% sodium stearate fumarate.

4. The donepezil hydrochloride composition according to claim 1, characterized in that, The moisture content of the particles in the third step is ≤1.0%.

5. The donepezil hydrochloride composition according to claim 1, characterized in that, The fourth step involves granulating the particles using a 1.0mm mesh screen.

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