Donepezil and memantine compound sustained release preparation and preparation process thereof

Abstract

The invention discloses a donepezil and memantine compound sustained release preparation and a preparation process thereof, and belongs to the technical field of pharmaceutical preparations. The preparation consists of a donepezil hydrochloride quick-release layer and a memantine hydrochloride slow-release layer, wherein the quick-release layer comprises donepezil, starch, mannitol and the like, and realizes quick disintegration through granulation of a low-substituted hydroxypropyl cellulose aqueous solution; the slow-release layer comprises memantine, pinoresinol diglucoside, a polylactic acid-glycolic acid copolymer and chitosan, and the slow-release layer and the composite slow-release material have a synergistic effect through a low-temperature grinding technology, so that the degradation of the memantine is inhibited, and the sustained release of the memantine is controlled. The problem that an existing compound preparation is poor in stability is solved, and a safe and effective treatment choice which is taken once a day is provided for a patient suffering from the Alzheimer disease.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a donepezil-memantine compound sustained-release preparation and a preparation process thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive decline, behavioral disorders, and loss of daily living ability. With the intensification of global aging, the number of Alzheimer's patients continues to rise, and it has become a major public health issue. At present, clinical treatment is mainly aimed at delaying the progression of the disease. The main drugs include acetylcholinesterase inhibitors (such as donepezil) and NMDA receptor antagonists (such as memantine). However, the efficacy of a single drug is limited, and long-term use is prone to drug resistance. Combination therapy has gradually become the mainstream treatment option. Studies have shown that donepezil improves cognitive function by inhibiting acetylcholine degradation, while memantine reduces neuronal damage by regulating glutamatergic neurotransmission. The combination of the two can exert a synergistic effect and significantly improve the therapeutic effect (such as the ADAGIO trial). However, the existing combination therapy is mostly taken in divided doses of two drugs, resulting in poor patient compliance, large fluctuations in blood drug concentrations, and increased risks of side effects such as gastrointestinal reactions and dizziness.

[0004] In 2014, the U.S. FDA approved the memantine / donepezil compound sustained-release capsule (trade name Namzaric), which is administered once a day for moderate to severe AD patients. The Chinese patent with publication number CN101247795A discloses a compound composition of memantine sustained-release agent (22.5-57.5 mg) and donepezil (1-10 mg).

[0005] A Chinese patent with publication number CN 105816441 A discloses a memantine hydrochloride-donepezil compound preparation, which uses memantine hydrochloride and donepezil hydrochloride as active pharmaceutical ingredients, and co-coats the memantine hydrochloride and donepezil hydrochloride on micropills. The slow release of memantine hydrochloride and the rapid release of donepezil hydrochloride are controlled by multi-layer coating, and finally filled into capsules. The problem of uneven filling that may exist in capsules filled with mixed micropills and granules is avoided, and industrial production is easier to achieve. Lactose and other excipients that can undergo Maillard reaction with memantine hydrochloride are not present, thereby ensuring the stability of the preparation.

[0006] A Chinese patent with publication number CN 111939139 A discloses a memantine hydrochloride sustained-release and donepezil hydrochloride immediate-release capsule and a preparation method thereof. The memantine hydrochloride sustained-release and donepezil hydrochloride immediate-release capsules are composed of memantine hydrochloride sustained-release pellets and donepezil hydrochloride granules in a mass ratio of 1.25 to 2.5:1.

[0007] However, memantine hydrochloride is sensitive to high temperature, high humidity and light environment, and has a high risk of photolysis and oxidation. Therefore, it is necessary to develop a sustained-release compound preparation to ensure smooth drug release and reliable long-term storage through excipient optimization, process innovation and strict stability testing. Summary of the invention

[0008] To overcome the shortcomings of the prior art, the present invention aims to provide a donepezil-memantine compound sustained-release preparation and a preparation process thereof, and solve the problem of poor stability of memantine hydrochloride in the existing compound preparations through excipient optimization and process innovation, so as to achieve clinical needs of stable drug release, long-term storage stability and once-daily administration.

[0009] The donepezil-memantine compound sustained-release preparation consists of a donepezil hydrochloride immediate-release layer and a memantine hydrochloride sustained-release layer; calculated by weight ratio, the donepezil hydrochloride immediate-release layer consists of 5-15 parts of donepezil hydrochloride, 80-120 parts of starch, 20-40 parts of mannitol, 4-10 parts of sodium carboxymethyl starch, 2-5 parts of low-substituted hydroxypropyl cellulose, and 0.5-3 parts of lubricant; granulation is carried out through an aqueous solution of low-substituted hydroxypropyl cellulose to ensure rapid disintegration and release of donepezil. The memantine hydrochloride sustained-release layer is composed of 10-35 parts of memantine hydrochloride, 10-40 parts of microcrystalline cellulose, 80-120 parts of starch, 10-20 parts of dextrin, 5-15 parts of pinoresinol diglucoside, 10-25 parts of polylactic acid-glycolic acid copolymer PLGA (CAS No.: 34346-01-5, 50:50, purchased from MacLean Reagent), 10-25 parts of chitosan, and 0.5-3 parts of lubricant; pinoresinol diglucoside is combined with low-temperature grinding technology to inhibit the degradation of memantine, and polylactic acid-glycolic acid copolymer is compounded with chitosan to form a synergistic sustained-release system to control the sustained release of drugs.

[0010] The specific preparation process of the donepezil-memantine compound sustained-release preparation comprises the following steps:

[0011] (1) Donepezil hydrochloride and memantine hydrochloride are sieved through 80 mesh sieves respectively for later use;

[0012] (2) placing donepezil hydrochloride, starch, and mannitol in a high-speed shear granulator and mixing for 5 to 15 minutes; spraying a 2.0 to 6.5% by mass low-substituted hydroxypropyl cellulose aqueous solution to prepare a soft material, drying, granulating, adding sodium carboxymethyl starch and a lubricant, and mixing for 10 to 20 minutes to obtain a donepezil hydrochloride immediate-release layer;

[0013] (3) dissolving polylactic acid-glycolic acid copolymer and chitosan in a 5% to 10% by mass dichloromethane-0.2% to 2% acetic acid solution, and spray drying to prepare a composite sustained-release material; grinding pinoresinol diglucoside in a low-temperature 2-8° C. freeze grinder for 2-5 min (humidity 25% to 40%), and grinding with memantine hydrochloride at a low temperature of 2-8° C. for 5-15 min (humidity 25% to 40%) to obtain a memantine hydrochloride-pinoresinol diglucoside blend; mixing the memantine hydrochloride-pinoresinol diglucoside blend with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, adding ethanol, preparing a soft material, drying, granulating, adding a lubricant, and mixing for 10 to 20 min to obtain a memantine hydrochloride sustained-release layer;

[0014] (4) The immediate-release layer and the sustained-release layered tablets had a pre-compression pressure of 2 kN and a main compression pressure of 15 kN. The coating used a hydroxypropyl methylcellulose coating solution with a solid content of 8%, and the coating weight gain was 2-3%.

[0015] The preparation method of dichloromethane-acetic acid solution is to take the mass fraction 10% dichloromethane (DCM)-mass fraction 2% acetic acid (HAc) solution as an example: use a precision balance to weigh 100g dichloromethane (density 1.33g / mL, corresponding volume is about 75.2mL) and 20g acetic acid (density 1.05g / mL, corresponding volume is about 19.0mL). Transfer the weighed dichloromethane and acetic acid to a glass beaker. Slowly add 880g deionized water, stir with a magnetic stirrer (speed 300-500rpm) while adding, and ultrasonic treatment (5-10 minutes) to promote dispersion.

[0016] It should be noted that PLGA-chitosan can be dissolved in a 5% to 10% methylene chloride-0.2 to 2% acetic acid solution without precipitation, stratification or phase separation. The present invention uses GC to detect the residual methylene chloride in the nepezil-memantine compound sustained-release preparation, which meets the requirements of the Chinese Pharmacopoeia.

[0017] Compared with the prior art, the technical effects of the present invention are:

[0018] 1. Improved stability:

[0019] (1) The present invention introduces pinoresinol diglucoside as an antioxidant into a memantine preparation, and experiments have shown that it significantly inhibits the photolysis and oxidation of memantine.

[0020] (2) Low temperature grinding process: Low temperature (2-8°C) grinding is used to promote the compatibility of drugs and excipients, forming a stable blend, and cooperating with pinoresinol diglucoside to improve the stability of memantine hydrochloride.

[0021] 2. Optimization of sustained-release effect:

[0022] (1) PLGA-chitosan synergistic sustained release: The gel properties of PLGA and chitosan are combined to achieve a 22h dissolution rate ≥ 90%, with an ideal sustained release effect.

[0023] (2) Solvent system optimization: The composite sustained-release material was prepared using dichloromethane-acetic acid solution to ensure that the structure of the sustained-release layer was uniform and the dissolution curve was more consistent with the ideal sustained-release model. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 : Change trend of memantine hydrochloride content in nepezil-memantine compound sustained-release preparations.

[0025] Figure 2 : Dissolution curve of donepezil hydrochloride in donepezil-memantine combination sustained-release preparation. DETAILED DESCRIPTION

[0026] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0027] Example 1 Donepezil-Memantine Compound Sustained Release Preparation

[0028] formula:

[0029]

[0030] Preparation process:

[0031] (1) Donepezil hydrochloride and memantine hydrochloride are sieved through 80 mesh sieves respectively for later use;

[0032] (2) Preparation of donepezil hydrochloride immediate-release layer: donepezil hydrochloride, starch, and mannitol were placed in a high-speed shear granulator and mixed for 10 minutes; a 3.5% by mass low-substituted hydroxypropylcellulose aqueous solution was sprayed to prepare a soft material, which was dried and granulated; sodium carboxymethyl starch and a lubricant were added and mixed for 15 minutes to obtain a donepezil hydrochloride immediate-release layer;

[0033] (3) Preparation of memantine hydrochloride sustained-release layer: polylactic acid-glycolic acid copolymer and chitosan were dissolved in a 7% by mass dichloromethane-0.5% acetic acid solution, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside was ground at low temperature (5°C) for 3 minutes, and then ground with memantine hydrochloride at low temperature (5°C) for 10 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend was mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol was added to prepare a soft material, dried, granulated, a lubricant was added, and mixed for 15 minutes to obtain a memantine hydrochloride sustained-release layer;

[0034] (4) Double-layer tableting, pre-compression pressure 2kN, main compression pressure 15kN, to obtain double-layer tablets, and coating the double-layer tablets with a hydroxypropyl methylcellulose coating solution with a solid content of 8%, with a coating weight gain of 2.5%.

[0035] Example 2 Donepezil-Memantine Compound Sustained Release Preparation

[0036] formula:

[0037]

[0038] Preparation process:

[0039] (1) Donepezil hydrochloride and memantine hydrochloride are sieved through 80 mesh sieves respectively for later use;

[0040] (2) Preparation of donepezil hydrochloride immediate-release layer: donepezil hydrochloride, starch, and mannitol were placed in a high-speed shear granulator and mixed for 10 minutes; a 4.5% by mass low-substituted hydroxypropylcellulose aqueous solution was sprayed to prepare a soft material, dried, granulated, and sodium carboxymethyl starch and a lubricant were added, and mixed for 15 minutes to obtain a donepezil hydrochloride immediate-release layer;

[0041] (3) Preparation of memantine hydrochloride sustained-release layer: polylactic acid-glycolic acid copolymer and chitosan were dissolved in a solution of 8% by mass of dichloromethane-1.5% acetic acid, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside was ground at low temperature (5°C) for 4 minutes, and then ground with memantine hydrochloride at low temperature (5°C) for 10 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend was mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol was added to prepare a soft material, dried, granulated, a lubricant was added, and mixed for 15 minutes to obtain a memantine hydrochloride sustained-release layer;

[0042] (4) Double-layer tableting, pre-compression pressure 2kN, main compression pressure 15kN, to obtain double-layer tablets, and coating the double-layer tablets with a hydroxypropyl methylcellulose coating solution with a solid content of 8%, with a coating weight gain of 2.5%.

[0043] Example 3 Donepezil-Memantine Compound Sustained Release Preparation

[0044] formula:

[0045]

[0046] Preparation process:

[0047] (1) Donepezil hydrochloride and memantine hydrochloride are sieved through 80 mesh sieves respectively for later use;

[0048] (2) Preparation of donepezil hydrochloride immediate-release layer: donepezil hydrochloride, starch, and mannitol were placed in a high-speed shear granulator and mixed for 5 minutes; a 2.0% low-substituted hydroxypropylcellulose aqueous solution was sprayed to prepare a soft material, dried, granulated, and sodium carboxymethyl starch and a lubricant were added, and mixed for 10 minutes to obtain a donepezil hydrochloride immediate-release layer;

[0049] (3) Preparation of memantine hydrochloride sustained-release layer: polylactic acid-glycolic acid copolymer and chitosan were dissolved in a 5% by mass dichloromethane-0.2% acetic acid solution, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside was ground at low temperature (2°C) for 2 minutes, and then ground with memantine hydrochloride at low temperature (2°C) for 5 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend was mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol was added to prepare a soft material, dried, granulated, a lubricant was added, and mixed for 10 minutes to obtain a memantine hydrochloride sustained-release layer;

[0050] (4) Double-layer tableting, pre-compression pressure 2kN, main compression pressure 15kN, to obtain double-layer tablets, and coating the double-layer tablets with a hydroxypropyl methylcellulose coating solution with a solid content of 8%, and the coating weight gain is 2.0%.

[0051] Example 4 Donepezil-Memantine Compound Sustained Release Preparation

[0052] formula:

[0053]

[0054]

[0055] Preparation process:

[0056] (1) Donepezil hydrochloride and memantine hydrochloride are sieved through 80 mesh sieves respectively for later use;

[0057] (2) Preparation of donepezil hydrochloride immediate-release layer: donepezil hydrochloride, starch, and mannitol were placed in a high-speed shear granulator and mixed for 15 minutes; a 6.5% mass fraction low-substituted hydroxypropylcellulose aqueous solution was sprayed to prepare a soft material, dried, granulated, and sodium carboxymethyl starch and a lubricant were added, and mixed for 20 minutes to obtain a donepezil hydrochloride immediate-release layer;

[0058] (3) Preparation of memantine hydrochloride sustained-release layer: polylactic acid-glycolic acid copolymer and chitosan were dissolved in a 10% by mass dichloromethane-2% acetic acid solution, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside was ground at low temperature (8°C) for 5 minutes, and then ground with memantine hydrochloride at low temperature (8°C) for 15 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend was mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol was added to prepare a soft material, dried, granulated, a lubricant was added, and mixed for 20 minutes to obtain a memantine hydrochloride sustained-release layer;

[0059] (4) Double-layer tableting, pre-compression pressure 2kN, main compression pressure 15kN, to obtain double-layer tablets, and use 8% solid content of hydroxypropyl methylcellulose coating solution to coat the double-layer tablets, the coating weight gain is 3.0%.

[0060] Stability of donepezil-memantine combination sustained-release preparation

[0061] Stability test group A: pinoresinol diglucoside was not added to the formula, and only memantine hydrochloride was ground at low temperature (8°C) for 15 minutes. The other formulas and preparation processes were the same as those in Example 1. (For clarity, step 3 of memantine hydrochloride layer sustained-release layer preparation is described in detail: polylactic acid-glycolic acid copolymer and chitosan were dissolved in a 7% by mass dichloromethane-0.5% acetic acid solution, and spray-dried to prepare a composite sustained-release material; memantine hydrochloride was ground at low temperature (5°C) for 10 minutes, mixed with microcrystalline cellulose, starch, dextrin, and composite sustained-release material, ethanol was added, soft material was prepared, dried, granulated, lubricant was added, and mixed for 15 minutes to obtain a memantine hydrochloride layer sustained-release layer.)

[0062] Stability test group B: pinoresinol diglucoside and memantine hydrochloride were only physically mixed, and low-temperature grinding technology was not used. The other formulas and preparation processes were the same as those in Example 1. (For clarity, step 3 of preparing the memantine hydrochloride layer sustained-release layer is described in detail: polylactic acid-glycolic acid copolymer and chitosan are dissolved in a 7% by mass dichloromethane-0.5% acetic acid solution, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside is mixed with memantine hydrochloride to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend is mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol is added, a soft material is prepared, dried, granulated, a lubricant is added, and mixed for 15 minutes to obtain a memantine hydrochloride layer sustained-release layer.)

[0063] Stability test group C: The grinding temperature of pinoresinol diglucoside and memantine hydrochloride was 25°C at room temperature, and the other formulas and preparation processes were the same as those in Example 1. (For clarity, the preparation of the memantine hydrochloride layer sustained-release layer in step 3 is described in detail: polylactic acid-glycolic acid copolymer and chitosan are dissolved in a 7% methylene chloride-0.5% acetic acid solution by mass fraction, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside is ground at room temperature (25°C) for 3 minutes, and then ground with memantine hydrochloride at room temperature (25°C) for 10 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend is mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol is added, a soft material is prepared, dried, granulated, a lubricant is added, and mixed for 15 minutes to obtain a memantine hydrochloride layer sustained-release layer.)

[0064] Stability test group D: replace pinoresinol diglucoside with 6.8g microcrystalline cellulose and 1.2g water-soluble carboxymethyl cellulose, and the other formulas and preparation processes are the same as those in Example 1. (For clarity, step 3 of the preparation of the memantine hydrochloride layer sustained-release layer is described in detail: polylactic acid-glycolic acid copolymer and chitosan are dissolved in a 7% methylene chloride-0.5% acetic acid solution by mass, and spray-dried to prepare a composite sustained-release material; microcrystalline cellulose and water-soluble carboxymethyl cellulose are mixed, ground at low temperature (5°C) for 3min, and then ground with memantine hydrochloride at low temperature (5°C) for 10min to obtain a blend; the blend is mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol is added, a soft material is prepared, dried, granulated, a lubricant is added, and mixed for 15min to obtain a memantine hydrochloride layer sustained-release layer.)

[0065] The donepezil-memantine compound sustained-release preparations prepared in Examples 1 to 4 and stability test group A to stability test group D were placed at 40°C±2°C, relative humidity 60%±5%, and light 4500lx±500xl for 6 months, and the contents of donepezil hydrochloride and memantine hydrochloride were detected on the 1st day, 30th day, 90th day, and 180th day according to the provisions of the 2020 edition of the Chinese Pharmacopoeia.

[0066] Table 1 Memantine hydrochloride content and content reduction rate in donepezil-memantine compound sustained-release preparation (%)

[0067]

[0068]

[0069] Table 1 shows the content of memantine hydrochloride and its decreasing rate in donepezil-memantine compound sustained-release preparation. Figure 1 The figure shows the changing trend of the content of memantine hydrochloride in the compound sustained-release preparation of nepezil-memantine. The stability of group A in the stability test without pinoresinol diglucoside is the worst, indicating that pinoresinol diglucoside is crucial to maintaining the stability of memantine hydrochloride. Although the stability of group D in the stability test replaced with microcrystalline cellulose and carboxymethyl cellulose is better than that of group A in the stability test, it is still significantly lower than that of groups 1 to 4 in Examples 1 to 4, further verifying the irreplaceability of pinoresinol diglucoside. In Examples 1 to 4, pinoresinol diglucoside is combined with cryogenic grinding technology, and the decrease rate of memantine hydrochloride content is only 0.07 to 0.12%, showing the improvement of stability by process optimization. The decrease rates of memantine hydrochloride content in stability test group B and stability test group C are significantly higher than those in the example group, indicating that cryogenic grinding can promote the compatibility of drugs and excipients and inhibit degradation. The combination of pinoresinol diglucoside and cryogenic grinding process is the core factor in improving the stability of memantine hydrochloride content in compound sustained-release preparations. The lack of one of them or the change of process conditions will significantly reduce the stability of the drug.

[0070] Donepezil hydrochloride itself is relatively stable. The donepezil hydrochloride content in the donepezil-memantine compound sustained-release preparations prepared in Examples 1 to 4 and stability test group A to stability test group D on the 1st, 30th, 90th and 180th days of the test is relatively stable, and the donepezil hydrochloride content decrease rate is within 0.15%. The relevant data are not shown here.

[0071] A trial on the sustained-release effect of donepezil-memantine compound sustained-release preparation

[0072] Sustained-release test group A: polylactic acid-glycolic acid copolymer is not added to the formula, only chitosan is used as the sustained-release material, and the other formulas and preparation processes are the same as those in Example 1. (For clarity, step 3 of the preparation of the memantine hydrochloride layer sustained-release layer is described in detail: chitosan is dissolved in a 7% by mass dichloromethane-0.5% acetic acid solution, and spray-dried to prepare a sustained-release material; pinoresinol diglucoside is ground at low temperature (5°C) for 3 minutes, and then ground with memantine hydrochloride at low temperature (5°C) for 10 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend is mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol is added, a soft material is prepared, dried, granulated, a lubricant is added, and mixed for 15 minutes to obtain a memantine hydrochloride layer sustained-release layer.)

[0073] Sustained-release test group B: chitosan was not added to the formula, only polylactic acid-glycolic acid copolymer was used as the sustained-release material, and the other formulas and preparation processes were the same as those in Example 1. (For clarity, step 3 of the preparation of the memantine hydrochloride layer sustained-release layer is described in detail: polylactic acid-glycolic acid copolymer was dissolved in a 7% by mass dichloromethane-0.5% acetic acid solution, and spray-dried to prepare a sustained-release material; pinoresinol diglucoside was ground at low temperature (5°C) for 3 minutes, and then ground with memantine hydrochloride at low temperature (5°C) for 10 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend was mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol was added, a soft material was prepared, dried, granulated, a lubricant was added, and mixed for 15 minutes to obtain a memantine hydrochloride layer sustained-release layer.)

[0074] Sustained-release test group C: polylactic acid and chitosan are used as sustained-release materials in the formula, and the other formulas and preparation processes are the same as those in Example 1. (For clarity, step 3 of the preparation of the memantine hydrochloride layer sustained-release layer is described in detail: polylactic acid and chitosan are dissolved in a 7% by mass dichloromethane-0.5% acetic acid solution, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside is ground at low temperature (5°C) for 3 minutes, and then ground with memantine hydrochloride at low temperature (5°C) for 10 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend is mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol is added, a soft material is prepared, dried, granulated, a lubricant is added, and mixed for 15 minutes to obtain a memantine hydrochloride layer sustained-release layer.)

[0075] Sustained-release test group D: The formula uses polylactic acid-glycolic acid copolymer and chitosan as sustained-release materials, and the solvent is a 7% chloroform-0.5% citric acid solution by mass. The other formulas and preparation processes are the same as those in Example 1. (For clarity, the preparation of the memantine hydrochloride layer sustained-release layer is described in detail in step 3: polylactic acid-glycolic acid copolymer and chitosan are dissolved in a 7% chloroform-0.5% citric acid solution by mass, and spray-dried to prepare a composite sustained-release material; pinoresinol diglucoside is ground at low temperature (5°C) for 3 minutes, and then ground with memantine hydrochloride at low temperature (5°C) for 10 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; the memantine hydrochloride-pinoresinol diglucoside blend is mixed with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, ethanol is added, a soft material is prepared, dried, granulated, a lubricant is added, and mixed for 15 minutes to obtain a memantine hydrochloride layer sustained-release layer.)

[0076] Sustained-release test group E: low-substituted hydroxypropyl cellulose was not added to the formula, and the other formulas and preparation processes were the same as those in Example 1. (For clarity, step 2 is described in detail. Preparation of donepezil hydrochloride immediate-release layer: donepezil hydrochloride, starch, and mannitol were placed in a high-speed shear granulator and mixed for 10 minutes; an appropriate amount of purified water was sprayed to prepare a soft material, dried, granulated, sodium carboxymethyl starch and a lubricant were added, and mixed for 15 minutes to obtain a donepezil hydrochloride immediate-release layer;

[0077] Sustained-release test group F: The low-substituted hydroxypropyl cellulose in the formula was replaced with sodium alginate, and the other formulas and preparation processes were the same as those in Example 1. (For clarity, step 2 of the preparation of the donepezil hydrochloride immediate-release layer is described in detail: donepezil hydrochloride, starch, and mannitol are placed in a high-speed shear granulator and mixed for 10 minutes; a 3.5% sodium alginate aqueous solution is sprayed to prepare a soft material, dried, granulated, sodium carboxymethyl starch and a lubricant are added, and mixed for 15 minutes to obtain the donepezil hydrochloride immediate-release layer.)

[0078] Sustained-release test group G: low-substituted hydroxypropyl cellulose was directly added to the formula, and the other formulas and preparation processes were the same as those in Example 1. (For clarity, step 2 of the preparation of donepezil hydrochloride immediate-release layer is described in detail: donepezil hydrochloride, starch, mannitol, and low-substituted hydroxypropyl cellulose were placed in a high-speed shear granulator and mixed for 10 minutes; an appropriate amount of purified water was sprayed to prepare a soft material, dried, granulated, sodium carboxymethyl starch and a lubricant were added, and mixed for 15 minutes to obtain the donepezil hydrochloride immediate-release layer.)

[0079] The solubility of the donepezil-memantine compound sustained-release preparations prepared in Examples 1 to 4 and sustained-release test group A to sustained-release test group G was determined according to the dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia.

[0080] Table 2 Dissolution of Memantine Hydrochloride

[0081]

[0082] The sustained release effect of the ideal sustained release preparation is about 20% dissolved in 2h, about 47% dissolved in 10h, about 75% dissolved in 16h, and more than 90% dissolved in 22h. In Table 2, the sustained release effect of the donepezil-memantine compound sustained release preparation of Examples 1 to 4 is relatively ideal, indicating that chitosan and polylactic acid-glycolic acid copolymer have a synergistic sustained release effect. The sustained release effect of chitosan or polylactic acid-glycolic acid alone in the sustained release test group A and the sustained release test group B is insufficient. The sustained release effect of the sustained release test group C is also not ideal. It is speculated that the gel sustained release system may not be fully formed, resulting in a decrease in sustained release performance. The sustained release test group D also shows that the solvent system has an effect on the sustained release effect of the donepezil-memantine compound sustained release preparation, affecting the dispersibility and release behavior.

[0083] Figure 2 This is the dissolution curve of donepezil hydrochloride in the donepezil-memantine compound sustained-release preparation. In the preparation process of the donepezil-memantine compound sustained-release preparation in Examples 1 to 4, spraying of an appropriate amount of low-substituted hydroxypropylcellulose solution enables complete dissolution of donepezil hydrochloride.

Claims

1. A donepezil-memantine compound sustained-release preparation, characterized in that: The donepezil-memantine compound sustained-release preparation consists of a donepezil hydrochloride immediate-release layer and a memantine hydrochloride sustained-release layer; Calculated by weight ratio, the donepezil hydrochloride immediate-release layer consists of 5-15 parts of donepezil hydrochloride, 80-120 parts of starch, 20-40 parts of mannitol, 4-10 parts of sodium carboxymethyl starch, 2-5 parts of low-substituted hydroxypropyl cellulose, and 0.5-3 parts of lubricant; the memantine hydrochloride sustained-release layer consists of 10-35 parts of memantine hydrochloride, 10-40 parts of microcrystalline cellulose, 80-120 parts of starch, 10-20 parts of dextrin, 5-15 parts of pinoresinol diglucoside, 10-25 parts of polylactic acid-glycolic acid copolymer, 10-25 parts of chitosan, and 0.5-3 parts of lubricant.

2. The donepezil-memantine compound sustained-release preparation according to claim 1, characterized in that: The lubricant is selected from at least one of magnesium stearate, talcum powder and micro-powder silica gel.

3. The donepezil-memantine compound sustained-release preparation according to claim 1, characterized in that: The lubricant is magnesium stearate.

4. The donepezil-memantine compound sustained-release preparation according to claim 1, characterized in that: The donepezil hydrochloride rapid-release layer is composed of 10 parts by weight of donepezil hydrochloride, 100 parts by weight of starch, 30 parts by weight of mannitol, 7 parts by weight of sodium carboxymethyl starch, 3 parts by weight of low-substituted hydroxypropyl cellulose, and 1 part by weight of a lubricant.

5. The donepezil-memantine compound sustained-release preparation according to claim 1, characterized in that: The memantine hydrochloride sustained-release layer is composed of 14 parts by weight of memantine hydrochloride, 20 parts by weight of microcrystalline cellulose, 90 parts by weight of starch, 12 parts by weight of dextrin, 8 parts by weight of pinoresinol diglucoside, 15 parts by weight of polylactic acid-glycolic acid copolymer, 15 parts by weight of chitosan, and 1 part by weight of lubricant.

6. The donepezil-memantine compound sustained-release preparation according to claim 1, characterized in that: The memantine hydrochloride sustained-release layer is composed of 28 parts by weight of memantine hydrochloride, 30 parts by weight of microcrystalline cellulose, 100 parts by weight of starch, 17 parts by weight of dextrin, 12 parts by weight of pinoresinol diglucoside, 20 parts by weight of polylactic acid-glycolic acid copolymer, 20 parts by weight of chitosan, and 1.5 parts by weight of lubricant.

7. A process for preparing the donepezil-memantine compound sustained-release preparation according to claim 1, characterized in that: The process comprises the following steps: (1) Donepezil hydrochloride and memantine hydrochloride are sieved through 80 mesh sieves respectively for later use; (2) placing donepezil hydrochloride, starch, and mannitol in a high-speed shear granulator and mixing for 5 to 15 minutes; spraying a 2.0 to 6.5% by mass low-substituted hydroxypropyl cellulose aqueous solution to prepare a soft material, drying, granulating, adding sodium carboxymethyl starch and a lubricant, and mixing for 10 to 20 minutes to obtain a donepezil hydrochloride immediate-release layer; (3) dissolving polylactic acid-glycolic acid copolymer and chitosan in a 5% to 10% by mass dichloromethane-0.2 to 2% acetic acid solution, and spray drying to prepare a composite sustained-release material; grinding pinoresinol diglucoside at a low temperature of 2 to 8° C. for 2 to 5 minutes, and then grinding with memantine hydrochloride at a low temperature of 2 to 8° C. for 5 to 15 minutes to obtain a memantine hydrochloride-pinoresinol diglucoside blend; mixing the memantine hydrochloride-pinoresinol diglucoside blend with microcrystalline cellulose, starch, dextrin, and a composite sustained-release material, adding ethanol, preparing a soft material, drying, granulating, adding a lubricant, and mixing for 10 to 20 minutes to obtain a memantine hydrochloride sustained-release layer; (4) Immediate-release layer and sustained-release layer tablet compression and coating.

8. The process according to claim 7, characterized in that The mass fraction of the low-substituted hydroxypropyl cellulose aqueous solution is 3.5-4.5%.

9. The process according to claim 7, characterized in that The parameters of the quick-release layer and the sustained-release laminated tablet are a pre-compression pressure of 2 kN and a main compression pressure of 15 kN.

10. The process according to claim 7, characterized in that The coating uses a hydroxypropyl methylcellulose coating solution with a solid content of 8%, and the coating weight gain is 2-3%.

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