Compound preparation containing memantine hydrochloride sustained-release pellets and donepezil and preparation method thereof

Abstract

The invention provides a memantine hydrochloride sustained-release pellet preparation with simple components and a compound capsule containing the memantine hydrochloride sustained-release pellet and donepezil, and provides a preparation method of the memantine hydrochloride sustained-release pellet preparation. The compound capsule has equivalent dissolution effect with a reference preparation # imgabs0 #, is good in stability and simple in preparation process, overcomes the defects of complex components and tedious process of the existing preparation, is convenient to operate, and reduces the manufacturing cost.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a compound preparation containing memantine hydrochloride sustained-release pellets and donepezil and a preparation method thereof. Background Art

[0002] Alzheimer's disease (AD) is a chronic progressive mental degeneration disease with memory loss, cognitive dysfunction, and mental and behavioral abnormalities as clinical features. With the acceleration of the aging process of society, the disease has gradually developed into a serious public health problem.

[0003] Memantine Hydrochloride is a specific non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It is the first FDA-approved drug for the treatment of moderate to severe Alzheimer's disease. Memantine Hydrochloride acts on the glutamine system in the brain, reduces background noise by interacting with NMDA receptors, and restores glutamine signals to a normal physiological state to improve learning and memory functions. Foreign clinical trial results show that memantine hydrochloride can effectively improve the cognition and normal life ability of patients with Alzheimer's disease.

[0004] Donepezil hydrochloride is a highly specific drug that can reversibly inhibit acetylcholinesterase in the brain, but has little effect on acetylcholinesterase in the peripheral system. Due to the specific inhibitory effect of donepezil hydrochloride on acetylcholinesterase in the brain, a large number of clinical studies have also proved that it has relatively good efficacy in the treatment of Alzheimer's disease (AD) with fewer side effects. At present, donepezil hydrochloride has become the first choice drug for the treatment of AD.

[0005] The combination of memantine hydrochloride and donepezil is a proven effective option for the treatment of moderate to severe Alzheimer's disease. This treatment method combines an N-methyl-D-aspartate (NMDA) receptor agonist with an acetylcholinesterase inhibitor, making the two mechanisms of action complementary and thus increasing the efficacy. The combined use of the two drugs produces a better therapeutic effect than the use of acetylcholinesterase inhibitors alone, and can more significantly improve patients' cognitive function, emotions, and daily living abilities. It is more effective than the use of donepezil hydrochloride alone, and has fewer toxic side effects, so it is worthy of clinical promotion and application.

[0006] The approved product is memantine hydrochloride-donepezil hydrochloride capsules, with the trade name Developed jointly by Forest and Adamas Pharmaceuticals, the specifications are memantine hydrochloride 14mg / donepezil hydrochloride 10mg and memantine hydrochloride 28mg / donepezil hydrochloride 10mg. The chemical names are 3,5-dimethyladamantine hydrochloride and (2RS)-2-[(1-benzylpyridin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-indanone-1-hydrochloride, and the molecular formulas are: C 12 H 21 N·HCl and C 24 H 29 NO3·HCl, and the molecular weights are 215.76 and 415.96, respectively. The formula uses colloidal silicon dioxide, corn starch, ethyl cellulose, hydroxymethyl cellulose, lactose monohydrate, magnesium stearate, medium chain triglycerides, microcrystalline cellulose, oleic acid, polyethylene glycol, povidone, sucrose pellets and talcum powder, and the capsule shell contains gelatin, titanium dioxide, shellac glaze and edible black ink. The types and properties of the ingredients in the formula are complex, making it difficult to control the preparation process, resulting in a low product yield and large differences in uniformity.

[0007] Used in patent CN101247795B Ethyl cellulose dispersion is a sustained-release material that needs to be stored at 25°C. It is temperature sensitive and has harsh storage conditions, which makes transportation and storage more difficult. Summary of the invention

[0008] In order to solve the technical problems existing in the prior art of the above-mentioned memantine hydrochloride sustained-release micropellets, the present invention provides a new memantine hydrochloride sustained-release micropellets and sustained-release capsules and a preparation method thereof, which have a comparable dissolution effect to the prior art and have better stability, a simpler formula, lower cost, and a less difficult preparation process that is easy to control.

[0009] In a first aspect of the present invention, a memantine hydrochloride sustained-release pellet is provided, comprising:

[0010] Blank pellets;

[0011] A drug-loaded coating layer wrapping the blank pill core, wherein the drug-loaded coating layer comprises memantine hydrochloride, a binder, and an anti-adhesive agent;

[0012] A separation layer encapsulating the drug-loaded coating layer; and

[0013] The sustained-release layer wraps the isolation layer, and the sustained-release layer comprises a sustained-release material and a pore-forming agent.

[0014] In some embodiments, the binder is selected from one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose or povidone, or two or more thereof mixed in any proportion; more preferably, the binder is povidone.

[0015] In some embodiments, the isolation layer material consists of Opadry coating powder.

[0016] In some embodiments, the sustained-release layer material is ethyl cellulose, preferably one selected from ethyl cellulose N10, ethyl cellulose N22 and ethyl cellulose N100 or a combination of two or more in any proportion. Preferably, the sustained-release layer material is ethyl cellulose N10 or ethyl cellulose N100.

[0017] In some embodiments, the pore former is selected from one of hypromellose, povidone and polyethylene glycol, or a combination of two or more thereof mixed in any proportion. Preferably, the pore former is hypromellose.

[0018] In some embodiments, the mass ratio of ethyl cellulose to hypromellose is 20-200:1, preferably the mass ratio of ethyl cellulose to hypromellose is 24-100:1.

[0019] In some embodiments, the anti-sticking agent is one of talc, magnesium stearate or micro-powdered silica gel, or a combination of two or more of the above in any proportion, preferably talc.

[0020] In some embodiments, the memantine hydrochloride sustained-release pellets comprise the following components in weight percentage:

[0021]

[0022] In some embodiments, the memantine hydrochloride sustained-release pellets comprise the following components in weight percentage:

[0023]

[0024] The sum of the weight percentages of the various components is 100%.

[0025] In some embodiments, the memantine hydrochloride sustained-release pellets comprise the following components in weight percentage:

[0026]

[0027]

[0028] The sum of the weight percentages of the various components is 100%.

[0029] The second aspect of the present invention provides a method for preparing the memantine hydrochloride sustained-release pellets according to any one of the first aspects, comprising the following steps:

[0030] (1) preparing a drug-loaded coating suspension containing memantine hydrochloride, povidone, and talc;

[0031] (2) coating the blank pellets with drug in a fluidized bed to obtain drug-coated pellets;

[0032] (3) preparing a barrier coating solution including an Opadry film coating premix;

[0033] (4) coating the drug-loaded coated pellets with an isolation layer in a fluidized bed to obtain isolation layer coated pellets;

[0034] (5) preparing a sustained-release layer coating solution comprising ethyl cellulose and hypromellose;

[0035] (6) In a fluidized bed, the isolation layer-coated pellets are coated with a sustained-release layer to obtain memantine hydrochloride sustained-release pellets.

[0036] In some embodiments, the solvent used in step (1) is about 40% ethanol solution.

[0037] In some embodiments, the solvent used in step (5) is about 60% isopropanol solution.

[0038] The third aspect of the present invention provides a composite capsule, comprising the memantine hydrochloride sustained-release pellets described in any one of the first aspect or the memantine hydrochloride sustained-release pellets prepared by the preparation method described in the second aspect; and donepezil hydrochloride immediate-release granules.

[0039] In some embodiments, the donepezil hydrochloride rapid-release granules include donepezil hydrochloride and further include a filler, a disintegrant, a binder, and a lubricant.

[0040] In some embodiments, the filler is selected from one or more of lactose, lactose monohydrate, corn starch and microcrystalline cellulose, preferably lactose and / or microcrystalline cellulose.

[0041] In some embodiments, the disintegrant is selected from one or more of microcrystalline cellulose, dry starch, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, preferably microcrystalline cellulose.

[0042] In some embodiments, the binder is selected from one or more of povidone, hydroxypropyl cellulose, corn starch and water, preferably corn starch.

[0043] In some embodiments, the lubricant is selected from one or more of silicon dioxide, magnesium stearate and sodium lauryl sulfate, preferably silicon dioxide and / or magnesium stearate.

[0044] In some embodiments, the donepezil hydrochloride immediate-release granules include donepezil hydrochloride, lactose, microcrystalline cellulose, corn starch, silicon dioxide, and magnesium stearate.

[0045] In some embodiments, the donepezil hydrochloride immediate-release granules include 5-15% donepezil hydrochloride, 32-37% lactose, 32-40% microcrystalline cellulose, 14-18% corn starch, 1-3% silicon dioxide and 0.5-2% magnesium stearate, wherein the sum of the weight percentages of each component is 100%.

[0046] In some embodiments, the donepezil hydrochloride immediate-release granules are prepared by a wet process, comprising

[0047] 1) premixing lactose and microcrystalline cellulose in a wet granulator, and then adding corn starch and donepezil hydrochloride to premix;

[0048] 2) using corn starch as a binder for wet granulation; using a granulator to wet granulate the granulated material;

[0049] 3) The wet granulated material is added into a fluidized bed for drying;

[0050] 4) using a granulator to dry granulate the dried granules;

[0051] 5) adding the weighed silicon dioxide to the prepared particles for secondary dry granulation;

[0052] 6) Add all the granules after secondary dry granulation into a mixer for mixing, and add magnesium stearate for total mixing.

[0053] In some embodiments, the mass ratio of the effective drugs memantine hydrochloride and donepezil hydrochloride in the capsule is 7-28:10, preferably the mass ratio of the effective drugs memantine hydrochloride and donepezil hydrochloride in the capsule is 7:10, 14:10, 21:10 or 28:10.

[0054] Beneficial effects of the present invention:

[0055] (1) The memantine hydrochloride sustained-release pellets of the present invention use ethyl cellulose, especially ethyl cellulose N10 or ethyl cellulose N100, and hydroxypropyl methylcellulose or polyethylene glycol (such as polyethylene glycol 6000) as sustained-release layer materials, which have simple ingredients, reduce the difficulty of process and storage, and achieve the same in vitro properties and in vivo effects by controlling the composition ratio and dosage of the sustained-release materials.

[0056] (2) In the preparation process of the memantine hydrochloride sustained-release micropellets of the present invention, the solvent used in the drug-loading layer is about 40% ethanol solution, and the solvent used in the sustained-release layer is about 60% isopropanol. The concentration of the organic solution is low, and the process safety is higher.

[0057] (3) The auxiliary material components of the formula of the present invention are simple and the process parameters are easy to control.

[0058] (4) memantine hydrochloride sustained-release pellets and donepezil hydrochloride immediate-release granules prepared by the formula and process of the present invention and It has a considerable dissolution effect and good stability.

[0059] (5) A compound capsule preparation of memantine hydrochloride sustained-release pellets and donepezil hydrochloride immediate-release granules prepared by the formula and process of the present invention and The reference preparation was administered orally in a randomized crossover test in healthy subjects. Or a self-developed compound preparation (daily dose of memantine hydrochloride 28 mg / donepezil hydrochloride 10 mg) prepared by the formula and process of the present invention is used to determine the concentrations of memantine and donepezil in plasma at different time points after administration, calculate the pharmacokinetic parameters and evaluate the bioequivalence of the two preparations. The expected results show that there is no significant difference in the pharmacokinetic parameters, and the preparation of the present invention and the reference preparation are bioequivalent. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 This is the dissolution curve of the samples in Examples 1-5 in pH 1.2 / NaCl at 100 rpm using the basket method.

[0061] Figure 2 This is the dissolution curve of the samples of Examples 6-8 in pH 1.2 / NaCl at 100 rpm using the basket method.

[0062] Figure 3 This is the dissolution curve of the samples of Examples 9-15 in pH 1.2 / NaCl at 100 rpm using the basket method.

[0063] Figure 4 This is the dissolution curve of the samples of Comparative Examples 1-3 in pH 1.2 / NaCl at 100 rpm using the basket method. DETAILED DESCRIPTION

[0064] The following examples further illustrate the present invention, but do not limit the present invention.

[0065] The reference preparation (RLD) in the following examples purchased from ALLERGAN SALES LLC; povidone K30 purchased from Ashland Chemical Co., Ltd.; talc purchased from Imevys Talc Italy SP.A; Opadry coating premix powder purchased from Shanghai Colorcon Coating Technology Co., Ltd.; hypromellose purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.; polyethylene glycol 6000 purchased from Clariant Produkte GmbH; ethyl cellulose purchased from Ashland Chemical Co., Ltd.; Ethylcellulose aqueous dispersion was purchased from Shanghai Colorcon Coating Technology Co., Ltd.; sucrose pellets were purchased from JRS PHARMA.

[0066] Unless otherwise specified, the raw materials and reagents used in the specific embodiments of the present invention can be obtained from commercial sources.

[0067] Example 1-5 Preparation of Memantine Hydrochloride Sustained Release Pellets

[0068] Table 1 Dosage of each component of memantine hydrochloride sustained-release pellets

[0069]

[0070] The specific steps are as follows:

[0071] Weigh each raw material according to the amount of each component in Table 1;

[0072] Preparation of drug-loaded coating solution and drug-loaded coating in fluidized bed: under stirring conditions, povidone K30, memantine hydrochloride API, and talcum powder are slowly added to a 40% ethanol-water solution, stirred evenly, and then the drug solution is sprayed onto the blank pellet cores, and the drug-loaded pellets are obtained after drying;

[0073] Fluidized bed isolation layer coating: add Opadry film coating premix to purified water under stirring conditions, stir until dissolved, spray the isolation layer coating solution onto the drug-loaded pellets, and dry to obtain isolation pellets;

[0074] Sustained-release layer coating in a fluidized bed: Ethyl cellulose and hydroxypropyl methylcellulose are slowly added to a 60% isopropyl alcohol-water solution under stirring, respectively, and after stirring until dissolved, the sustained-release coating liquid is sprayed onto the isolation pellets and dried to obtain memantine hydrochloride sustained-release pellets.

[0075] Example 6-8 Preparation of Memantine Hydrochloride Sustained Release Pellets

[0076] According to the formulation in Table 2, the memantine hydrochloride sustained-release pellets of Examples 6-8 were prepared according to steps similar to those of Examples 1-5.

[0077] Table 2 Dosage of each component of memantine hydrochloride sustained-release pellets

[0078]

[0079]

[0080] Example 9-15 Preparation of Donepezil Hydrochloride Immediate Release Granules

[0081] Table 3 Dosage of each component of Donepezil Hydrochloride Immediate Release Granules

[0082]

[0083]

[0084] The specific steps are as follows:

[0085] (1) Weigh the raw and auxiliary materials according to the amount of each component in Table 3;

[0086] (2) Premixing: Lactose and microcrystalline cellulose are premixed in a wet granulator, and then a certain amount of corn starch and donepezil hydrochloride are added and premixed;

[0087] (3) Wet granulation: Wet granulation is performed using a binder made from corn starch;

[0088] (4) Wet granulation: The granulated material is wet granulated in a granulator, with a 3*3 screen and a speed of 100-300 rpm;

[0089] (5) Drying: The wet granulated material is added into a fluidized bed for drying;

[0090] (6) Dry granulation: The dried granules are granulated using a granulator with a screen of 1.0-1.5 mm round holes and a rotation speed of 100-300 rpm. The weighed silicon dioxide is added to the prepared granules for secondary dry granulation;

[0091] (7) Total mixing: Then add all the granules after secondary dry granulation into a mixer for mixing, and finally continue to add magnesium stearate into the mixer for total mixing.

[0092] Experimental Example 16

[0093] The raw and auxiliary materials were weighed according to the dosage of each component in Table 4, and memantine hydrochloride sustained-release pellets were prepared according to the method in Experimental Example 1.

[0094] Table 4 Dosage of each component of memantine hydrochloride sustained-release pellets

[0095]

[0096]

[0097] Example 17 Filling capsules

[0098] The memantine hydrochloride sustained-release pellets obtained in Examples 1-8 and 16 and the donepezil hydrochloride immediate-release granules obtained in Examples 9-15 were filled into capsules at a main drug ratio of 7 mg / 10 mg, 14 mg / 10 mg, 21 mg / 10 mg, and 28 mg / 10 mg to obtain memantine hydrochloride and donepezil sustained-release capsules.

[0099] Example 1 and Example 9, Example 2 and Example 10, Example 3 and Example 11, Example 4 and Example 12, Example 5 and Example 13, Example 6 and Example 14, Example 7 and Example 15, Example 8 and Example 9, Example 16 and Example 10 were respectively filled at a ratio of 28 mg / 10 mg to obtain memantine hydrochloride donepezil sustained-release capsules for dissolution measurement.

[0100] Test Example 1

[0101] The in vitro release of the drug of the capsule sample filled in Example 17 (the ratio of memantine hydrochloride sustained-release pellets and donepezil hydrochloride immediate-release granules is 28 mg / 10 mg) was studied, and the release was determined according to the first method (basket method) of the fourth part of the 2020 edition of the Chinese Pharmacopoeia 0931 dissolution and release determination method, pH1.2 / NaCl buffer, medium volume of 900 ml, speed of 100 rpm, temperature of 37 ± 0.5 ° C. 1.2 ml was sampled at the specified sampling point, 1.2 ml was infused, filtered with a 0.45 μm microporous membrane, detected using HPLC, and then the cumulative dissolution was calculated.

[0102] Sampling time point:

[0103] Donepezil hydrochloride: 5, 10, 15, 20, 30 min

[0104] Memantine hydrochloride: 1, 2, 3, 4, 6, 8, 10, 12 hours

[0105] According to the above dissolution curve determination method, the dissolution curve of the self-made preparation was determined. The results are shown in Tables 5-7 and Figure 1-3 dissolution curve.

[0106] Table 5 Dissolution results of memantine hydrochloride sustained-release pellets in pH 1.2 / NaCl medium basket method at 100 rpm Example 1-5

[0107]

[0108] Note: f2 value, or similarity factor, refers to the degree of similarity between the in vitro dissolution of the homemade sample and the reference RLD. The closer the f2 value is to 100, the more similar the two curves are. In general, when the f2 value is higher than 50, the two curves are considered to be similar and the test and reference products are equivalent.

[0109] Table 6 Example 6-8 pH 1.2 / NaCl basket method 100rpm dissolution results

[0110]

[0111] Table 7 Dissolution results of donepezil hydrochloride immediate release granules pH 1.2 / NaCl medium basket method 100 rpm for Examples 9-15

[0112]

[0113]

[0114] The test results show that in pH 1.2 / NaCl medium, the memantine hydrochloride sustained-release pellets samples of Examples 1-5 have the same Similar dissolution curves, the ratio of ethyl cellulose / hydroxypropyl methyl cellulose selected in the present invention is 20-200:1, preferably 24-100:1, and the content of ethyl cellulose is 11%-20%.

[0115] In pH 1.2 / NaCl medium, the memantine hydrochloride sustained-release pellet samples of Examples 6-8 also had the same Similar dissolution curves, the ratio of ethyl cellulose / polyethylene glycol 6000 selected in the present invention is 10-12:1, and the content of ethyl cellulose is 6%-9%.

[0116] The 15-min cumulative release of the donepezil hydrochloride rapid-release granules sample of Example 9-15 is not less than 85%, which meets the requirements of medicines.

[0117] Test Example 2 Stability Test

[0118] Example 16 and Example 10 were filled at a ratio of 28 mg / 10 mg to obtain memantine hydrochloride donepezil sustained-release capsules, which were divided into high-density polyethylene bottles, sealed and placed under accelerated test and long-term test conditions:

[0119] Accelerated test: Place the sample at 40℃±2℃ and 75%±5% relative humidity for 6 months, and take samples at 0, 3, and 6 months for in vitro drug release testing.

[0120] Long-term test: Place at 25℃±2℃ and 60%±5% relative humidity for 12 months, and take samples at 0, 6, and 12 months for in vitro drug release testing.

[0121] According to the first method (basket method) of the dissolution and release determination method of Part IV 0931 of the 2020 edition of the Chinese Pharmacopoeia, pH 1.2 / NaCl buffer was used, the medium volume was 900 ml, the speed was 100 rpm, and the temperature was 37 ± 0.5 ° C. 1.2 ml was sampled at the specified sampling point, 1.2 ml was replenished, filtered with a 0.45 μm microporous membrane, tested using HPLC, and then the cumulative dissolution was calculated. The results are shown in Tables 8 and 9.

[0122] Table 8 Dissolution results of memantine hydrochloride sustained-release pellets pH 1.2 / NaCl basket method 100 rpm

[0123]

[0124]

[0125] Note: f2 value, or similarity factor, refers to the degree of similarity between the in vitro dissolution of the homemade sample and the reference RLD. The closer the f2 value is to 100, the more similar the two curves are. In general, when the f2 value is higher than 50, it can be considered that the two curves are similar and the test and reference RLDs are equivalent.

[0126] Table 9 Dissolution results of donepezil hydrochloride immediate release granules pH 1.2 / NaCl medium basket method 100rpm

[0127]

[0128] The test results showed that the memantine hydrochloride sustained-release pellets sample in the filled capsules had the same Similar dissolution effect, after long-term and accelerated storage, the dissolution curve is still similar to the reference preparation, indicating that the formulation has good stability; Donepezil immediate-release granules are also similar to the reference preparation after long-term and accelerated storage. It has the same dissolution effect and better stability.

[0129] Comparative Examples 1-3

[0130] Preparation of memantine hydrochloride sustained-release pellets

[0131] Ethylcellulose aqueous dispersion is a fully formulated sustained-release aqueous coating system comprising ethylcellulose, a plasticizer and a stabilizer, wherein ethylcellulose is used as a polymer to control the drug release rate. As the sustained-release material, PEG6000 is used as the pore-forming agent. According to the formula in Table 10, the memantine hydrochloride sustained-release pellets of Comparative Examples 1-3 are obtained according to the preparation method of Examples 1-5.

[0132] Table 10 Dosage of each component of memantine hydrochloride sustained-release pellets

[0133]

[0134]

[0135] The memantine hydrochloride sustained-release pellets of Comparative Examples 1-3 were respectively filled with the donepezil hydrochloride immediate-release granules of Example 10 at a main drug ratio of 28 mg / 10 mg into capsules, and the dissolution curve was measured according to the dissolution curve measurement method in Test Example 1. The results are shown in Tables 11 and 11 below. Figure 4 Dissolution curve.

[0136] Table 11 Comparative Examples 1-3 pH 1.2 / NaCl Basket Method 100 rpm Dissolution Results

[0137]

[0138]

[0139] The test results show that the use of The comparative examples 1-3 samples of ethylcellulose aqueous dispersion as sustained-release coating materials have the same release rate as the reference preparation in pH 1.2 / NaCl medium. Similar dissolution profiles.

[0140] Stability test: The memantine hydrochloride sustained-release pellets obtained in Comparative Example 4 and the donepezil hydrochloride immediate-release granules obtained in Experimental Example 10 were filled into capsules at a ratio of 28 mg / 10 mg of the main drug to obtain memantine hydrochloride donepezil sustained-release capsules. Sample stability study: The filled capsules were divided into high-density polyethylene bottles, sealed and placed under accelerated test and long-term test conditions:

[0141] Accelerated test: Place at 40℃±2℃ and relative humidity 75%±5% for 6 months, and take samples for testing at 0, 3, and 6 months.

[0142] Long-term test: Place at 25℃±2℃ and 60%±5% relative humidity for 12 months, and take samples for testing at 0, 6, and 12 months. See Table 12 and Table 13 for dissolution test results.

[0143] Table 12 Comparative Example 4 Memantine Hydrochloride Sustained Release Pellets pH 1.2 / NaCl Basket Method 100rpm Dissolution Results

[0144]

[0145] Note: f2 value, or similarity factor, refers to the degree of similarity between the in vitro dissolution of the homemade sample and the reference RLD. The closer the f2 value is to 100, the more similar the two curves are. In general, when the f2 value is higher than 50, the two curves are considered to be similar and the test and reference products are equivalent.

[0146] Table 13 Comparative Example 4 Donepezil Hydrochloride Immediate Release Granules pH 1.2 / NaCl Basket Method 100rpm Dissolution Results

[0147]

[0148] The test results in Table 12 and Table 13 show that the memantine hydrochloride sustained-release pellets obtained in Comparative Example 4 have the same Similar dissolution curves, but the dissolution behavior of the sustained-release component changed after placement under long-term conditions and accelerated conditions, and the dissolution curve was not similar to that of the reference preparation, indicating that the stability of the formulation was poor.

[0149] and Ethylcellulose aqueous dispersion is sensitive to temperature, has strict storage and transportation conditions, and has difficult process conditions. However, the present invention uses ethylcellulose N10 or ethylcellulose N100 as a sustained-release coating material, and adds pore-forming agent hydroxypropyl methylcellulose or polyethylene glycol 6000 (PEG6000), which has simple ingredients and reduces the difficulty of process and storage.

[0150] The present invention has been described by the above embodiments, but it should be understood that the above embodiments are only for the purpose of example and description, and are not intended to limit the present invention to the scope of the described embodiments. In addition, it can be understood by those skilled in the art that the present invention is not limited to the above embodiments, and more variations and modifications can be made according to the teachings of the present invention, and these variations and modifications all fall within the scope of the protection claimed by the present invention. The protection scope of the present invention is defined by the attached claims and their equivalents.

Claims

1. A memantine hydrochloride sustained-release pellet comprising: Blank pellets; A drug-loaded coating layer wrapping the blank pill core, wherein the drug-loaded coating layer comprises memantine hydrochloride, a binder, and an anti-adhesive agent; A separation layer encapsulating the drug-loaded coating layer; and The sustained-release layer wraps the isolation layer, and the sustained-release layer comprises a sustained-release material and a pore-forming agent.

2. The memantine hydrochloride sustained-release pellets according to claim 1, wherein The binder is selected from one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose and povidone or two or more thereof mixed in any proportion; more preferably, the binder is povidone.

3. The memantine hydrochloride sustained-release pellets according to any one of claims 1 to 2, wherein: The isolation layer material is composed of Opadry coating powder.

4. The memantine hydrochloride sustained-release pellets according to any one of claims 1 to 3, wherein: The sustained-release layer material is ethyl cellulose, preferably one selected from ethyl cellulose N10, ethyl cellulose N22 and ethyl cellulose N100 or a combination of two or more thereof mixed in any proportion. Preferably, the sustained-release layer material is ethyl cellulose N10 or ethyl cellulose N100.

5. The memantine hydrochloride sustained-release pellets according to any one of claims 1 to 4, wherein: The pore former is selected from one of hydroxypropyl methylcellulose, povidone and polyethylene glycol, or a combination of two or more thereof mixed in any proportion; preferably, the pore former is hydroxypropyl methylcellulose or polyethylene glycol.

6. The memantine hydrochloride sustained-release pellets according to claim 5, wherein: The mass ratio of ethyl cellulose to hydroxypropyl methyl cellulose is 20-200:1, preferably the mass ratio of ethyl cellulose to hydroxypropyl methyl cellulose is 24-100:

1.

7. The memantine hydrochloride sustained-release pellets according to any one of claims 1 to 6, wherein: The anti-sticking agent is one of talc, magnesium stearate or micro-powder silica gel, or a combination of two or more of the above in any proportion, preferably talc.

8. The memantine hydrochloride sustained-release pellets according to any one of claims 1 to 7, wherein: Contains the following components in weight percentage:

9. The memantine hydrochloride sustained-release pellets according to any one of claims 1 to 8, wherein: Contains the following components in weight percentage: Wherein, the sum of weight percentages of each component is 100%; or Contains the following components in weight percentage: The sum of the weight percentages of the various components is 100%.

10. A method for preparing the memantine hydrochloride sustained-release pellets according to any one of claims 1 to 9, comprising the following steps: (1) preparing a drug-loaded coating suspension containing memantine hydrochloride, povidone, and talc; (2) coating the blank pellets with drug in a fluidized bed to obtain drug-coated pellets; (3) preparing a barrier coating solution including an Opadry film coating premix; (4) coating the drug-loaded coated pellets with an isolation layer in a fluidized bed to obtain isolation layer coated pellets; (5) preparing a sustained-release layer coating solution comprising ethyl cellulose and hypromellose; (6) In a fluidized bed, the isolation layer-coated pellets are coated with a sustained-release layer to obtain memantine hydrochloride sustained-release pellets.

11. The preparation method according to claim 10, wherein the solvent used in step (1) is about 40% ethanol solution.

12. The preparation method according to claim 10, wherein the solvent used in step (5) is about 60% isopropanol solution.

13. A composite capsule comprising the memantine hydrochloride sustained-release pellets according to any one of claims 1 to 9 or the memantine hydrochloride sustained-release pellets prepared by the preparation method according to any one of claims 10 to 12; and Donepezil hydrochloride immediate-release granules.

14. The composite capsule according to claim 13, wherein the donepezil hydrochloride rapid-release granules comprise donepezil hydrochloride, a filler, a disintegrant, a binder and a lubricant; Preferably, the filler is selected from one or more of lactose, lactose monohydrate, corn starch and microcrystalline cellulose, preferably lactose and / or microcrystalline cellulose; Preferably, the disintegrant is selected from one or more of microcrystalline cellulose, dry starch, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, preferably microcrystalline cellulose; Preferably, the binder is selected from one or more of povidone, hydroxypropyl cellulose, corn starch and water, preferably corn starch; Preferably, the lubricant is selected from one or more of silicon dioxide, magnesium stearate and sodium lauryl sulfate, preferably silicon dioxide and / or magnesium stearate.

15. The composite capsule according to claim 14, wherein the donepezil hydrochloride immediate-release granules comprise donepezil hydrochloride, lactose, microcrystalline cellulose, corn starch, silicon dioxide and magnesium stearate.

16. The composite capsule according to claim 15, wherein the donepezil hydrochloride immediate-release granules comprise about 5-15% donepezil hydrochloride, about 32-37% lactose, about 32-40% microcrystalline cellulose, about 14-18% corn starch, about 1-3% silicon dioxide and about 0.5-2% magnesium stearate, wherein: The sum of the weight percentages of each component is 100%.

17. The composite capsule according to any one of claims 13 to 16, wherein the donepezil hydrochloride immediate-release granules are prepared by a wet method, comprising: (1) premixing lactose and microcrystalline cellulose in a wet granulator, and then adding corn starch and donepezil hydrochloride to premix; (2) using a binder made of corn starch for wet granulation; and using a granulator to wet granulate the granulated material; (3) adding the wet granulated material into a fluidized bed for drying; (4) using a granulator to dry granulate the dried granules; (5) adding the weighed silicon dioxide to the prepared particles for secondary dry granulation; (6) Add all the granules after secondary dry granulation into a mixer for mixing, and add magnesium stearate for total mixing.

18. The composite capsule according to any one of claims 13 to 17, wherein the mass ratio of the effective drugs memantine hydrochloride and donepezil hydrochloride in the capsule is 7-28:10, preferably the mass ratio of the effective drugs memantine hydrochloride and donepezil hydrochloride in the capsule is 7:10, 14:10, 21:10 or 28:10.

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