Memantine hydrochloride sustained-release capsule and preparation method thereof

Abstract

The invention relates to the technical field of sustained-release capsules, in particular to a memantine hydrochloride sustained-release capsule and a preparation method thereof. The memantine hydrochloride sustained-release capsule disclosed by the invention is formed by filling memantine hydrochloride sustained-release pills; the sustained-release pill sequentially comprises a blank pill core, a main medicine layer, an isolation coating layer and a sustained-release coating layer from inside to outside, the main medicine layer is prepared from the following raw materials in parts by weight: 25 to 30 parts of memantine hydrochloride, 3 to 7 parts of hydroxypropyl methyl cellulose E, 1 to 2 parts of medicine carrying microspheres, 20 to 30 parts of PEG6000 and 4 to 5 parts of talcum powder. The memantine hydrochloride sustained-release capsule disclosed by the invention is small in release amount difference no matter in 0d or 10d, not only meets the sustained-release standard, but also can exist relatively stably, and a burst release phenomenon is avoided.

Description

Technical Field

[0001] The present invention relates to the technical field of sustained-release capsules, and in particular to a memantine hydrochloride sustained-release capsule and a preparation method thereof. Background Art

[0002] Memantine hydrochloride is one of the current drugs for the treatment of moderate to severe Alzheimer's disease. It is a new, low-to-moderate affinity, voltage-dependent, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that can non-competitively block NMDA receptors, reduce excessive excitation of NMDA receptors caused by glutamate, prevent cell apoptosis, and improve memory. It is a new generation of drugs for improving cognitive function.

[0003] At present, the dosage forms of memantine hydrochloride applied for in China include tablets, oral solutions, capsules, sustained-release capsules, dispersible tablets, orally disintegrating tablets and injections. Oral memantine preparations are rapidly absorbed and reach peak concentrations in a short period of time. Although multiple administrations can be used to compensate for fluctuations in blood drug concentrations, this will increase the risk of side effects in patients. Sustained-controlled-release technology can better solve this technical problem.

[0004] Patent technology document CN104013592B discloses a memantine hydrochloride sustained-release pill and a preparation method thereof, wherein the capsule is filled with memantine hydrochloride sustained-release pellets, and the memantine hydrochloride sustained-release pellets sequentially include a blank pill core, a main drug layer containing memantine hydrochloride, an isolation coating layer and a sustained-release coating layer from the inside to the outside. The invention has good stability and no burst release phenomenon, ensures that the drug is continuously, evenly and slowly released, and improves the efficacy of the product.

[0005] However, when it is used in clinical treatment, its sustained-release function needs to be further improved. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a memantine hydrochloride sustained-release capsule and a preparation method thereof, so as to provide a sustained-release capsule capable of continuously releasing the memantine hydrochloride drug.

[0007] Based on the above purpose, the present invention provides a memantine hydrochloride sustained-release capsule, which is filled with memantine hydrochloride sustained-release pills; the sustained-release pills include a blank pill core, a main drug layer, an isolation coating layer, and a sustained-release coating layer from the inside to the outside;

[0008] The main drug layer comprises the following raw materials in parts by weight: 25-30 parts of memantine hydrochloride, 3-7 parts of hydroxypropyl methylcellulose E, 1-2 parts of drug-loaded microspheres, 20-30 parts of PEG6000 and 4-5 parts of talc;

[0009] The isolation coating layer comprises the following raw materials in parts by weight: 7-10 parts of hydroxypropyl methylcellulose and 1-2 parts of talc;

[0010] The sustained-release coating layer comprises the following raw materials in parts by weight: 29-30 parts of ethyl cellulose 10cp, 11-13 parts of PEG6000 and 2-4 parts of triethyl citrate;

[0011] The preparation steps of the drug-loaded microspheres are as follows:

[0012] S1: Dissolve hexadecyltrimethylammonium bromide in deionized water, add ether, ammonia water and ethanol under magnetic stirring, then quickly add tetraethyl orthosilicate and KH-550 dropwise to the reaction system, stir for 4-6 hours, centrifuge and wash after the reaction, disperse it in ethanol, then add HCl, react at 70-75°C for 24-26 hours, centrifuge, wash and dry to obtain amino silica;

[0013] Preferably, in step S1, the dosage ratio of hexadecyltrimethylammonium bromide, ether, ammonia water, ethanol, tetraethyl orthosilicate, KH-550 and deionized water is 0.5-1g:3-5ml:0.1-1ml:1-2ml:15-25ml:1-2ml:100ml.

[0014] S2: adding the amino silica to N,N-dimethylformamide, adding succinic anhydride and triethanolamine, stirring for 6-7 hours, centrifuging, washing, and drying to obtain carboxylated porous silica;

[0015] Preferably, in step S2, the usage ratio of the amino silicon dioxide, N,N-dimethylformamide, succinic anhydride and triethanolamine is 1-2g 100-200ml 9-18g 4-5ml.

[0016] S3: melt mPEG at 65°C under vacuum, add PNC while stirring, keep for 2 hours, then add THF solution, react at 40°C for 1 hour to obtain mPEG solution, slowly add it to gelatin, stir evenly, dialyze for 3 days, and then freeze-dry to obtain GEL-PEG;

[0017] Preferably, the usage ratio of mPEG, PNC, THF and gelatin in step S3 is 0.25-0.3 g:16-20 mg:20 ml:1-2 g.

[0018] S4: carboxylated porous silica was added to deionized water, and then EDC was added. After stirring for 10 min, a solution was obtained. GEL-mPEG was dissolved in deionized water and stirred evenly. The two were mixed, stirred for 2 h, and then dialyzed for 3 days. The modified porous silica was lyophilized to obtain the solution.

[0019] Preferably, in step S4, the usage ratio of the carboxylated porous silica, deionized water, EDC, and GEL-mPEG is 2-4 g: 100-200 ml: 0.1 g: 3-5 g.

[0020] Preferably, the blank pellet core is any one of a microcrystalline cellulose pellet core and a sucrose pellet core, and the particle size is 0.3-0.8 mm.

[0021] Preferably, the molecular weight of the mPEG is 5000.

[0022] Preferably, the molecular weight of the gelatin is 100,000.

[0023] Furthermore, the present invention also provides a method for preparing memantine hydrochloride sustained-release capsules, comprising the following steps:

[0024] (1) dissolving hydroxypropyl methylcellulose in deionized water at 80-90° C. to obtain a hydroxypropyl methylcellulose solution; then dissolving PEG6000 and memantine hydrochloride in deionized water to obtain a memantine hydrochloride solution; mixing the hydroxypropyl methylcellulose solution and the memantine hydrochloride solution, stirring evenly, adding talcum powder and drug-loaded microspheres to obtain a drug-containing coating solution; spraying the drug-containing coating solution onto blank pill cores using a peristaltic pump, controlling the material temperature between 36° C. and 40° C., and drying for 5-10 minutes to obtain a main drug layer pellet;

[0025] (2) dissolving hydroxypropyl methylcellulose in deionized water at 80-90° C. to obtain a hydroxypropyl methylcellulose solution, then adding talcum powder, stirring evenly to obtain an isolation coating solution; using a peristaltic pump to spray the isolation coating solution onto the main drug layer pellets, controlling the material temperature between 36° C. and 40° C., and drying for 5-10 minutes to obtain isolation layer pellets;

[0026] (3) triethyl citrate, PEG6000 and deionized water are mixed and stirred to obtain a mixed solution, and then ethyl cellulose is added and stirred to obtain a sustained-release coating solution; the sustained-release coating solution is sprayed onto the isolation layer pellets using a peristaltic pump, the material temperature is controlled between 36° C. and 40° C., and the mixture is dried for 5 to 10 minutes to obtain memantine hydrochloride sustained-release pellets;

[0027] (4) The coated sustained-release pellets are loaded into hard gelatin capsules in a conventional manner to obtain memantine hydrochloride sustained-release capsules.

[0028] Beneficial effects of the present invention: The memantine hydrochloride sustained-release capsule of the present invention has a small difference in release amount whether at 0 days or at 10 days, which not only meets the standard of sustained release but also can exist relatively stably.

[0029] The memantine hydrochloride sustained-release capsule of the present invention is added with drug-loaded microspheres, which can serve as a physical barrier and enhance the overall mechanical properties. The drug-loaded microspheres are also loaded with a certain amount of memantine hydrochloride, and the double encapsulation of GEL-mPEG further ensures the sustained-release performance and stability, and does not cause a sudden release phenomenon. DETAILED DESCRIPTION

[0030] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments.

[0031] Embodiment 1: A method for preparing memantine hydrochloride sustained-release capsules, the specific steps are as follows:

[0032] (1) 0.5 g of hexadecyltrimethylammonium bromide was dissolved in deionized water, 3 ml of ether, 0.1 ml of ammonia water and 1 ml of ethanol were added under magnetic stirring, and the mixture was stirred at 1000 r / min for 30 min. Subsequently, 15 ml of tetraethyl orthosilicate and 1 ml of KH-550 were rapidly added dropwise to the reaction system, and the mixture was stirred at 2000 r / min for 4 h. After the reaction was completed, the mixture was centrifuged at 8000 r / min for 10 min, and the precipitate was washed 3 times with anhydrous ethanol, and then dispersed in ethanol. HCl was then added, and the mixture was reacted at 70° C. for 24-26 h, and then centrifuged at 8000 r / min for 15 min. The precipitate was washed 3 times with anhydrous ethanol, and dried to obtain amino silica;

[0033] (2) Add 1 g of amino-modified silica to 100 ml of N,N-dimethylformamide, add 9 g of succinic anhydride and 4 ml of triethanolamine, stir for 6 h, centrifuge at 8000 r / min for 10 min, wash the precipitate with anhydrous ethanol three times, and dry to obtain carboxylated porous silica;

[0034] (3) Melt 0.25 g mPEG at 65 °C under vacuum, add 16 mg PNC while stirring, keep for 2 h, then add 20 ml THF solution, react at 40 °C for 1 h to obtain mPEG solution, slowly add it to 1 g gelatin, stir evenly, dialyze for 3 days, and then freeze-dry to obtain GEL-PEG;

[0035] (4) 2 g of carboxylated porous silica was added to 100 ml of deionized water, followed by the addition of 0.1 g of EDC, and the mixture was stirred for 10 min to obtain a solution. 3 g of GEL-mPEG was dissolved in 5 ml of deionized water and stirred evenly. The two were mixed, stirred for 2 h, and then dialyzed for 3 days, and freeze-dried to obtain the modified porous silica.

[0036] (5) 0.2 g of memantine hydrochloride was dissolved in 200 ml of deionized water, and then 0.8 g of modified porous silica was added and stirred for 24 h, dialyzed, and freeze-dried to obtain drug-loaded microspheres;

[0037] (6) Dissolving hydroxypropyl methylcellulose in deionized water at 80° C. to obtain a hydroxypropyl methylcellulose solution; then dissolving PEG6000 and memantine hydrochloride in deionized water to obtain a memantine hydrochloride solution; mixing the hydroxypropyl methylcellulose solution and the memantine hydrochloride solution, stirring evenly, adding talcum powder and drug-loaded microspheres to obtain a drug-containing coating solution; manually adding blank pill cores into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 35° C., using a peristaltic pump to spray the drug-containing coating solution onto the blank pill cores, controlling the material temperature between 36° C., and drying for 5 minutes to obtain a main drug layer pellet;

[0038] (7) dissolving hydroxypropyl methylcellulose in deionized water at 80° C. to obtain a hydroxypropyl methylcellulose solution, then adding talcum powder, stirring evenly to obtain an isolation coating solution; manually adding the main drug layer pellets into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 35° C., using a peristaltic pump to spray the isolation coating solution onto the main drug layer pellets, controlling the material temperature at 36° C., and drying for 5 minutes to obtain isolation layer pellets;

[0039] (8) Triethyl citrate, PEG6000 and deionized water are mixed and stirred to obtain a mixed solution, and then ethyl cellulose is added and stirred to obtain a sustained-release coating solution; the isolation layer pellets are added into the material barrel of the fluidized bed by manual feeding, and heating is started until the material temperature is maintained at 35° C. The sustained-release coating solution is sprayed onto the isolation layer pellets by a peristaltic pump, and the material temperature is controlled at 36° C. The pellets are dried for 5 minutes to obtain isolation layer pellets of memantine hydrochloride sustained-release pellets.

[0040] Embodiment 2: A method for preparing memantine hydrochloride sustained-release capsules, the specific steps are as follows:

[0041] (1) 0.8 g of hexadecyltrimethylammonium bromide was dissolved in deionized water, 4 ml of ether, 0.4 ml of ammonia water and 1 ml of ethanol were added under magnetic stirring, and the mixture was stirred at 1500 r / min for 50 min. Subsequently, 20 ml of tetraethyl orthosilicate and 2 ml of KH-550 were rapidly added dropwise to the reaction system, and the mixture was stirred at 4000 r / min for 5 h. After the reaction was completed, the mixture was centrifuged at 9000 r / min for 14 min, and the precipitate was washed with anhydrous ethanol for 4 times, and then dispersed in ethanol. HCl was then added, and the mixture was reacted at 74° C. for 25 h, and then centrifuged at 9000 r / min for 19 min. The precipitate was washed with anhydrous ethanol for 4 times, and dried to obtain amino silica;

[0042] (2) Add 1.5 g of amino-modified silica to 150 ml of N,N-dimethylformamide, add 15 g of succinic anhydride and 5 ml of triethanolamine, stir for 7 h, centrifuge at 12000 r / min for 15 min, wash the precipitate with anhydrous ethanol 5 times, and dry to obtain carboxylated porous silica;

[0043] (3) 0.28 g mPEG was melted at 65 °C under vacuum, and 18 mg PNC was added while stirring for 2 h. Then 20 ml THF solution was added and reacted at 40 °C for 1 h to obtain mPEG solution, which was slowly added to 1.5 g gelatin, stirred evenly, dialyzed for 3 days, and then freeze-dried to obtain GEL-PEG;

[0044] (4) 3 g of carboxylated porous silica was added to 150 ml of deionized water, followed by the addition of 0.1 g of EDC, and the mixture was stirred for 10 min to obtain a solution. 34 g of GEL-mPEG was dissolved in 8 ml of deionized water and stirred evenly. The two were mixed, stirred for 2 h, and then dialyzed for 3 days, and freeze-dried to obtain the modified porous silica.

[0045] (5) 0.25 g of memantine hydrochloride was dissolved in 250 ml of deionized water, and then 0.9 g of modified porous silica was added and stirred for 24 h, dialyzed, and freeze-dried to obtain drug-loaded microspheres;

[0046] (6) Dissolving hydroxypropyl methylcellulose in deionized water at 85° C. to obtain a hydroxypropyl methylcellulose solution; then dissolving PEG6000 and memantine hydrochloride in deionized water to obtain a memantine hydrochloride solution; mixing the hydroxypropyl methylcellulose solution and the memantine hydrochloride solution, stirring evenly, adding talcum powder and drug-loaded microspheres to obtain a drug-containing coating solution; manually adding blank pill cores into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 35° C., using a peristaltic pump to spray the drug-containing coating solution onto the blank pill cores, controlling the material temperature at 36° C., and drying for 10 minutes to obtain a main drug layer pellet;

[0047] (7) dissolving hydroxypropyl methylcellulose in deionized water at 85° C. to obtain a hydroxypropyl methylcellulose solution, then adding talcum powder, stirring evenly to obtain an isolation coating solution; manually adding the main drug layer pellets into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 40° C., using a peristaltic pump to spray the isolation coating solution onto the main drug layer pellets, controlling the material temperature at 36° C., and drying for 10 minutes to obtain isolation layer pellets;

[0048] (8) Triethyl citrate, PEG6000 and deionized water are mixed and stirred to obtain a mixed solution, and then ethyl cellulose is added and stirred to obtain a sustained-release coating solution; the isolation layer pellets are added into the material barrel of the fluidized bed by manual feeding, and heating is started until the material temperature is maintained at 40° C. The sustained-release coating solution is sprayed onto the isolation layer pellets by a peristaltic pump, and the material temperature is controlled at 40° C. The pellets are dried for 10 minutes to obtain isolation layer pellets of memantine hydrochloride sustained-release pellets.

[0049] Embodiment 3: A method for preparing memantine hydrochloride sustained-release capsules, the specific steps are as follows:

[0050] (1) 1 g of hexadecyltrimethylammonium bromide was dissolved in deionized water, and 5 ml of ether, 1 ml of ammonia water and 2 ml of ethanol were added under magnetic stirring, and the mixture was stirred at 2000 r / min for 60 min. Subsequently, 25 ml of tetraethyl orthosilicate and 2 ml of KH-550 were rapidly added dropwise to the reaction system, and the mixture was stirred at 5000 r / min for 6 h. After the reaction was completed, the mixture was centrifuged at 12000 r / min for 15 min, and the precipitate was washed with anhydrous ethanol for 5 times, and then dispersed in ethanol. HCl was then added, and the mixture was reacted at 5° C. for 26 h, and then the mixture was centrifuged at 12000 r / min for 20 min. The precipitate was washed with anhydrous ethanol for 5 times, and then dried to obtain amino silica;

[0051] (2) Add 2 g of amino-modified silica to 200 ml of N,N-dimethylformamide, add 18 g of succinic anhydride and 5 ml of triethanolamine, stir for 7 h, centrifuge at 12000 r / min for 15 min, wash the precipitate with anhydrous ethanol 5 times, and dry to obtain carboxylated porous silica;

[0052] (3) 0.3 g mPEG was melted at 65 °C under vacuum, and 20 mg PNC was added while stirring for 2 h. Then 20 ml THF solution was added and reacted at 40 °C for 1 h to obtain mPEG solution, which was slowly added to 2 g gelatin. After stirring, the solution was dialyzed for 3 days and then freeze-dried to obtain GEL-PEG.

[0053] (4) 4 g of carboxylated porous silica was added to 200 ml of deionized water, followed by the addition of 0.1 g of EDC, and the mixture was stirred for 10 min to obtain a solution. 5 g of GEL-mPEG was dissolved in 10 ml of deionized water and stirred evenly. The two were mixed, stirred for 2 h, and then dialyzed for 3 days, and freeze-dried to obtain modified porous silica.

[0054] (5) 0.3 g of memantine hydrochloride was dissolved in 300 ml of deionized water, and then 1 g of modified porous silica was added and stirred for 24 h, dialyzed, and freeze-dried to obtain drug-loaded microspheres;

[0055] (6) Dissolving hydroxypropyl methylcellulose in deionized water at 90° C. to obtain a hydroxypropyl methylcellulose solution; then dissolving PEG6000 and memantine hydrochloride in deionized water to obtain a memantine hydrochloride solution; mixing the hydroxypropyl methylcellulose solution and the memantine hydrochloride solution, stirring evenly, adding talcum powder and drug-loaded microspheres to obtain a drug-containing coating solution; manually adding blank pill cores into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 40° C., using a peristaltic pump to spray the drug-containing coating solution onto the blank pill cores, controlling the material temperature at 40° C., and drying for 10 minutes to obtain a main drug layer pellet;

[0056] (7) dissolving hydroxypropyl methylcellulose in deionized water at 90° C. to obtain a hydroxypropyl methylcellulose solution, then adding talcum powder, stirring evenly to obtain an isolation coating solution; manually adding the main drug layer pellets into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 40° C., using a peristaltic pump to spray the isolation coating solution onto the main drug layer pellets, controlling the material temperature at 40° C., and drying for 10 minutes to obtain isolation layer pellets;

[0057] (8) Triethyl citrate, PEG6000 and deionized water are mixed and stirred to obtain a mixed solution, and then ethyl cellulose is added and stirred to obtain a sustained-release coating solution; the isolation layer pellets are added into the material barrel of the fluidized bed by manual feeding, and heating is started until the material temperature is maintained at 40° C. The sustained-release coating solution is sprayed onto the isolation layer pellets by a peristaltic pump, and the material temperature is controlled at 40° C. The pellets are dried for 10 minutes to obtain isolation layer pellets of memantine hydrochloride sustained-release pellets.

[0058] Comparative Example 1: A method for preparing memantine hydrochloride sustained-release capsules, the specific steps are as follows:

[0059] (1) 0.8 g of hexadecyltrimethylammonium bromide was dissolved in deionized water, 4 ml of ether, 0.4 ml of ammonia water and 1 ml of ethanol were added under magnetic stirring, and the mixture was stirred at 1500 r / min for 50 min. Subsequently, 20 ml of tetraethyl orthosilicate and 2 ml of KH-550 were rapidly added dropwise to the reaction system, and the mixture was stirred at 4000 r / min for 5 h. After the reaction was completed, the mixture was centrifuged at 9000 r / min for 14 min, and the precipitate was washed with anhydrous ethanol for 4 times, and then dispersed in ethanol. HCl was then added, and the mixture was reacted at 74° C. for 25 h, and then centrifuged at 9000 r / min for 19 min. The precipitate was washed with anhydrous ethanol for 4 times, and dried to obtain amino silica;

[0060] (2) Add 1.5 g of amino-modified silica to 150 ml of N,N-dimethylformamide, add 15 g of succinic anhydride and 5 ml of triethanolamine, stir for 7 h, centrifuge at 12000 r / min for 15 min, wash the precipitate with anhydrous ethanol 5 times, and dry to obtain carboxylated porous silica;

[0061] (3) 0.28 g mPEG was melted at 65 °C under vacuum, 18 mg PNC was added while stirring, and the mixture was kept for 2 h. Then 20 ml THF solution was added and reacted at 40 °C for 1 h to obtain mPEG solution. 3 g carboxylated porous silica was added to 150 ml deionized water, and then 0.1 g EDC was added and stirred for 10 min to obtain a solution. 34 g GEL-mPEG was dissolved in 8 ml deionized water and stirred evenly. The two were mixed, stirred for 2 h, and then dialyzed for 3 days. The modified porous silica was lyophilized to obtain the modified porous silica.

[0062] (4) 0.25 g of memantine hydrochloride was dissolved in 250 ml of deionized water, and then 0.9 g of modified porous silica was added and stirred for 24 h, dialyzed, and freeze-dried to obtain drug-loaded microspheres;

[0063] (5) dissolving hydroxypropyl methylcellulose in deionized water at 85° C. to obtain a hydroxypropyl methylcellulose solution; then dissolving PEG6000 and memantine hydrochloride in deionized water to obtain a memantine hydrochloride solution; mixing the hydroxypropyl methylcellulose solution and the memantine hydrochloride solution, stirring evenly, adding talcum powder and drug-loaded microspheres to obtain a drug-containing coating solution; manually adding blank pill cores into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 35° C., using a peristaltic pump to spray the drug-containing coating solution onto the blank pill cores, controlling the material temperature at 36° C., and drying for 10 minutes to obtain a main drug layer pellet;

[0064] (6) dissolving hydroxypropyl methylcellulose in deionized water at 85° C. to obtain a hydroxypropyl methylcellulose solution, then adding talcum powder, stirring evenly to obtain an isolation coating solution; manually adding the main drug layer pellets into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 40° C., using a peristaltic pump to spray the isolation coating solution onto the main drug layer pellets, controlling the material temperature at 36° C., and drying for 10 minutes to obtain isolation layer pellets;

[0065] (7) Triethyl citrate, PEG6000 and deionized water are mixed and stirred to obtain a mixed solution, and then ethyl cellulose is added and stirred to obtain a sustained-release coating solution; the isolation layer pellets are added into the material barrel of the fluidized bed by manual feeding, and heating is started until the material temperature is maintained at 40° C. The sustained-release coating solution is sprayed onto the isolation layer pellets by a peristaltic pump, and the material temperature is controlled at 40° C. The pellets are dried for 10 minutes to obtain isolation layer pellets of memantine hydrochloride sustained-release pellets.

[0066] Comparative Example 2: A method for preparing memantine hydrochloride sustained-release capsules, the specific steps are as follows:

[0067] (1) 0.8 g of hexadecyltrimethylammonium bromide was dissolved in deionized water, 4 ml of ether, 0.4 ml of ammonia water and 1 ml of ethanol were added under magnetic stirring, and the mixture was stirred at 1500 r / min for 50 min. Subsequently, 20 ml of tetraethyl orthosilicate and 2 ml of KH-550 were rapidly added dropwise to the reaction system, and the mixture was stirred at 4000 r / min for 5 h. After the reaction was completed, the mixture was centrifuged at 9000 r / min for 14 min, and the precipitate was washed with anhydrous ethanol for 4 times, and then dispersed in ethanol. HCl was then added, and the mixture was reacted at 74° C. for 25 h, and then centrifuged at 9000 r / min for 19 min. The precipitate was washed with anhydrous ethanol for 4 times, and dried to obtain amino silica;

[0068] (2) Add 1.5 g of amino-modified silica to 150 ml of N,N-dimethylformamide, add 15 g of succinic anhydride and 5 ml of triethanolamine, stir for 7 h, centrifuge at 12000 r / min for 15 min, wash the precipitate with anhydrous ethanol 5 times, and dry to obtain carboxylated porous silica;

[0069] (3) 0.25 g of memantine hydrochloride was dissolved in 250 ml of deionized water, and then 0.9 g of carboxylated porous silica was added and stirred for 24 h, dialyzed, and freeze-dried to obtain drug-loaded microspheres;

[0070] (4) dissolving hydroxypropyl methylcellulose in deionized water at 85° C. to obtain a hydroxypropyl methylcellulose solution; then dissolving PEG6000 and memantine hydrochloride in deionized water to obtain a memantine hydrochloride solution; mixing the hydroxypropyl methylcellulose solution and the memantine hydrochloride solution, stirring evenly, adding talcum powder and drug-loaded microspheres to obtain a drug-containing coating solution; manually adding blank pill cores into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 35° C., using a peristaltic pump to spray the drug-containing coating solution onto the blank pill cores, controlling the material temperature at 36° C., and drying for 10 minutes to obtain a main drug layer pellet;

[0071] (5) dissolving hydroxypropyl methylcellulose in deionized water at 85° C. to obtain a hydroxypropyl methylcellulose solution, then adding talcum powder, stirring evenly to obtain an isolation coating solution; manually adding the main drug layer pellets into the material barrel of the fluidized bed, starting heating until the material temperature is maintained at 40° C., using a peristaltic pump to spray the isolation coating solution onto the main drug layer pellets, controlling the material temperature at 36° C., and drying for 10 minutes to obtain isolation layer pellets;

[0072] (6) Triethyl citrate, PEG6000 and deionized water are mixed and stirred to obtain a mixed solution, and then ethyl cellulose is added and stirred to obtain a sustained-release coating solution; the isolation layer pellets are added into the material barrel of the fluidized bed by manual feeding, and heating is started until the material temperature is maintained at 40° C., and the sustained-release coating solution is sprayed onto the isolation layer pellets by a peristaltic pump, and the material temperature is controlled at 40° C. and dried for 10 minutes to obtain isolation layer pellets of memantine hydrochloride sustained-release pellets.

[0073] Comparative Example 3: A method for preparing memantine hydrochloride sustained-release capsules, the specific steps are as follows:

[0074] The difference from Example 2 is that there are no drug-loaded microspheres, and the remaining steps are the same as Example 2.

[0075] Performance Testing

[0076] The memantine hydrochloride sustained-release capsules prepared in the examples and comparative examples were placed in a 92.5% high humidity environment, and samples were taken at 0d, 5d, and 10d. According to the dissolution test method of the Chinese Pharmacopoeia, the basket method was used, and the sustained-release capsules were tested for dissolution curves at 100 rpm in 900 ml, 37°C pH 1.2 buffer solution. The test results are shown in Table 1:

[0077] Table 1 Performance test results

[0078]

[0079] Data analysis: The memantine hydrochloride sustained-release capsules of the present invention have a small difference in release amount whether at 0 days or at 10 days, which not only meets the standard of sustained release but also can exist relatively stably.

[0080] The memantine hydrochloride sustained-release capsule of the present invention has both sustained-release performance and stability significantly improved by adding drug-loaded microspheres. This is mainly because, on the one hand, the drug-loaded microspheres can serve as a physical barrier to isolate the contact area of ​​the remaining water, and can enhance the overall mechanical properties, making the interior more stable and able to exist in the body for a longer time; on the other hand, it also carries a certain amount of memantine hydrochloride, and at the same time, through the double encapsulation of GEL-mPEG, the sustained-release performance and stability are further guaranteed, and the sudden release phenomenon will not occur.

[0081] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention is limited to these examples. Under the concept of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

Claims

1. A memantine hydrochloride sustained-release capsule, characterized in that: The memantine hydrochloride sustained-release capsule is filled with memantine hydrochloride sustained-release pills; the sustained-release pills sequentially include a blank pill core, a main drug layer, an isolation coating layer, and a sustained-release coating layer from the inside out; The main drug layer comprises the following raw materials in parts by weight: 25-30 parts of memantine hydrochloride, 3-7 parts of hydroxypropyl methylcellulose E, 1-2 parts of drug-loaded microspheres, 20-30 parts of PEG6000 and 4-5 parts of talc; The isolation coating layer comprises the following raw materials in parts by weight: 7-10 parts of hydroxypropyl methylcellulose and 1-2 parts of talc; The sustained-release coating layer comprises the following raw materials in parts by weight: 29-30 parts of ethyl cellulose 10cp, 11-13 parts of PEG6000 and 2-4 parts of triethyl citrate; The preparation steps of the drug-loaded microspheres are as follows: S1: Dissolve hexadecyltrimethylammonium bromide in deionized water, add ether, ammonia water and ethanol under magnetic stirring, then quickly add tetraethyl orthosilicate and KH-550 dropwise to the reaction system, stir for 4-6 hours, centrifuge and wash after the reaction, disperse it in ethanol, then add HCl, react at 70-75°C for 24-26 hours, centrifuge, wash and dry to obtain amino silica; The usage ratio of hexadecyltrimethylammonium bromide, ether, ammonia water, ethanol, tetraethyl orthosilicate, KH-550 and deionized water in step S1 is 0.5-1g:3-5ml:0.1-1ml:1-2ml:15-25ml:1-2ml:100ml; S2: adding the amino silica to N,N-dimethylformamide, adding succinic anhydride and triethanolamine, stirring for 6-7 hours, centrifuging, washing, and drying to obtain carboxylated porous silica; In step S2, the usage ratio of the amino silicon dioxide, N,N-dimethylformamide, succinic anhydride and triethanolamine is 1-2g 100-200ml 9-18g 4-5ml; S3: mPEG was melted at 65°C under vacuum, and PNC was added while stirring for 2 h. Then THF solution was added and reacted at 40°C for 1 h to obtain mPEG solution, which was slowly added to gelatin. After stirring evenly, it was dialyzed for 3 days and then freeze-dried to obtain GEL-PEG. The ratio of mPEG, PNC, THF and gelatin used in step S3 is 0.25-0.3 g:16-20 mg:20 ml:1-2 g; S4: carboxylated porous silica was added to deionized water, and then EDC was added. After stirring for 10 min, a solution was obtained. GEL-mPEG was dissolved in deionized water and stirred evenly. The two were mixed, stirred for 2 h, and then dialyzed for 3 days. The modified porous silica was lyophilized to obtain the solution. The usage ratio of the carboxylated porous silica, deionized water, EDC, and GEL-mPEG in step S4 is 2-4 g: 100-200 ml: 0.1 g: 3-5 g.

2. The memantine hydrochloride sustained-release capsule according to claim 1, characterized in that The blank pellet core is any one of a microcrystalline cellulose pellet core and a sucrose pellet core, and the particle size is 0.3-0.8 mm.

3. A method for preparing the memantine hydrochloride sustained-release capsule according to any one of claims 1 to 2, characterized in that: The following steps are involved: (1) Dissolving hydroxypropyl methylcellulose in deionized water at 80-90° C. to obtain a hydroxypropyl methylcellulose solution; then dissolving PEG6000 and memantine hydrochloride in deionized water to obtain a memantine hydrochloride solution; mixing the hydroxypropyl methylcellulose solution and the memantine hydrochloride solution, stirring evenly, adding talcum powder and drug-loaded microspheres to obtain a drug-containing coating solution; using a peristaltic pump to spray the drug-containing coating solution onto the blank pill core, controlling the material temperature between 36° C. and 40° C., and drying for 5-10 minutes to obtain a main drug layer pellet; (2) dissolving hydroxypropyl methylcellulose in deionized water at 80-90°C to obtain a hydroxypropyl methylcellulose solution, then adding talcum powder and stirring evenly to obtain an isolation coating solution; spraying the isolation coating solution onto the main drug layer pellets using a peristaltic pump, controlling the material temperature between 36°C and 40°C, and drying for 5-10 minutes to obtain isolation layer pellets; (3) triethyl citrate, PEG6000 and deionized water are mixed and stirred to obtain a mixed solution, and then ethyl cellulose is added and stirred to obtain a sustained-release coating solution; the sustained-release coating solution is sprayed onto the isolation layer pellets using a peristaltic pump, the material temperature is controlled between 36°C and 40°C, and dried for 5-10 minutes to obtain memantine hydrochloride sustained-release pellets; (4) The coated sustained-release pellets are loaded into hard gelatin capsules in a conventional manner to obtain memantine hydrochloride sustained-release capsules.

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