CN114748443A - Memantine hydrochloride sustained-release pellet and preparation method thereof - Google Patents
Memantine hydrochloride sustained-release pellet and preparation method thereof Download PDFInfo
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- CN114748443A CN114748443A CN202210420833.8A CN202210420833A CN114748443A CN 114748443 A CN114748443 A CN 114748443A CN 202210420833 A CN202210420833 A CN 202210420833A CN 114748443 A CN114748443 A CN 114748443A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a sustained-release pellet containing memantine hydrochloride and a preparation method thereof. The memantine hydrochloride sustained-release pellet comprises a blank pellet core, a drug loading coating layer, an isolation coating layer and a sustained-release coating layer, wherein sustained-release materials of the sustained-release coating layer mainly comprise ethyl cellulose aqueous dispersion and contain hydroxyethyl cellulose in a proper proportion. The memantine hydrochloride sustained-release pellets can be further prepared into sustained-release preparations such as granules, capsules or tablets. The invention utilizes the incompatible film formed by dispersing and wrapping the water-soluble hydroxyethyl cellulose around the hydrophobic ethyl cellulose and the water absorption thereof to retard the further aggregation and fusion of the ethyl cellulose, thereby obtaining the memantine hydrochloride sustained-release pellet with better stability, and the invention has no use of organic solvents such as ethanol, and the like, is more economical, environment-friendly and safe, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a medicinal preparation containing memantine hydrochloride sustained-release pellets and a preparation method thereof.
Technical Field
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Memantine Hydrochloride (Memantine Hydrochloride), an N-methyl-D-aspartate (NMDA) receptor antagonist, is the first drug to treat dementia of the moderate to severe alzheimer type, and it binds preferentially to the cation channels manipulated by the NMDA receptor, which may be relevant for its therapeutic effect. Foremost in 2003, memantine hydrochloride tablets were developed under the name Namenda; the company subsequently developed an oral solution of memantine hydrochloride in 2005, with a specification of 2 mg/ml. Memantine hydrochloride sustained release capsules were also developed by Forest Laboratories LLC and were approved for sale in the united states at 6 months 2010 under the trade name Namenda XR and having specifications of 7mg, 14mg, 21mg and 28mg, and have been approved for sale in countries in the united states, argentina, and the like. With the aging of the population in China and the attention on Alzheimer's disease, the memantine hydrochloride preparation has better application prospect.
Because the Alzheimer disease needs to be taken for a long time, compared with common tablets and oral solutions, the memantine hydrochloride sustained-release capsule can reduce the taking times, improve the medication compliance of patients, ensure that the sustained-release preparation has a more stable drug release process, and avoid the safety and effectiveness problems possibly caused by large fluctuation of blood concentration. However, compared with the common preparation, the preparation process of the sustained-release preparation is relatively complex, the technical difficulty is higher, and the sustained-release preparation is mainly embodied in two aspects, firstly, the drug release needs to have the sustained, uniform and slow drug release characteristics without burst release behavior; secondly, the stability is good, and the change of drug release characteristics along with storage conditions or time is avoided. Therefore, how to develop a product with good sustained-release behavior and good stability is a key technical problem for developing a memantine hydrochloride sustained-release preparation.
The oral sustained-release solid preparation can be simply divided into a unit administration preparation (such as a sustained-release tablet) and a multi-unit administration preparation (such as a sustained-release pellet and a micro-tablet), compared with the sustained-release tablet, the multi-unit administration preparation disperses the medicine in a plurality of independent units, the multi-unit administration preparation can disperse after entering the body, the influence of food is small, the influence of the abnormity of the individual unit medicine release behavior on the whole medicine release behavior of the preparation is small, the medicine release behavior is more stable, the local irritation of the medicine is also avoided, the oral sustained-release solid preparation has obvious clinical application advantages, and the former research manufacturer Forest Laboratories LLC develops the medicine into the memantine hydrochloride sustained-release pellet with the characteristic of multi-unit administration.
According to Namenda XR review information and product use instructions published by FDA, Namenda XR selects a blank sucrose pellet core as a carrier, adopts a fluidized bed bottom spraying technology to coat memantine hydrochloride on the blank pellet core, and uses ethyl cellulose aqueous dispersion as a slow release material to carry out slow release coating and other treatments. Although the ethyl cellulose aqueous dispersion is widely applied to a pharmaceutical preparation as a common slow-release coating material, the film forming mechanism of the aqueous dispersion is complex, and instability phenomenon exists in drug release control, namely physical aging problem, so that the preparation process of a slow-release preparation using the material is complex, the aging problem of the preparation is difficult to effectively solve, and the stability problem of product dissolution rate reduction of the original developing agent Namenda XR also exists under the condition of high temperature.
The patent CN 103181914B extrudes and rolls the round pellets or the drug-containing pellets obtained by solution drug application or suspension drug application, and carries out sustained-release coating on the drug-containing pellets with controllable shape and granularity, so that the thickness of the film formed by the coating is controllable, and the drug release can be sustained and more uniformly and slowly released. However, the used slow-release coating solution is a polyacrylic resin aqueous dispersion, and the problem of physical aging also exists, the aging time needs 24 hours, and the energy consumption is high; meanwhile, memantine hydrochloride is a medicament which is easy to dissolve in water, and the risk of migration of a medicament-containing layer to a slow release layer exists; in addition, organic solvents such as ethanol and the like are used in the preparation process, so that the explosion-proof requirement of equipment and the safety problem of production operation are increased.
In patent CN 104013592B, an isolation coating layer is added between the drug-containing pellets containing memantine hydrochloride and the sustained-release coating layer, so that the problems of drug migration and burst release in a high-humidity environment are solved, and meanwhile, the sustained-release material of the sustained-release layer mainly selects ethyl cellulose solid powder and is prepared into sustained-release layer coating liquid through ethanol dissolution, so that aggregation and fusion of ethyl cellulose aqueous dispersion are avoided, and the stability is relatively improved. However, because ethyl cellulose has poor water solubility, a large amount of high-concentration ethanol needs to be used for dissolution in the preparation process, so that the solvent cost is increased, and the explosion-proof performance requirement and the safety production risk of equipment are increased.
Patents CN 103816135B and CN 105769794B have modified sustained release pellets into micro-tablets or compressed pellets into pellet tablets, although the preparation process is relatively simple, the consistency is not comparable to the original drug formulation, and the clinical advantage of multi-unit drug delivery dosage form is not achieved.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a memantine hydrochloride sustained-release capsule which has the characteristics of continuous, uniform and slow release, no burst release behavior and good stability and a preparation method thereof, thereby providing more reliable technical support for the treatment of patients with Alzheimer disease type dementia by memantine hydrochloride.
As can be seen from the FDA approval information and the instruction of use of the original developer Namenda XR, the formulation of Namenda XR is composed of memantine hydrochloride, sucrose pellet cores (sugar spheres), povidone (polyvinylpyrrolidone), hypromellose (hypromellose), talc (talc), polyethylene glycol (polyethylene glycol), ethylcellulose (ethylcellulose), ammonium hydroxide (ammonium hydroxide), oleic acid (oleic acid), medium chain triglyceride (medium chain triglyceride), and gelatin hollow capsules (hard gelatin capsules), and the combination of the commercially available preparation process and formulation of the aqueous dispersion of ethylcellulose indicates that ethylcellulose, ammonium hydroxide, oleic acid, and medium chain triglyceride in the original developer formulation are the aqueous dispersion of ethylcellulose. Meanwhile, the dissolution rate of the original developer Namenda XR is determined to show that the dissolution rate of the Namenda XR shows a descending trend under an accelerating condition (40 +/-2 ℃ and 75 +/-5% RH), and the dissolution rate is more obviously reduced under a high-temperature condition of 60 ℃, so that the storage condition is specified to be 20-25 ℃ for storage, and the effective period is specified to be shorter 2 years, but the potential stability problem can cause the reduction of the product effectiveness. This stability problem is mainly due to the use of an aqueous ethylcellulose dispersion as a slow-release material. Although the ethyl cellulose aqueous dispersion is widely applied to pharmaceutical preparations as a common slow-release coating material, the film forming mechanism of the aqueous dispersion is complex, and instability phenomenon exists in drug release control, namely physical aging problem, so that the preparation process of the slow-release preparation using the material is complex. Therefore, it is necessary to solve the problem of dissolution stability of the product in vitro by adopting a proper preparation process or a proper prescription.
In the research of the invention, the film forming process of the polymer water dispersion of the ethyl cellulose is roughly divided into 3 stages, firstly, in the initial stage of application, polymer particles are deposited on the surface of a material, and at the moment, water volatilizes at a certain evaporation rate; secondly, capillary pore canals are formed in the water evaporation process, so that polymer particles are drawn close by using the capillary acting force, and the water evaporation rate is gradually reduced in the stage; finally, the rate of water evaporation plateaus and polymer film formation is generally considered complete. However, as moisture diffuses between the polymers, the polymer film further coalesces, making the polymer film denser, a process known as physical aging. Although the problem of physical aging can be prevented by sufficiently diffusing water among polymers through long-time high-temperature treatment, the process is slow, the curing treatment time in the preparation process is not enough to be completely solved, and the energy consumption cost in the production process is high due to long-time high temperature treatment. Through a large number of experimental researches and explorations, the invention unexpectedly discovers that when a certain amount of hydroxyethyl cellulose is added into the ethyl cellulose aqueous dispersion, particularly the mass ratio of the hydroxyethyl cellulose to the ethyl cellulose aqueous dispersion is 1-2: 15, the prepared memantine hydrochloride sustained-release pellet has better dissolution stability under accelerated and long-term conditions, and the innovation is also the point of the invention. The reason may be that water-soluble hydroxyethyl cellulose is added into the ethyl cellulose water dispersion to form an incompatible film wrapped around the hydrophobic ethyl cellulose, so that the further aggregation and fusion of the ethyl cellulose are retarded, and meanwhile, as the hydroxyethyl cellulose has stronger hygroscopicity, water in the formed polymer film is mainly concentrated in the hydroxyethyl cellulose, the further aggregation and fusion of the ethyl cellulose film are retarded, so that the stability of the polymer film is improved.
Specifically, the technical scheme of the invention is as follows:
one of the purposes of the invention is to provide a memantine hydrochloride sustained-release pellet with good sustained-release behavior and good stability, which consists of a blank pellet core, a drug-carrying coating layer, an isolation coating layer and a sustained-release coating layer, wherein the sustained-release coating layer comprises an ethyl cellulose aqueous dispersion and hydroxyethyl cellulose, and the mass ratio of the ethyl cellulose aqueous dispersion to the hydroxyethyl cellulose is 15: 1 to 2. .
Further, the memantine hydrochloride sustained-release pellet disclosed by the invention has the advantages that the blank pellet core is selected from a sucrose pellet core or a microcrystalline cellulose pellet core, the sucrose pellet core is preferred, and the particle size of the blank pellet core is 0.60-0.71 mm.
Further, the memantine hydrochloride sustained-release pellet comprises a drug-loading coating layer, a binder and an anti-sticking agent; the adhesive is selected from one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose, preferably the adhesive is polyvinylpyrrolidone, and the antisticking agent is talcum powder; the mass ratio of the memantine hydrochloride, the adhesive and the anti-sticking agent is 10: 2-5: 0.5-1.5, and the optimal mass ratio is 10: 3.5: 1.
further, the isolation coating layer of the memantine hydrochloride sustained-release pellet comprises hydroxypropyl methylcellulose, polyethylene glycol and talcum powder; the mass ratio of the hydroxypropyl methylcellulose, the polyethylene glycol and the talcum powder is 10: 1-3: 1-3, wherein the optimal mass ratio is 10: 2: 2.
further, the memantine hydrochloride sustained-release pellet comprises a sustained-release coating layer, wherein the sustained-release coating layer comprises ethyl cellulose aqueous dispersion, a pore-forming agent, hydroxyethyl cellulose and an anti-sticking agent, the pore-forming agent is selected from one or more of triethyl citrate, polyethylene glycol, triglyceride and dibutyl sebacate, the polyethylene glycol is preferred, and the anti-sticking agent is talcum powder; the mass ratio of the ethyl cellulose aqueous dispersion to the pore-foaming agent to the hydroxyethyl cellulose to the anti-sticking agent is 30: 1.5-4.0: 2-4: 0.5-1.5, and the optimal mass ratio is 30: 2.5: 3: 1.
the invention also aims to provide a memantine hydrochloride sustained-release preparation which is prepared by adopting the memantine hydrochloride sustained-release pellet. The sustained-release pellet can be directly used as granules, can be coated with enteric coating to prepare enteric-coated pellets, and can be filled into empty capsules to prepare sustained-release capsules or compressed into tablets for use.
One specific example of the invention is a memantine hydrochloride sustained release capsule, the dosage of memantine hydrochloride is 7mg, 14mg, 21mg or 28mg per unit dose.
The invention also aims to provide a preparation method of the memantine hydrochloride sustained-release pellet.
The preparation method of the memantine hydrochloride sustained-release pellet comprises the following steps: respectively preparing a drug-loaded layer, an isolation layer and a sustained-release coating solution according to the prescription amount, applying the drug to the hollow pellet core by adopting a fluidized bed bottom spraying mode, and sequentially coating the drug-loaded layer, the isolation layer and the sustained-release layer to prepare the sustained-release pellet. And filling the qualified sustained-release pellets into a hard capsule shell to further obtain the memantine hydrochloride sustained-release capsule.
Furthermore, in the drug-loaded layer coating process, the memantine hydrochloride sustained-release pellet provided by the invention is prepared by firstly crushing memantine hydrochloride to obtain micropowder with the particle size D90 being below 15 microns, and dispersing the micronized memantine hydrochloride, an adhesive and an anti-sticking agent into purified water to prepare a drug-loaded layer coating solution; and then adding the blank pellet core into a fluidized bed pan, spraying a drug-loaded layer coating solution into the pan for coating, controlling the temperature of the material to be between 25 and 35 ℃ in the coating process, and drying the material for 10min when the coating is finished and the temperature of the material reaches 40 to 55 ℃ to obtain the drug-loaded pellet containing memantine hydrochloride.
Further, in the process of coating the isolation layer, firstly, adding hydroxypropyl methylcellulose into purified water at 60-80 ℃, uniformly stirring and dispersing, cooling to room temperature, adding polyethylene glycol and talcum powder, uniformly stirring, and preparing an isolation layer coating solution; and then adding the drug-loaded pellets containing memantine hydrochloride into a fluidized bed pan, spraying the isolating layer coating solution for coating, controlling the temperature of the materials to be between 45 and 55 ℃ in the coating process, and drying the materials for 10min when the coating is finished and the temperature of the materials reaches 40 to 55 ℃ to obtain the isolating layer pellets.
Further, in the sustained-release coating process of the memantine hydrochloride sustained-release pellet, the ethyl cellulose water dispersion and the hydroxyethyl cellulose (pore-forming agent and anti-sticking agent can be further added) are dispersed in the purified water to prepare a sustained-release coating solution; then adding the isolated layer micropills into a fluidized bed pot, spraying the sustained-release layer coating liquid for coating, controlling the temperature of the materials to be between 30 and 40 ℃ in the coating process, and drying the materials for 2 hours at the temperature of between 40 and 55 ℃ after the coating is finished to obtain the sustained-release layer micropills.
Compared with the prior art, the invention has the advantages that:
(1) according to the memantine hydrochloride sustained-release pellet, hydroxyethyl cellulose is added into the ethyl cellulose aqueous dispersion to serve as a stabilizer, the water-soluble hydroxyethyl cellulose is used for dispersing and wrapping an incompatible film formed around the hydrophobic ethyl cellulose, meanwhile, the hydroxyethyl cellulose has strong hygroscopicity, so that water in a formed polymer film is mainly concentrated in the hydroxyethyl cellulose, the ethyl cellulose film is prevented from further gathering and fusing, the stability of the polymer film is improved, and the prepared memantine hydrochloride sustained-release pellet is good in dissolution stability.
(2) In the preparation process of the memantine hydrochloride sustained-release pellet, no organic solvent such as ethanol is used, the curing time is short, the explosion-proof requirement on equipment is avoided, the production operation process is safer, the overhigh production energy consumption is avoided, and the memantine hydrochloride sustained-release pellet is more suitable for industrial production.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a scanning electron microscope image of the section of the memantine hydrochloride sustained-release pellet of the invention.
FIG. 2 is a sectional local scanning electron microscope image of the memantine hydrochloride sustained-release pellet of the invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods or materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
Prescription:
the preparation process comprises the following steps:
(1) coating the drug-loaded layer: pulverizing memantine hydrochloride raw material with jet mill to obtain memantine hydrochloride micropowder with particle diameter D90Controlling the thickness within 15 μm; dispersing the memantine hydrochloride micro powder, polyvidone K30 and talcum powder in a proper amount of purified water,preparing a drug-loaded coating solution; putting the blank sucrose pellet core into a fluidized bed, coating the surface of the sucrose pellet core with drug-loaded layer coating liquid by adopting a bottom spraying mode, controlling the temperature of the materials to be within the range of 25-35 ℃ in the coating process, drying the materials for 10min when the coating is finished and enabling the temperature of the materials to reach 40-55 ℃, and then cooling the materials to be below 35 ℃ to obtain the drug-loaded layer pellet.
(2) Coating with an isolating layer: adding hydroxypropyl methylcellulose E5 into purified water at 60-80 ℃, uniformly stirring and dispersing, cooling to room temperature, adding polyethylene glycol 400 and talcum powder, uniformly stirring, and preparing into an isolation layer coating solution; then adding the drug-loaded layer pellets into a fluidized bed, coating the surfaces of the drug-loaded layer pellets with an isolating layer coating solution by adopting a bottom spraying mode, controlling the material temperature between 45 ℃ and 55 ℃ in the coating process, drying the material for 10min when the coating is finished and enabling the material temperature to reach 40 ℃ to 55 ℃, and then cooling to below 35 ℃ to obtain the isolating layer pellets.
(3) Coating of the slow release layer: dispersing Stilsilk E-7-19030, polyethylene glycol 400, hydroxyethyl cellulose and pulvis Talci in purified water to obtain delayed release coating solution; then adding the isolated layer micro-pills into a fluidized bed, coating the surface of the isolated layer micro-pills with a slow release layer coating solution by adopting a bottom spraying mode, controlling the temperature of the material to be 30-40 ℃ in the coating process, drying the material for 2 hours when the coating is finished and enabling the temperature of the material to reach 40-55 ℃, and then cooling the material to be below 35 ℃ to obtain the slow release layer micro-pills.
(4) And (3) filling capsules: according to the content of the medicines in the memantine hydrochloride sustained-release pellets and the specification of filling according to needs, the number of the memantine hydrochloride sustained-release pellets to be filled is reduced, and then the capsule filling agent is adopted to fill the corresponding number of sustained-release pellets into the gelatin hollow capsule, thus obtaining the capsule.
Example 2
Prescription:
the preparation process comprises the following steps:
(1) coating the drug-loaded layer: gas for memantine hydrochloride bulk drugPulverizing with fluid pulverizer to obtain memantine hydrochloride micropowder with particle diameter D90Controlling the thickness within 15 μm; dispersing the memantine hydrochloride micro powder, polyvidone K30 and talcum powder in a proper amount of purified water to prepare a drug-loaded layer coating solution; putting a blank sucrose pellet core into a fluidized bed, coating the surface of the sucrose pellet core with a drug-loaded layer coating solution by adopting a bottom spraying mode, controlling the material temperature within the range of 25-35 ℃ in the coating process, drying the material for 10min when the coating is finished and the material temperature reaches 40-55 ℃, and then cooling to the material temperature below 35 ℃ to obtain drug-loaded layer pellets.
(2) Coating an isolation layer: adding hydroxypropyl methylcellulose E5 into purified water at 60-80 ℃, stirring and dispersing uniformly, cooling to room temperature, adding polyethylene glycol 400 and talcum powder, stirring uniformly, and preparing into an isolation layer coating solution; then adding the drug-loaded layer pellets into a fluidized bed, coating the surfaces of the drug-loaded layer pellets with an isolating layer coating solution by adopting a bottom spraying mode, controlling the material temperature between 45 ℃ and 55 ℃ in the coating process, drying the material for 10min when the coating is finished and enabling the material temperature to reach 40 ℃ to 55 ℃, and then cooling to below 35 ℃ to obtain the isolating layer pellets.
(3) Coating of the slow release layer: dispersing Stilsilk E-7-19030, polyethylene glycol 400, hydroxyethyl cellulose and pulvis Talci in purified water to obtain delayed release coating solution; then adding the isolated layer pellets into a fluidized bed, coating the surface of the isolated layer pellets with a sustained-release coating solution by adopting a bottom spraying mode, controlling the temperature of the materials to be between 30 and 40 ℃ in the coating process, drying the materials for 2 hours when the temperature of the materials reaches 40 to 55 ℃ after the coating is finished, and then cooling the materials to be below 35 ℃ to obtain the sustained-release layer pellets.
(4) And (3) filling capsules: according to the content of the medicines in the memantine hydrochloride sustained-release pellets and the specification of filling according to needs, the number of the memantine hydrochloride sustained-release pellets to be filled is reduced, and then the capsule filling agent is adopted to fill the corresponding number of sustained-release pellets into the gelatin hollow capsule, thus obtaining the capsule.
Example 3
Prescription:
the preparation process comprises the following steps:
(1) coating the drug-loaded layer: pulverizing memantine hydrochloride raw material with jet mill to obtain memantine hydrochloride micropowder with particle diameter D90Controlling the thickness within 15 μm; dispersing the memantine hydrochloride micro powder, polyvidone K30 and talcum powder in a proper amount of purified water to prepare a drug-loaded layer coating solution; putting a blank sucrose pellet core into a fluidized bed, coating the surface of the sucrose pellet core with a drug-loaded layer coating solution by adopting a bottom spraying mode, controlling the material temperature within the range of 25-35 ℃ in the coating process, drying the material for 10min when the coating is finished and the material temperature reaches 40-55 ℃, and then cooling to the material temperature below 35 ℃ to obtain drug-loaded layer pellets.
(2) Coating an isolation layer: adding hydroxypropyl methylcellulose E5 into purified water at 60-80 ℃, uniformly stirring and dispersing, cooling to room temperature, adding polyethylene glycol 400 and talcum powder, uniformly stirring, and preparing into an isolation layer coating solution; then adding the drug-loaded layer pellets into a fluidized bed, coating the surfaces of the drug-loaded layer pellets with an isolating layer coating solution by adopting a bottom spraying mode, controlling the material temperature between 45 ℃ and 55 ℃ in the coating process, drying the material for 10min when the coating is finished and enabling the material temperature to reach 40 ℃ to 55 ℃, and then cooling to below 35 ℃ to obtain the isolating layer pellets.
(3) Coating of the slow release layer: dispersing the Sulisi E-7-19030, the polyethylene glycol 400, the hydroxyethyl cellulose and the talcum powder in purified water to prepare a slow-release coating liquid; then adding the isolated layer pellets into a fluidized bed, coating the surface of the isolated layer pellets with a sustained-release coating solution by adopting a bottom spraying mode, controlling the temperature of the materials to be between 30 and 40 ℃ in the coating process, drying the materials for 2 hours when the temperature of the materials reaches 40 to 55 ℃ after the coating is finished, and then cooling the materials to be below 35 ℃ to obtain the sustained-release layer pellets.
(4) And (3) filling capsules: according to the content of the medicines in the memantine hydrochloride sustained-release pellets and the specification of filling according to needs, the number of the memantine hydrochloride sustained-release pellets to be filled is reduced, and then the capsule filling agent is adopted to fill the corresponding number of sustained-release pellets into the gelatin hollow capsule, thus obtaining the capsule.
Comparative example 1
Prescription:
the preparation process comprises the following steps:
(1) coating the drug-loaded layer: pulverizing memantine hydrochloride raw material with jet mill to obtain memantine hydrochloride micropowder with particle diameter D90Controlling the thickness within 15 μm; dispersing the memantine hydrochloride micro powder, polyvidone K30 and talcum powder in a proper amount of purified water to prepare a drug-loaded layer coating solution; putting the blank sucrose pellet core into a fluidized bed, coating the surface of the sucrose pellet core with drug-loaded layer coating liquid by adopting a bottom spraying mode, controlling the temperature of the materials to be within the range of 25-35 ℃ in the coating process, drying the materials for 10min when the coating is finished and enabling the temperature of the materials to reach 40-55 ℃, and then cooling the materials to be below 35 ℃ to obtain the drug-loaded layer pellet.
(2) Coating an isolation layer: adding hydroxypropyl methylcellulose E5 into purified water at 60-80 ℃, uniformly stirring and dispersing, cooling to room temperature, adding polyethylene glycol 400 and talcum powder, uniformly stirring, and preparing into an isolation layer coating solution; then adding the drug-loaded layer pellets into a fluidized bed, coating the surfaces of the drug-loaded layer pellets with an isolating layer coating solution by adopting a bottom spraying mode, controlling the material temperature between 45 ℃ and 55 ℃ in the coating process, drying the material for 10min when the coating is finished and enabling the material temperature to reach 40 ℃ to 55 ℃, and then cooling to below 35 ℃ to obtain the isolating layer pellets.
(3) Coating of the slow release layer: dispersing Stilsilk E-7-19030, polyethylene glycol 400 and pulvis Talci in purified water to obtain delayed release coating solution; then adding the isolated layer pellets into a fluidized bed, coating the surface of the isolated layer pellets with a sustained-release coating solution by adopting a bottom spraying mode, controlling the temperature of the materials to be between 30 and 40 ℃ in the coating process, drying the materials for 2 hours when the temperature of the materials reaches 40 to 55 ℃ after the coating is finished, and then cooling the materials to be below 35 ℃ to obtain the sustained-release layer pellets.
(4) And (3) filling capsules: converting the quantity of the memantine hydrochloride sustained-release pellets to be filled according to the medicine content of the memantine hydrochloride sustained-release pellets and the specification required to be filled, and then filling the sustained-release pellets with a corresponding quantity of capsule filling agent into a gelatin hollow capsule to obtain the finished product.
Comparative example 2
Prescription:
the preparation process comprises the following steps:
(1) coating the drug-loaded layer: pulverizing memantine hydrochloride raw material with jet mill to obtain memantine hydrochloride micropowder with particle diameter D90Controlling the thickness within 15 μm; dispersing the memantine hydrochloride micro powder, polyvidone K30 and talcum powder in a proper amount of purified water to prepare a drug-loaded layer coating solution; putting a blank sucrose pellet core into a fluidized bed, coating the surface of the sucrose pellet core with a drug-loaded layer coating solution by adopting a bottom spraying mode, controlling the material temperature within the range of 25-35 ℃ in the coating process, drying the material for 10min when the coating is finished and the material temperature reaches 40-55 ℃, and then cooling to the material temperature below 35 ℃ to obtain drug-loaded layer pellets.
(2) Coating with an isolating layer: adding hydroxypropyl methylcellulose E5 into purified water at 60-80 ℃, stirring and dispersing uniformly, cooling to room temperature, adding polyethylene glycol 400 and talcum powder, stirring uniformly, and preparing into an isolation layer coating solution; then adding the drug-loaded layer pellets into a fluidized bed, coating the surfaces of the drug-loaded layer pellets with an isolating layer coating solution by adopting a bottom spraying mode, controlling the material temperature between 45 ℃ and 55 ℃ in the coating process, drying the material for 10min when the coating is finished and enabling the material temperature to reach 40 ℃ to 55 ℃, and then cooling to below 35 ℃ to obtain the isolating layer pellets.
(3) Coating of the slow release layer: dispersing Stilsilk E-7-19030, polyethylene glycol 400, hydroxyethyl cellulose and pulvis Talci in purified water to obtain delayed release coating solution; then adding the isolated layer micro-pills into a fluidized bed, coating the surface of the isolated layer micro-pills with a slow release layer coating solution by adopting a bottom spraying mode, controlling the temperature of the material to be 30-40 ℃ in the coating process, drying the material for 2 hours when the coating is finished and enabling the temperature of the material to reach 40-55 ℃, and then cooling the material to be below 35 ℃ to obtain the slow release layer micro-pills.
(4) And (3) filling capsules: according to the content of the medicines in the memantine hydrochloride sustained-release pellets and the specification of filling according to needs, the number of the memantine hydrochloride sustained-release pellets to be filled is reduced, and then the capsule filling agent is adopted to fill the corresponding number of sustained-release pellets into the gelatin hollow capsule, thus obtaining the capsule.
Comparative example 3
Prescription:
the preparation process comprises the following steps:
(1) coating the drug-loaded layer: pulverizing memantine hydrochloride raw material with jet mill to obtain memantine hydrochloride micropowder with particle diameter D90Controlling the thickness within 15 μm; dispersing the memantine hydrochloride micro powder, polyvidone K30 and talcum powder in a proper amount of purified water to prepare a drug-loaded layer coating solution; putting the blank sucrose pellet core into a fluidized bed, coating the surface of the sucrose pellet core with drug-loaded layer coating liquid by adopting a bottom spraying mode, controlling the temperature of the materials to be within the range of 25-35 ℃ in the coating process, drying the materials for 10min when the coating is finished and enabling the temperature of the materials to reach 40-55 ℃, and then cooling the materials to be below 35 ℃ to obtain the drug-loaded layer pellet.
(2) Coating an isolation layer: adding hydroxypropyl methylcellulose E5 into purified water at 60-80 ℃, stirring and dispersing uniformly, cooling to room temperature, adding polyethylene glycol 400 and talcum powder, stirring uniformly, and preparing into an isolation layer coating solution; then adding the drug-loaded layer pellets into a fluidized bed, coating the surfaces of the drug-loaded layer pellets with an isolating layer coating solution by adopting a bottom spraying mode, controlling the material temperature between 45 ℃ and 55 ℃ in the coating process, drying the material for 10min when the coating is finished and enabling the material temperature to reach 40 ℃ to 55 ℃, and then cooling to below 35 ℃ to obtain the isolating layer pellets.
(3) Coating of the slow release layer: dispersing Stilsilk E-7-19030, polyethylene glycol 400, hydroxyethyl cellulose and pulvis Talci in purified water to obtain delayed release coating solution; then adding the isolated layer pellets into a fluidized bed, coating the surface of the isolated layer pellets with a sustained-release coating solution by adopting a bottom spraying mode, controlling the temperature of the materials to be between 30 and 40 ℃ in the coating process, drying the materials for 2 hours when the temperature of the materials reaches 40 to 55 ℃ after the coating is finished, and then cooling the materials to be below 35 ℃ to obtain the sustained-release layer pellets.
(4) And (3) filling capsules: according to the content of the medicines in the memantine hydrochloride sustained-release pellets and the specification of filling according to needs, the number of the memantine hydrochloride sustained-release pellets to be filled is reduced, and then the capsule filling agent is adopted to fill the corresponding number of sustained-release pellets into the gelatin hollow capsule, thus obtaining the capsule.
Comparative example 4
Prescription:
the preparation process comprises the following steps:
(1) coating the drug-loaded layer: pulverizing memantine hydrochloride raw material with jet mill to obtain memantine hydrochloride micropowder with particle diameter D90Controlling the thickness within 15 μm; dispersing the memantine hydrochloride micro powder, polyvidone K30 and talcum powder in a proper amount of purified water to prepare a drug-loaded layer coating solution; putting the blank sucrose pellet core into a fluidized bed, coating the surface of the sucrose pellet core with drug-loaded layer coating liquid by adopting a bottom spraying mode, controlling the temperature of the materials to be within the range of 25-35 ℃ in the coating process, drying the materials for 10min when the coating is finished and enabling the temperature of the materials to reach 40-55 ℃, and then cooling the materials to be below 35 ℃ to obtain the drug-loaded layer pellet.
(2) Coating an isolation layer: adding hydroxypropyl methylcellulose E5 into purified water at 60-80 ℃, uniformly stirring and dispersing, cooling to room temperature, adding polyethylene glycol 400 and talcum powder, uniformly stirring, and preparing into an isolation layer coating solution; then adding the drug-loaded layer pellets into a fluidized bed, coating the surfaces of the drug-loaded layer pellets with an isolating layer coating solution by adopting a bottom spraying mode, controlling the material temperature between 45 ℃ and 55 ℃ in the coating process, drying the material for 10min when the coating is finished and enabling the material temperature to reach 40 ℃ to 55 ℃, and then cooling to below 35 ℃ to obtain the isolating layer pellets.
(3) Coating of the slow release layer: dispersing Stilsilk E-7-19030, polyethylene glycol 400, hypromellose and pulvis Talci in purified water to obtain delayed release coating solution; then adding the isolated layer pellets into a fluidized bed, coating the surface of the isolated layer pellets with a sustained-release coating solution by adopting a bottom spraying mode, controlling the temperature of the materials to be between 30 and 40 ℃ in the coating process, drying the materials for 2 hours when the temperature of the materials reaches 40 to 55 ℃ after the coating is finished, and then cooling the materials to be below 35 ℃ to obtain the sustained-release layer pellets.
(4) And (3) filling capsules: converting the quantity of the memantine hydrochloride sustained-release pellets to be filled according to the medicine content of the memantine hydrochloride sustained-release pellets and the specification required to be filled, and then filling the sustained-release pellets with a corresponding quantity of capsule filling agent into a gelatin hollow capsule to obtain the finished product.
Test example 1 evaluation of in vitro dissolution Curve
Taking the memantine hydrochloride sustained-release capsules prepared in the examples 1-3 and the comparative examples 1-4 respectively, and selecting an in-vitro dissolution curve method with distinguishing force to the product prescription process, namely: the basket method, take sodium chloride acid solution (2 g of sodium chloride, add right amount of water to dissolve, add 7ml of hydrochloric acid, dilute to 1000ml with water, mix, get final product) 900ml as dissolution medium, the rotational speed is 100 revolutions per minute, the temperature is 37.0 ℃, the operation of the law, sample and detect in 1, 2, 3, 4, 6, 8 and 12 hours respectively, the dissolution test result is shown in the following table:
the results show that similar factors f2 of the dissolution curves of the memantine hydrochloride sustained-release capsules prepared by the formula (examples 1-3) in a sodium chloride hydrochloric acid dissolution medium and the conventional preparation sold in the market are all larger than 50, the dissolution curves are similar, the dissolution rate is increased to a certain extent along with the increase of the proportion of hydroxyethyl cellulose in the sustained-release layer formula, and the characteristics are also shown in the comparative examples. The memantine hydrochloride sustained-release capsule prepared by adopting hydroxypropyl methylcellulose close to hydroxyethyl cellulose has a slightly-fast dissolution curve as a whole, but the similarity f2 with the in vitro dissolution curve of a commercial product can reach 66, which shows that the dissolution curve is similar to that of the original preparation.
Test example 2 evaluation of dissolution stability
The commercially available Namenda XR, the memantine hydrochloride sustained-release capsules obtained in the examples 1-3 and the comparative examples 1-4 are subjected to blister packaging by using aluminum foil and PVC/PVDC composite hard sheets, the outer package is packaged by using a paper box, the paper box is placed under the conditions of high temperature of 60 ℃ for 10 days and acceleration of temperature of 40 +/-2 ℃ and relative humidity of 25 +/-2%, the change situation of the dissolution rate is inspected, and the detection results are shown in the following table.
According to the quality standard of the memantine hydrochloride sustained-release capsules USP, the dissolution amount of each capsule in 1 hour, 4 hours, 8 hours and 12 hours is respectively less than 21%, 32% -57%, 66% -91% and more than 80% of the marked amount, although the original developer Namenda XR meets the quality standard regulation under the conditions of high temperature and acceleration, the in-vitro dissolution rate has an obvious descending trend compared with a sample in 0 day. Although the dissolution rates of the memantine hydrochloride sustained-release capsules prepared by the formula (examples 1-3) of the invention at various time points are slightly reduced, the dissolution rates are basically consistent with those of the samples in 0 day, which shows that the addition of a proper amount of hydroxyethyl cellulose into ethyl cellulose water dispersion can stabilize the outer sustained-release film. Reference is made to the formulation composition of the original study Namenda XR, but comparative example 1, which has not been cured for a long period of time, shows a significant drop in vitro dissolution, which corresponds to the material aging characteristics of ethylcellulose itself. Good stabilization was not shown when the amount of hydroxyethylcellulose was lower or higher than a certain proportion of the amount (comparative examples 2, 3) or replaced with similar hypromellose (comparative example 4).
Experimental example 3 internal structure of memantine hydrochloride sustained-release pellet
The content of the memantine hydrochloride sustained-release capsule prepared in example 1 is taken, the cross section and the local section of the sustained-release pellet are observed by adopting a scanning electron microscope, and the test result is shown in figure 1 and figure 2. As can be seen from figure 1, the formed memantine hydrochloride sustained-release pellet has good roundness, the inside of the pellet core is a spherical sucrose pellet core, the outer layer is a uniformly distributed and thick drug-loaded layer, and then the outer layer of the drug-loaded layer is provided with an isolation layer and a sustained-release layer with different textures. Fig. 2 can more clearly understand the distribution of the outer isolation layer and the sustained-release layer, that is, the outermost layer is a sustained-release layer with a compact texture, and the isolation layer with a relatively loose texture is adjacent to the sustained-release layer. From the thickness distribution of the film, the thickness of the isolating layer and the slow-release layer coating film is uniform.
Although the present application has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. The memantine hydrochloride sustained-release pellet comprises a blank pellet core, a drug loading coating layer, an isolation coating layer and a sustained-release coating layer, and is characterized in that the sustained-release coating layer comprises an ethyl cellulose aqueous dispersion and hydroxyethyl cellulose, wherein the mass ratio of the ethyl cellulose aqueous dispersion to the hydroxyethyl cellulose is 15: 1 to 2.
2. The memantine hydrochloride sustained-release pellet of claim 1, wherein the blank pellet core is selected from sucrose pellet core or microcrystalline cellulose pellet core.
3. The memantine hydrochloride sustained-release pellet of claim 2, wherein the blank pellet core has a particle size of 0.60mm-0.71 mm.
4. The memantine hydrochloride sustained-release pellet of claim 1, wherein the drug-loaded coating layer comprises memantine hydrochloride, a binder and an anti-sticking agent; the adhesive is selected from one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose, and the antisticking agent is talcum powder; the mass ratio of the memantine hydrochloride, the adhesive and the anti-sticking agent is 10: 2-5: 0.5 to 1.5.
5. The memantine hydrochloride sustained-release pellet of claim 1, wherein said isolating coating layer comprises hypromellose, polyethylene glycol and talc; the mass ratio of the hydroxypropyl methylcellulose, the polyethylene glycol and the talcum powder is 10: 1-3: 1 to 3.
6. The memantine hydrochloride sustained-release pellet of claim 1, wherein the sustained-release coating layer further comprises a pore-forming agent and an anti-sticking agent, and the pore-forming agent is selected from one or more of triethyl citrate, polyethylene glycol, triglyceride and dibutyl sebacate.
7. A memantine hydrochloride sustained-release pellet as claimed in claim 6, wherein the pore-forming agent is polyethylene glycol and the anti-sticking agent is talc.
8. A memantine hydrochloride sustained-release preparation, which is characterized in that granules, capsules or tablets prepared from the memantine hydrochloride sustained-release pellets of any one of claims 1 to 7 are adopted.
9. The preparation method of the memantine hydrochloride sustained-release pellet as claimed in any one of claims 1 to 7, characterized in that the preparation method comprises the following steps: respectively preparing a drug-loaded layer, an isolation layer and a slow-release coating solution according to the prescription amount, applying drugs to the hollow pellet core by adopting a fluidized bed bottom spraying mode, and sequentially coating the drug-loaded layer, the isolation layer and the slow-release layer to prepare a slow-release pellet, wherein in the slow-release layer coating process, the ethyl cellulose aqueous dispersion and the hydroxyethyl cellulose are dispersed in purified water to prepare the slow-release coating solution; then adding the isolated layer micropills into a fluidized bed pot, spraying the sustained-release layer coating liquid for coating, controlling the temperature of the materials to be between 30 and 40 ℃ in the coating process, and drying the materials for 2 hours at the temperature of between 40 and 55 ℃ after the coating is finished to obtain the sustained-release layer micropills.
10. The preparation method of memantine hydrochloride sustained-release pellets according to claim 9, characterized in that: pore-forming agent and antisticking agent are also added in the preparation process of the slow-release coating liquid.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115572101A (en) * | 2022-10-31 | 2023-01-06 | 山西格瑞特建筑科技股份有限公司 | Slow-release air entraining agent and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104013592A (en) * | 2014-06-10 | 2014-09-03 | 浙江京新药业股份有限公司 | Memantine hydrochloride slow-release pill and preparation method thereof |
| CN106474092A (en) * | 2016-12-27 | 2017-03-08 | 哈药集团技术中心 | A kind of memantine slow-release micro-pill and preparation method thereof |
| CN107773553A (en) * | 2016-08-26 | 2018-03-09 | 江苏先声药业有限公司 | A kind of memantine sustained release pellet and preparation method thereof |
| WO2021217388A1 (en) * | 2020-04-26 | 2021-11-04 | 江苏天士力帝益药业有限公司 | Memantine hydrochloride extended-release capsule and preparation method therefor |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104013592A (en) * | 2014-06-10 | 2014-09-03 | 浙江京新药业股份有限公司 | Memantine hydrochloride slow-release pill and preparation method thereof |
| CN107773553A (en) * | 2016-08-26 | 2018-03-09 | 江苏先声药业有限公司 | A kind of memantine sustained release pellet and preparation method thereof |
| CN106474092A (en) * | 2016-12-27 | 2017-03-08 | 哈药集团技术中心 | A kind of memantine slow-release micro-pill and preparation method thereof |
| WO2021217388A1 (en) * | 2020-04-26 | 2021-11-04 | 江苏天士力帝益药业有限公司 | Memantine hydrochloride extended-release capsule and preparation method therefor |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115572101A (en) * | 2022-10-31 | 2023-01-06 | 山西格瑞特建筑科技股份有限公司 | Slow-release air entraining agent and preparation method and application thereof |
| CN115572101B (en) * | 2022-10-31 | 2023-08-04 | 山西格瑞特建筑科技股份有限公司 | Sustained-release air entraining agent and preparation method and application thereof |
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