CN108969506A - A kind of memantine sustained release pellet and preparation method thereof - Google Patents
A kind of memantine sustained release pellet and preparation method thereof Download PDFInfo
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- CN108969506A CN108969506A CN201811055531.5A CN201811055531A CN108969506A CN 108969506 A CN108969506 A CN 108969506A CN 201811055531 A CN201811055531 A CN 201811055531A CN 108969506 A CN108969506 A CN 108969506A
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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
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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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
- A61K9/48—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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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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Abstract
The present invention provides a kind of memantine sustained release pellets and preparation method thereof, belong to technical field of medicine.It from inside to outside include pellet core, barrier layer and slow release layer；The mass ratio of the pellet core, barrier layer and slow release layer is 1:0.025~0.07:0.12~0.16；The pellet core includes blank capsule core and medicated layer, and the medicated layer includes active ingredient hydrochloric acid Memantine and auxiliary material.The present invention both ensure that barrier layer and slow release layer to the covered effect of medicated layer, made active constituent have slow release effect by being 0.025~0.07:0.12~0.16:1 by the mass ratio control of barrier layer and slow release layer and pellet core；Slow release layer can make the active constituent of medicated layer at the appointed time with position slow release, efficiently play the drug effect of active constituent；In addition, medicated layer and slow release layer can be effectively isolated open by barrier layer, influence of the medicated layer to slow release layer slow release effect is avoided.
Description
Technical field
The present invention relates to technical field of medicine more particularly to a kind of memantine sustained release pellet and its preparation sides
Method.
Background technique
Memantine (memantine) be US and European first approval in treating, the drug of severe dementia patient.
The entitled 1-amino-3,5-dimethylglycine amine hydrochlorate of memantine chemistry, is a kind of with the non-competing of medium compatibility
Striving property nmda receptor antagonist, molecular formula C12H21NHCl, relative molecular mass 215.76 arrive the powder of off-white color for white,
It is soluble easily in water；Its structural formula are as follows:
Memantine can both block calcium channel in pathological conditions, while reduce the excitability mind of Glutamatergic
Through toxic effect, normal learning and memory is formed；The neuron under pathology virulent state can also be protected, to reach improvement
The purpose of dementia symptom.The complete blocking effect of the blocking of the magnesium ion of this and physiological and high-affinity nmda receptor antagonist is not
Together.(tau protein abnormal phosphorylation model, Glutamatergic are different for the multinomial transgenic animal model experiment of memantine therapy mechanism
Norm type and other lead to serious neurological neuropathy model) confirm: 1. memantine not only to NMDA induce generate damage after
Cholinergic neuron there is protective effect, it is also causing toxicity inhibited to secondary mitochondria dysfunction institute；2. salt
Sour Memantine can also be horizontal by reducing A β in central nervous system, and the toxic effect for inhibiting A β to generate improves recognizing for animal
Know ability；3. memantine reduces the tau protein abnormal phosphorylation of AD sample animal model.
Oral 3~7h of Memantine reaches blood concentration peak value, and food does not influence its absorption, t1/2For 60~80h, it is evenly distributed appearance
9~11L/kg of product, plasma protein binding rate 45%, 57~82% with prototype, remaining is with metabolite N-3,5- dimethyl-grape
Glycuronide, 6- hydroxyl Memantine and 1- nitroso-deamination Memantine form are drained through urine.These metabolites do not have
There is NMDA antagonistic activity.
Because the compliance of patient can be reduced with the increase of administration number of times, and rate of release will lead to more greatly faster
The adverse events of frequency, it is even more serious particularly with meeting for this product patient, therefore reduce administration number of times and be easier to receive an acclaim.Cause
This, prepares that a kind of containing Memantine or pharmaceutically the sustained release preparation of acceptable salt is the problem of being concerned.
Prior art preparation memantine sustained release preparation is mainly by laggard to memantine hydrochloride raw material micronization processes
Row multiple coatings obtain, and solvent mostly uses ethyl alcohol, are unfavorable for explosion-proof；And the slow release speed of memantine sustained release preparation is not
, active constituent release is unstable, and the drug effect for reducing active constituent plays.
Summary of the invention
In view of this, the purpose of the present invention is to provide a kind of memantine sustained release pellets and preparation method thereof.This hair
The solvent that the memantine sustained release pellet of bright offer does not use ethyl alcohol etc. explosive can by optimizing the structure and composition of pellet
Effectively to control the release of memantine, the safe and effective of medication ensure that, be suitable for industrialized production.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of memantine sustained release pellets, gentle including pellet core, barrier layer from inside to outside
Release layer；The mass ratio of the pellet core, barrier layer and slow release layer is 1:0.025~0.07:0.12~0.16；The drug containing
Capsule core includes blank capsule core and medicated layer, and the medicated layer includes active ingredient hydrochloric acid Memantine and auxiliary material.
Preferably, the mass ratio of blank capsule core, active ingredient hydrochloric acid Memantine and auxiliary material is 1~6 in the pellet core:
1:0.1~0.3.
Preferably, the blank capsule core includes sugar-pill and/or microcrystalline cellulose vegetable pill.
Preferably, the auxiliary material includes adhesive.
Preferably, described adhesive includes one in polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose
Kind is several.
Preferably, the ingredient of the barrier layer is film coating pre-mix dose.
Preferably, the slow release layer includes Sustained release coating materials, pore-foaming agent and plasticizer；The Sustained release coating materials, cause
The mass ratio of hole agent and plasticizer is 100:8~12:10~50.
Preferably, the Sustained release coating materials are Aquacoat；The plasticizer includes lemon triethylenetetraminehexaacetic acid
One or more of ester, tributyl citrate and dibutyl sebacate；The pore-foaming agent is polyvinyl alcohol/polyethylene glycol copolymerization
Object.
The present invention also provides the preparation methods of memantine sustained release pellet described in above-mentioned technical proposal, including following step
It is rapid:
Ingredient in medicated layer, barrier layer and slow release layer is mixed with solvent, forms corresponding medicated layer solution, isolation
Medicated layer solution is coated in blank capsule core by clothing layer solution and slow release layer solution by fluidized bed coating technique, then again according to
It is secondary that barrier layer solution and slow release layer solution are coated on pellet, form the memantine sustained release pellet.
The present invention provides a kind of memantine sustained release pellets, gentle including pellet core, barrier layer from inside to outside
Release layer；The mass ratio of the pellet core, barrier layer and slow release layer is 1:0.025~0.07:0.12~0.16；The drug containing
Capsule core includes blank capsule core and medicated layer, and the medicated layer includes active ingredient hydrochloric acid Memantine and auxiliary material.The present invention pass through by
Barrier layer and slow release layer and the control of the mass ratio of pellet core are 0.025~0.07:0.12~0.16:1, both ensure that isolation
Clothing layer and slow release layer have the function that active constituent is sustained to the covered effect of medicated layer；Meanwhile slow release layer can make medicated layer
In active constituent at the appointed time with position slow release, efficiently play active constituent drug effect；In addition, barrier layer
Medicated layer and slow release layer can be effectively isolated open, avoid influence of the medicated layer to slow release layer slow release effect.
Further, by controlling the component and content of slow release layer, active ingredient hydrochloric acid Memantine is made to pass through slow release layer
Micropore slow release, avoids the phenomenon that active constituent is released, and has ensured the safe and effective of medication, and quality is stablized.
Detailed description of the invention
Fig. 1 is that release profiles of the sample in hydrochloric acid (pH 1.2) compare figure (100rpm)；
Fig. 2 is that release profiles of the sample in acetate media (pH 4.5) compare figure (100rpm)；
Fig. 3 is that release profiles of the sample in phosphoric acid salt medium (pH 6.8) compare figure (100rpm)；
Fig. 4 is that the release profiles of sample in an aqueous medium compare figure (100rpm)；
Fig. 5 is that release profiles of the sample in phosphoric acid salt medium (pH 7.5) compare figure (200rpm).
Specific embodiment
The present invention provides a kind of memantine sustained release pellets, gentle including pellet core, barrier layer from inside to outside
Release layer；The mass ratio of the pellet core, barrier layer and slow release layer is 1:0.025~0.07:0.12~0.16；The drug containing
Capsule core includes blank capsule core and medicated layer, and the medicated layer includes active ingredient hydrochloric acid Memantine and auxiliary material.
Pellet core in memantine sustained release pellet provided by the invention includes blank capsule core and medicated layer.In this hair
In bright, the blank capsule core preferably includes sugar-pill and/or microcrystalline cellulose vegetable pill；When the blank capsule core is mixture, this hair
The bright weight to each substance in the mixture does not have special restriction, is mixed using any weight ratio.The present invention
There is no special restriction to the source of the blank capsule core, using commercial product well known to those skilled in the art.At this
In invention, the blank capsule core is used as the coated carrier of active constituent, to form sustained release pellet pattern.
In the present invention, the medicated layer includes active ingredient hydrochloric acid Memantine and auxiliary material.In the present invention, the auxiliary material
Preferably include adhesive.In the present invention, described adhesive preferably includes polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl
One or more of base cellulose；When described adhesive is mixture, weight ratio of the present invention to substance each in mixture
There is no special restriction, using any weight ratio.The present invention does not have special restriction to the source of described adhesive, uses
Commercial product well known to those skilled in the art.
In the present invention, the mass ratio of blank capsule core, memantine and auxiliary material is preferably 1~6 in the pellet core:
1:0.1~0.3, more preferably 2~5:1:0.15~0.25, most preferably 3~4:1:0.2.In the present invention, the medicated layer
In active ingredient hydrochloric acid Memantine can be efficiently coated in blank capsule core under the action of adhesive, formed pattern it is excellent
Good pellet core.
The ingredient of barrier layer in memantine sustained release pellet provided by the invention is preferably film coating pre-mix dose.
In the present invention, the film coating pre-mix dose is preferably the Opadry for blocking happy Kanggong department.In an embodiment of the present invention, described
Containing adhesive, plasticizer etc. in film coating pre-mix dose, the active constituent in medicated layer can be effectively isolated with slow release layer, be kept away
Exempt from active constituent and destroy slow release layer, influences slow release effect.
Slow release layer in memantine sustained release pellet provided by the invention preferably include Sustained release coating materials, pore-foaming agent and
Plasticizer.In the present invention, the mass ratio of the Sustained release coating materials, pore-foaming agent and plasticizer be preferably 100:8~12:10~
50, more preferably 100:9~11:20~45, most preferably 100:10:30~40.In the present invention, the Sustained release coating materials
Preferably Aquacoat.In the present invention, the plasticizer preferably includes triethyl citrate, three fourth of citric acid
One or more of ester and dibutyl sebacate；When the plasticizer is mixture, weight ratio of the present invention to each substance
There is no special restriction, using any weight ratio.In the present invention, the pore-foaming agent is preferably polyvinyl alcohol/poly- second two
Alcohol copolymer.The present invention does not have special restriction to the source of the Sustained release coating materials, plasticizer and pore-foaming agent, using ability
Commercial product known to field technique personnel.In the present invention, the plasticizer in the slow release layer can make slow release layer with film
Form be supported on pellet, pore-foaming agent makes to be sustained layer film forms micropore in vivo, releases convenient for active constituent in medicated layer
It puts.
In the present invention, the pellet core in the memantine sustained release pellet, the quality of barrier layer and slow release layer
Than for 1:0.025~0.07:0.12~0.16, preferably 1:0.028~0.05:0.13~0.15, more preferably 1:0.03~
0.04:0.14.The present invention keeps memantine sustained release micro- by control barrier layer, the mass ratio of slow release layer and pellet core
Ball have relatively thin barrier layer and slow release layer, relatively thin barrier layer can by pellet core medicated layer and slow release layer have
Effect ground keeps apart, and avoids influence of the medicated layer to slow release layer slow release effect；Simultaneously slow release layer can make in medicated layer activity at
Divide at the appointed time with position slow release, gives full play to the drug effect of active constituent.
The present invention also provides the preparation methods of memantine sustained release pellet described in above-mentioned technical proposal, including following step
It is rapid:
Ingredient in medicated layer, barrier layer and slow release layer is mixed with coordinative solvent, formed corresponding medicated layer solution,
Medicated layer solution is coated in blank capsule core, then by barrier layer solution and slow release layer solution by fluidized bed coating technique
Successively barrier layer solution and slow release layer solution are coated on pellet again, form the memantine sustained release pellet.
In the present invention, the solvent of the medicated layer solution is preferably the alcohol mixed solvent of water and 95%.In the present invention
In, the volume ratio of the water and 95% ethyl alcohol is preferably 1:0.6~0.9, more preferably 1:0.65~0.85, and most preferably 1:
0.7~0.8.In the present invention, the mass ratio of drug containing composition of layer and solvent is preferably 1:5~7 in the medicated layer solution, more excellent
It is selected as 1:5.5~6.5, most preferably 1:6.The present invention does not have special restriction to the preparation method of the medicated layer solution, adopts
With preparation method of mixture well known to those skilled in the art.In an embodiment of the present invention, the medicated layer solution is excellent
It gated following steps to be prepared: 95% ethyl alcohol being mixed with water, obtains mixed solvent；Then drug containing composition of layer is added to
In the mixed solvent crosses 80 meshes, obtains medicated layer solution.
In the present invention, the medicated layer solution is preferred using the parameter of fluidized-bed process cladding blank capsule core are as follows: air inlet
Temperature is 55~60 DEG C, makes temperature of charge control at 35~40 DEG C；Atomizing pressure is 0.2~0.4Mpa；Continue after terminating hydrojet
Enter the wind 30min.
In the present invention, the solvent of the barrier layer solution is preferably water.In the present invention, the barrier layer solution
The mass ratio of middle barrier gown composition of layer and water is preferably 1:15~18, more preferably 1:15.5~17.5, and most preferably 1:16~
17.The present invention does not have special restriction to the preparation method of barrier layer solution, using mixing well known to those skilled in the art
Object preparation method.In an embodiment of the present invention, the barrier layer solution is preferably obtained by following steps: will be isolated
Clothing composition of layer is slowly dropped in solvent, crosses 80 meshes, forms barrier layer solution.
In the present invention, the barrier layer solution is preferred using the parameter of fluidized-bed process cladding pellet are as follows: air inlet temperature
Degree is 55~65 DEG C, makes temperature of charge control at 40~45 DEG C；Atomizing pressure is 0.2~0.4Mpa；Terminate hydrojet after continue into
Wind 30min.
In the present invention, the solvent of the slow release layer solution is preferably water.In the present invention, delay in the slow release layer solution
The mass ratio for releasing composition of layer and water is preferably 1:5~8, more preferably 1:5.5~7.5, most preferably 1:6~7.The present invention is to institute
The preparation method for stating slow release layer solution does not have special restriction, is using well known to a person skilled in the art preparation method of mixture
It can.In an embodiment of the present invention, the slow release layer solution is preferably prepared by following steps: pore-foaming agent being mixed with water, is obtained
To porogen solutions；Under stirring conditions, plasticizer is slowly dropped in slow release layer coating material, it is slow forms plasticizer-
Release coating material mixture；Under stirring conditions, porogen solutions plasticizer-Sustained release coating materials material is added drop-wise to mix
In object, 80 meshes are crossed, slow release layer solution is obtained.
In the present invention, the slow release layer solution is preferred using the parameter of fluidized-bed process cladding pellet are as follows: inlet air temperature
It is 55~65 DEG C, makes temperature of charge control at 40~43 DEG C；Atomizing pressure is 0.2~0.4Mpa；In 40~43 after hydrojet
DEG C continue dry 60min.
The preparation method of memantine sustained release pellet provided by the invention is easy to operate, and it is good micro- to be capable of forming pattern
Ball structure；And explosive etoh solvent is not used largely, improve production safety coefficient.
Memantine sustained release pellet provided by the invention and preparation method thereof is carried out below with reference to embodiment detailed
Illustrate, but they cannot be interpreted as limiting the scope of the present invention.
Embodiment 1
A kind of memantine sustained release pellet includes from inside to outside blank capsule core 400g, and medicated layer includes memantine
94.6g, adhesive PVP k3023.7g；Barrier layer is Opadry 18.2g；Slow release layer includes Sustained release coating materials ethyl cellulose
Element (30% aqueous dispersion) 179.5g, pore-foaming agent Kollicoat IR 4.3g, plasticizer triethyl citrate 16.2g；
The preparation method of above-mentioned memantine sustained release pellet, comprising the following steps:
The ethyl alcohol of 391.3g water and 285g 95% are mixed, mixed solvent is obtained；The ingredient of medicated layer is added to mixing
In solvent, 80 meshes are crossed, medicated layer solution is obtained；Medicated layer is coated in blank capsule core using fluidized-bed process, parameter are as follows:
Inlet air temperature is 55~60 DEG C, so that temperature of charge control is at 35~40 DEG C, atomizing pressure is 0.2~0.4MPa, terminates hydrojet
After continue dry 30min, take the dish out of the pot, obtain medicated layer pellet；
The ingredient Opadry of barrier layer is slowly dropped in 303.5g water, 80 meshes are crossed, forms barrier layer solution；
Barrier layer is coated to by medicated layer pellet, parameter using fluidized-bed process are as follows: inlet air temperature is 55~65 DEG C, so that material temperature
At 40~45 DEG C, atomizing pressure is 0.2~0.4MPa for degree control, continues dry 30min after terminating hydrojet, takes the dish out of the pot, be isolated
Clothing layer pellet；
Pore-foaming agent is mixed with 338.5g water, obtains porogen solutions；Under stirring conditions, plasticizer is slowly added dropwise
Into slow release layer coating material, plasticizer-Sustained release coating materials mixture is formed；Under stirring conditions, by porogen solutions
It is added drop-wise in plasticizer-Sustained release coating materials material blends, crosses 80 meshes, obtain slow release layer solution；Using fluidized-bed process
Slow release layer is coated to barrier layer pellet, parameter are as follows: inlet air temperature is 55~65 DEG C, so that temperature of charge control is 40~43
DEG C, atomizing pressure is that 0.2~0.4MPa takes the dish out of the pot in 40~43 DEG C of dry 60min after hydrojet, obtains memantine and delays
Release pellet；
Obtained memantine sustained release pellet is sieved, pellet content is detected, determines capsule loading amount, fills capsule.
Embodiment 2
A kind of memantine sustained release pellet includes from inside to outside blank capsule core 400g, and medicated layer includes memantine
94.6g, adhesive PVP k3023.7g；Barrier layer is Opadry 18.2g；Slow release layer includes Sustained release coating materials ethyl cellulose
Element (30% aqueous dispersion) 179.5g, pore-foaming agent Kollicoat IR 5.4g, plasticizer triethyl citrate 16.2g；
The preparation method of above-mentioned memantine sustained release pellet, comprising the following steps:
The ethyl alcohol of 391.3g water and 285g 95% are mixed, mixed solvent is obtained；The ingredient of medicated layer is added to mixing
In solvent, 80 meshes are crossed, medicated layer solution is obtained；Medicated layer is coated in blank capsule core using fluidized-bed process, parameter are as follows:
Inlet air temperature is 55~60 DEG C, so that temperature of charge control is at 35~40 DEG C, atomizing pressure is 0.2~0.4MPa, terminates hydrojet
After continue dry 30min, take the dish out of the pot, obtain medicated layer pellet；
The ingredient Opadry of barrier layer is slowly dropped in 303.5g water, 80 meshes are crossed, forms barrier layer solution；
Barrier layer is coated to by medicated layer pellet, parameter using fluidized-bed process are as follows: inlet air temperature is 55~65 DEG C, so that material temperature
At 40~45 DEG C, atomizing pressure is 0.2~0.4MPa for degree control, continues dry 30min after terminating hydrojet, takes the dish out of the pot, be isolated
Clothing layer pellet；
Pore-foaming agent is mixed with 337.4g water, obtains porogen solutions；Under stirring conditions, plasticizer is slowly added dropwise
Into slow release layer coating material, plasticizer-Sustained release coating materials mixture is formed；Under stirring conditions, by porogen solutions
It is added drop-wise in plasticizer-Sustained release coating materials material blends, crosses 80 meshes, obtain slow release layer solution；Using fluidized-bed process
Slow release layer is coated to barrier layer pellet, parameter are as follows: inlet air temperature is 55~65 DEG C, so that temperature of charge control is 40~43
DEG C, atomizing pressure is that 0.2~0.4MPa takes the dish out of the pot in 40~43 DEG C of dry 60min after hydrojet, obtains memantine and delays
Release pellet；
Obtained memantine sustained release pellet is sieved, pellet content is detected, determines capsule loading amount, fills capsule.
Embodiment 3
A kind of memantine sustained release pellet includes from inside to outside blank capsule core 400g, and medicated layer includes memantine
94.6g, adhesive PVP k3023.7g；Barrier layer is Opadry 18.2g；Slow release layer includes Sustained release coating materials ethyl cellulose
Element (30% aqueous dispersion) 179.5g, pore-foaming agent Kollicoat IR 6.5g, plasticizer triethyl citrate 16.2g；
The preparation method of above-mentioned memantine sustained release pellet, comprising the following steps:
The ethyl alcohol of 391.3g water and 285g 95% are mixed, mixed solvent is obtained；The ingredient of medicated layer is added to mixing
In solvent, 80 meshes are crossed, medicated layer solution is obtained；Medicated layer is coated in blank capsule core using fluidized-bed process, parameter are as follows:
Inlet air temperature is 55~60 DEG C, so that temperature of charge control is at 35~40 DEG C, atomizing pressure is 0.2~0.4MPa, terminates hydrojet
After continue dry 30min, take the dish out of the pot, obtain medicated layer pellet；
The ingredient Opadry of barrier layer is slowly dropped in 303.5g water, 80 meshes are crossed, forms barrier layer solution；
Barrier layer is coated to by medicated layer pellet, parameter using fluidized-bed process are as follows: inlet air temperature is 55~65 DEG C, so that material temperature
At 40~45 DEG C, atomizing pressure is 0.2~0.4MPa for degree control, continues dry 30min after terminating hydrojet, takes the dish out of the pot, be isolated
Clothing layer pellet；
Pore-foaming agent is mixed with 336.3g water, obtains porogen solutions；Under stirring conditions, plasticizer is slowly added dropwise
Into slow release layer coating material, plasticizer-Sustained release coating materials mixture is formed；Under stirring conditions, by porogen solutions
It is added drop-wise in plasticizer-Sustained release coating materials material blends, crosses 80 meshes, obtain slow release layer solution；Using fluidized-bed process
Slow release layer is coated to barrier layer pellet, parameter are as follows: inlet air temperature is 55~65 DEG C, so that temperature of charge control is 40~43
DEG C, atomizing pressure is that 0.2~0.4MPa takes the dish out of the pot in 40~43 DEG C of dry 60min after hydrojet, obtains memantine and delays
Release pellet；
Obtained memantine sustained release pellet is sieved, pellet content is detected, determines capsule loading amount, fills capsule.
Comparative example 1
A kind of memantine sustained release pellet includes from inside to outside blank capsule core 400g, and medicated layer includes memantine
94.6g, adhesive PVP k3023.7g；Barrier layer is Opadry 18.2g；Slow release layer includes Sustained release coating materials ethyl cellulose
Element (30% aqueous dispersion) 179.5g, pore-foaming agent Kollicoat IR 7.0g, plasticizer triethyl citrate 16.2g；
The preparation method of above-mentioned memantine sustained release pellet, comprising the following steps:
The ethyl alcohol of 391.3g water and 285g 95% are mixed, mixed solvent is obtained；The ingredient of medicated layer is added to mixing
In solvent, 80 meshes are crossed, medicated layer solution is obtained；Medicated layer is coated in blank capsule core using fluidized-bed process, parameter are as follows:
Inlet air temperature is 55~60 DEG C, so that temperature of charge control is at 35~40 DEG C, atomizing pressure is 0.2~0.4MPa, terminates hydrojet
After continue dry 30min, take the dish out of the pot, obtain medicated layer pellet；
The ingredient Opadry of barrier layer is slowly dropped in 303.5g water, 80 meshes are crossed, forms barrier layer solution；
Barrier layer is coated to by medicated layer pellet, parameter using fluidized-bed process are as follows: inlet air temperature is 55~65 DEG C, so that material temperature
At 40~45 DEG C, atomizing pressure is 0.2~0.4MPa for degree control, continues dry 30min after terminating hydrojet, takes the dish out of the pot, be isolated
Clothing layer pellet；
Pore-foaming agent is mixed with 335.8g water, obtains porogen solutions；Under stirring conditions, plasticizer is slowly added dropwise
Into slow release layer coating material, plasticizer-Sustained release coating materials mixture is formed；Under stirring conditions, by porogen solutions
It is added drop-wise in plasticizer-Sustained release coating materials material blends, crosses 80 meshes, obtain slow release layer solution；Using fluidized-bed process
Slow release layer is coated to barrier layer pellet, parameter are as follows: inlet air temperature is 55~65 DEG C, so that temperature of charge control is 40~43
DEG C, atomizing pressure is that 0.2~0.4MPa takes the dish out of the pot in 40~43 DEG C of dry 60min after hydrojet, obtains memantine and delays
Release pellet；
Obtained memantine sustained release pellet is sieved, pellet content is detected, determines capsule loading amount, fills capsule.
Comparative example 2
A kind of memantine sustained release pellet includes from inside to outside blank capsule core 400g, and medicated layer includes memantine
94.6g, adhesive PVP k3023.7g；Barrier layer is Opadry 18.2g；Slow release layer includes Sustained release coating materials ethyl cellulose
Element (30% aqueous dispersion) 179.5g, pore-foaming agent Kollicoat IR 3.8g, plasticizer triethyl citrate 16.2g；
The preparation method of above-mentioned memantine sustained release pellet, comprising the following steps:
The ethyl alcohol of 391.3g water and 285g 95% are mixed, mixed solvent is obtained；The ingredient of medicated layer is added to mixing
In solvent, 80 meshes are crossed, medicated layer solution is obtained；Medicated layer is coated in blank capsule core using fluidized-bed process, parameter are as follows:
Inlet air temperature is 55~60 DEG C, so that temperature of charge control is at 35~40 DEG C, atomizing pressure is 0.2~0.4MPa, terminates hydrojet
After continue dry 30min, take the dish out of the pot, obtain medicated layer pellet；
The ingredient Opadry of barrier layer is slowly dropped in 303.5g water, 80 meshes are crossed, forms barrier layer solution；
Barrier layer is coated to by medicated layer pellet, parameter using fluidized-bed process are as follows: inlet air temperature is 55~65 DEG C, so that material temperature
At 40~45 DEG C, atomizing pressure is 0.2~0.4MPa for degree control, continues dry 30min after terminating hydrojet, takes the dish out of the pot, be isolated
Clothing layer pellet；
Pore-foaming agent is mixed with 339.0g water, obtains porogen solutions；Under stirring conditions, plasticizer is slowly added dropwise
Into slow release layer coating material, plasticizer-Sustained release coating materials mixture is formed；Under stirring conditions, by porogen solutions
It is added drop-wise in plasticizer-Sustained release coating materials material blends, crosses 80 meshes, obtain slow release layer solution；Using fluidized-bed process
Slow release layer is coated to barrier layer pellet, parameter are as follows: inlet air temperature is 55~65 DEG C, so that temperature of charge control is 40~43
DEG C, atomizing pressure is that 0.2~0.4MPa takes the dish out of the pot in 40~43 DEG C of dry 60min after hydrojet, obtains memantine and delays
Release pellet；
Obtained memantine sustained release pellet is sieved, pellet content is detected, determines capsule loading amount, fills capsule.
Performance test
(1) the release in vitro result and release profiles of the capsule of above-mentioned memantine sustained release pellet preparation are measured
To be purchased from the commercial product NAMENDA XR Memantine hydrochloride sustained-release capsule of FOREST LABORATORIES LLC
(specification: 28mg) is reference；Make the glue of the memantine sustained release pellet preparation of Samples EXAMPLE 1~3 and comparative example 1~2 by oneself
The rule of capsule is also configured as 28mg.
Measuring method are as follows: sample is taken, according to dissolution rate and drug release determination method (Chinese Pharmacopoeia four general rules 0931 of version in 2015
Second method), dissolution medium 900mL, revolving speed 100r/min are operated according to methods, through 12 hours, continue to operate according to methods, respectively at 1h,
2h, 3h, 4h, 6h, 8h, 10h, 12h take solution 5mL (and fluid infusion 5mL simultaneously), and filtration, precision measures subsequent filtrate 1mL, set respectively
In 20mL measuring bottle, adds the chloro-carbonic acid -9- fluorenes methyl ester solution of 0.015mol/L and each 2mL of borate buffer solution of 0.5mol/L, set
In constant temperature oscillator, derivatization temperature is 35 DEG C, revolving speed is 200r/min oscillation 20min；After being placed at room temperature for 20min, solvent is used
(solvent be concentration be 0.05mol/L borate buffer solution 50:50 is mixed by volume with acetonitrile) be diluted to scale, shake up,
As test solution；According to the method measurement under content determination item, calculate every burst size, be released result such as table 1~
5；And release profiles are successively drawn as shown in Fig. 1~5.
Releasing result (100rpm) of 1 sample of table in hydrochloric acid (pH 1.2)
Release profiles (100rpm) of the corresponding sample in hydrochloric acid (pH 1.2) are as shown in Figure 1.
Releasing result (100rpm) of 2 sample of table in acetate media (pH 4.5)
| It is commercially available | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | |
| 1h | 9.95% | 4.56% | 5.90% | 8.21% | 5.90% | 3.69% |
| 2h | 27.14% | 25.34% | 28.28% | 29.58% | 29.32% | 24.63% |
| 3h | 47.69% | 41.37% | 45.86% | 49.17% | 55.39% | 39.42% |
| 4h | 62.48% | 59.24% | 62.68% | 64.67% | 73.71% | 55.74% |
| 6h | 84.34% | 80.68% | 84.26% | 87.61% | 90.45% | 77.92% |
| 8h | 94.83% | 90.62% | 94.25% | 97.21% | 97.25% | 88.38% |
| 10h | 100.23% | 97.69% | 100.92% | 103.12% | 100.92% | 93.57% |
| 12h | 104.06% | 100.52% | 102.29% | 103.17% | 100.29% | 98.18% |
Release profiles (100rpm) of the corresponding sample in medium (pH 4.5) are as shown in Figure 2.
Releasing result (100rpm) of 3 sample of table in phosphoric acid salt medium (pH 6.8)
| It is commercially available | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | |
| 1h | 10.29% | 4.59% | 5.15% | 8.67% | 12.30% | 2.67% |
| 2h | 28.57% | 20.86% | 22.61% | 25.18% | 30.51% | 13.20% |
| 3h | 47.62% | 39.67% | 42.07% | 46.06% | 50.17% | 25.53% |
| 4h | 63.58% | 56.24% | 59.51% | 61.67% | 67.83% | 40.24% |
| 6h | 84.85% | 78.58% | 79.08% | 84.41% | 88.96% | 60.69% |
| 8h | 92.22% | 90.46% | 90.70% | 93.07% | 94.59% | 74.50% |
| 10h | 98.42% | 96.89% | 99.10% | 100.06% | 98.85% | 80.54% |
| 12h | 100.17% | 99.61% | 99.38% | 100.13% | 99.48% | 87.00% |
Release profiles (100rpm) of the corresponding sample in medium (pH 6.8) are as shown in Figure 3.
The releasing result (100rpm) of 4 sample of table in an aqueous medium
| It is commercially available | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | |
| 1h | 9.01% | 4.72% | 7.02% | 7.83% | 9.84% | 3.24% |
| 2h | 26.22% | 24.68% | 29.02% | 30.62% | 34.76% | 14.85% |
| 3h | 45.01% | 48.63% | 52.76% | 55.15% | 60.19% | 29.35% |
| 4h | 61.80% | 62.27% | 70.75% | 72.72% | 76.08% | 43.63% |
| 6h | 82.84% | 76.76% | 89.23% | 90.03% | 92.91% | 62.73% |
| 8h | 94.16% | 88.56% | 92.79% | 96.57% | 98.68% | 76.95% |
| 10h | 97.41% | 96.72% | 96.67% | 99.82% | 99.45% | 86.55% |
| 12h | 97.59% | 97.16% | 97.58% | 98.06% | 99.89% | 91.44% |
The corresponding release profiles of sample in an aqueous medium are as shown in Figure 4.
Releasing result (200rpm) of 5 sample of table in phosphoric acid salt medium (pH 7.5)
| It is commercially available | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | |
| 1h | 12.52% | 10.64% | 13.57% | 16.05% | 21.35% | 8.62% |
| 2h | 27.83% | 26.52% | 28.68% | 31.34% | 37.72% | 23.37% |
| 3h | 39.43% | 36.62% | 35.82% | 40.32% | 47.29% | 32.49% |
| 4h | 54.10% | 45.47% | 46.90% | 52.96% | 62.45% | 40.51% |
| 6h | 72.56% | 66.86% | 68.41% | 74.47% | 83.68% | 59.95% |
| 8h | 85.78% | 78.21% | 80.34% | 82.25% | 95.56% | 72.76% |
Release profiles (200rpm) of the corresponding sample in medium (pH 7.5) are as shown in Figure 5.
It can be seen that the Memantine hydrochloride sustained-release capsule of Examples 1 to 3 preparation and commercially available sample from table 1~5 and Fig. 1~5
Product are almost the same；And the release profiles of the Memantine hydrochloride sustained-release capsule in comparative example 1~2 and commercial samples are inconsistent, compare
The release in the medium that pH is 1.2 of example 1 is obvious fast, and comparative example 2 is that release is obvious partially slow in 6.8 media and water in pH.Thus
Illustrate: memantine sustained release pellet of the invention can effectively control the release of active ingredient hydrochloric acid Memantine, and medicine
Object will not be released, and ensure the safe and effective of medication, and quality is stablized.
(2) stability test of Memantine hydrochloride sustained-release capsule
Using the stability of high effective liquid chromatography for measuring Memantine hydrochloride sustained-release capsule, the results are shown in Table 6.
The stability test result of Memantine hydrochloride sustained-release capsule in 6 Examples 1 to 3 of table
As can be seen from Table 6, Memantine hydrochloride sustained-release capsule provided by the invention has excellent stability.
The present invention is by being 0.025~0.07:0.12 by the mass ratio control of barrier layer and slow release layer and pellet core
~0.16:1 both ensure that barrier layer and slow release layer to the covered effect of medicated layer, haved the function that active constituent is sustained；Together
When, barrier layer and slow release layer can make the active constituent in medicated layer at the appointed time with position slow release, efficiently
Play the drug effect of active constituent；In addition, medicated layer and slow release layer can be effectively isolated open by barrier layer, medicated layer pair is avoided
The influence of slow release layer slow release effect.
Further, by controlling the component and content of slow release layer, active ingredient hydrochloric acid Memantine is made to pass through slow release layer
Micropore slow release, avoids the phenomenon that active constituent is released, and has ensured the safe and effective of medication, and quality is stablized.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (9)
1. a kind of memantine sustained release pellet includes pellet core, barrier layer and slow release layer from inside to outside；It is described to contain pill
The mass ratio of core, barrier layer and slow release layer is 1:0.025~0.07:0.12~0.16；The pellet core includes blank pill
Core and medicated layer, the medicated layer include active ingredient hydrochloric acid Memantine and auxiliary material.
2. memantine sustained release pellet according to claim 1, which is characterized in that blank pill in the pellet core
The mass ratio of core, active ingredient hydrochloric acid Memantine and auxiliary material is 1~6:1:0.1~0.3.
3. memantine sustained release pellet according to claim 1 or 2, which is characterized in that the blank capsule core packet
Include sugar-pill and/or microcrystalline cellulose vegetable pill.
4. memantine sustained release pellet according to claim 1 or 2, which is characterized in that the auxiliary material includes adhesive.
5. memantine sustained release pellet according to claim 4, which is characterized in that described adhesive includes polyethylene pyrrole
One or more of pyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
6. memantine sustained release pellet according to claim 1, which is characterized in that the ingredient of the barrier layer is thin
Film coating pre-mixing agent.
7. memantine sustained release pellet according to claim 1, which is characterized in that the slow release layer includes sustained release coating
Material, pore-foaming agent and plasticizer；The mass ratio of the Sustained release coating materials, pore-foaming agent and plasticizer be 100:8~12:10~
50。
8. memantine sustained release pellet according to claim 7, which is characterized in that the Sustained release coating materials are ethyl
Cellulose aqueous dispersions；The plasticizer includes one of triethyl citrate, tributyl citrate and dibutyl sebacate
Or it is several；The pore-foaming agent is polyvinyl alcohol/ethylene glycol copolymer.
9. the preparation method of any one of the claim 1~8 memantine sustained release pellet, comprising the following steps:
Ingredient in medicated layer, barrier layer and slow release layer is mixed with solvent, forms corresponding medicated layer solution, barrier layer
Medicated layer solution is coated in blank capsule core by solution and slow release layer solution by fluidized bed coating technique, then successively will again
Barrier layer solution and slow release layer solution are coated on pellet, obtain memantine sustained release pellet.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109846858A (en) * | 2018-12-18 | 2019-06-07 | 杭州和康药业有限公司 | A kind of Memantine hydrochloride sustained-release capsule 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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| WO2006138227A1 (en) * | 2005-06-16 | 2006-12-28 | Forest Laboratories, Inc. | Modified and immediate release memantine bead formulation |
| 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 |
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| WO2006138227A1 (en) * | 2005-06-16 | 2006-12-28 | Forest Laboratories, Inc. | Modified and immediate release memantine bead formulation |
| 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 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109846858A (en) * | 2018-12-18 | 2019-06-07 | 杭州和康药业有限公司 | A kind of Memantine hydrochloride sustained-release capsule 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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Application publication date: 20181211 |