CN104013592A - Memantine hydrochloride slow-release pill and preparation method thereof - Google Patents
Memantine hydrochloride slow-release pill and preparation method thereof Download PDFInfo
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- CN104013592A CN104013592A CN201410254808.2A CN201410254808A CN104013592A CN 104013592 A CN104013592 A CN 104013592A CN 201410254808 A CN201410254808 A CN 201410254808A CN 104013592 A CN104013592 A CN 104013592A
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Abstract
The invention discloses a memantine hydrochloride slow-release pill and a preparation method thereof. Packing inside a capsule is a memantine hydrochloride slow-release pill; the memantine hydrochloride slow-release pill sequentially comprises a hollow pill core, a main medicine layer containing memantine hydrochloride, an isolated coating layer and a slow-release coating layer from inside to outside. The memantine hydrochloride slow-release pill is good in stability and free of an initial burst release phenomenon, the condition that the medicine is lastingly, evenly and slowly released is ensured, and the curative effect of the product is improved.
Description
Technical field
The present invention relates to a kind of memantine slow release pill and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Along with the continuous growth of world population aging and the raising day by day of living standards of the people, the average life span, 2002, the 60 years old above old people in the whole world accounted for 20% of world population sum also along with prolongation, to the year two thousand fifty, old people's quantity is estimated to reach 21% of world's total population.Along with world population aging, senile dementia has become the matter of utmost importance of human health, and sickness rate is along with the progress of aged tendency of population is the trend rising year by year.At present whole world number of patients has exceeded 1,800 ten thousand, and China's number of patients approximately has 6,000,000, is the maximum country of number of patients in the world.The treatment of memantine (Memantine HCl) for moderate to the dementia of the Alzheimer type of severe.Alzheimer's disease (AD) is the irreversible sexual disorder that carries out that a kind of brain cell (neuron) worsens, and it causes cognitive function, main memory, judgement and reasoning, the forfeiture of sports coordination and Figure recognition.In the late period of this disease, all memories and intellectual function all may be lost.The people who suffers from Alzheimer's disease has problems aspect memory, judgement and thinking, thereby makes it be difficult to work or participate in daily life.It and alzheimer disease, the intelligence relevant with old-age group degenerate (intelligence is lost) relevant.Alzheimer disease is defined as two kinds of main Types: the Alzheimer type being caused by the atrophy of broad sense and being caused by vascular problem is mainly apoplexy etc.In people more than 80 years old, 20% suffers from Alzheimer's disease.Although there is the medicine that can improve symptom, Alzheimer's disease can not be cured at present.Memantine is approved for the treatment of middle severe to severe AD at present in Europe, and is used to the treatment of moderate to severe AD in the U.S..In addition, compared with accepting the AD patient of placebo, while giving memantine to severe AD patient in to the treatment of accepting medicine donepezil, produced the beyond thought larger alleviation of AD symptom.This result, is approved for compared with the therapeutic alliance of medicinal compound that AD treats and the control compound of use and does not produce any advantage comprising giving memantine and other to not showing in moderate AD patients slightly.WO2005/06790B has described one and has treated the slight method to severe Alzheimer's disease (AD), comprises the memantine or its pharmaceutically acceptable salt that the experimenter of needs are given to effective dose.The method is for the experimenter (naive subject) by not accepting treatment, and previously once accepted the treatment of other medicinal compound that is approved for AD treatment but before starting memantine administration, ended AChEI (acetylcholinesterase inhibitor) and treat the group that the experimenter earlier than a day forms.WO2006/009769 has described a kind of dosage form and in approximately 4 hours to approximately 24 hours, can maintain after administration the pharmaceutically useful polymeric matrix carrier of memantine rate of release.But the polymeric matrix that depends on numerous state-variables forms mechanism, and can directly to affect drug release characteristics be well-known in the art.This difficulty particularly in memantine compositions, because memantine medicine is water-soluble and have high osmosis, so the variation that any variation of substrate in forming all probably causes drug release and absorb.
CN101677960 described a kind of memantine prolongation discharge pharmaceutical composition, adopt lipid matter or with non-lipid matter together with as control drug release material.Lipid matter is as substrate control drug release, and non-lipid matter is as coating control drug release.But lipid matter can play prolongation, stop the release of water soluble drug memantine, but on being subject to more multifactorial impact in the control of drug releasing rate, as be subject to pharmaceutical composition volume size, the impact of surface area and food.As added with lipid matter, coating double factor carrys out adjustment release, and two variable factors to a certain extent more difficult control drug release reach desirable release profiles.As everyone knows, lipid matter compressibility is poor, if in formula large usage quantity, concerning final composition compressing, be also a problem.If adopt releasing piece at once, use the memantine dosage regimen of twice every day, this may not welcome by patient, because patient's compliance is along with the frequency of taking medicine increases and reduces.And, because absorption rate faster, give the adverse events that releasing piece at once may cause larger frequency.Therefore be, the problem of paying close attention to for the slow releasing preparation once a day of the pharmaceutically acceptable salt containing memantine or memantine.Patent CN1968684 has protected a kind of tune release formulation that comprises memantine, and mainly protecting a kind of HPMC of employing is the sustained release tablet for oral use of the memantine of skeleton slow-release material.Although slow releasing tablet can reach the effect of steady blood drug level, slow releasing tablet also exists to dash forward releases risk, has certain potential safety hazard.
CN103181914 has protected a kind of memantine slow releasing capsule, and mainly having protected capsule inner stuffing is memantine slow-release micro-pill, and slow-release micro-pill is made up of pastille piller and one deck sustained release coating of hydrochloric memantine.Although this patent has solved the prominent risk of releasing of slow releasing tablet, but this capsule, in the process of long-term storage, is vulnerable to the impact of wet environment, because memantine is very easily water-soluble material, there is the risk of medicated layer toward slow release layer migration, thereby have equally the prominent risk of releasing.
Patent CN103417491 has protected memantine sustained-release pellet preparation, has mainly protected celphere and the technique that is wrapped in outer field memantine medicament slow release composite bed, but the prominent risk of releasing of this technique existence same with patent CN103181914.
Summary of the invention
The object of the invention is to, a kind of memantine slow release pill and preparation method thereof is provided.Good stability of the present invention, nothing are dashed forward and are released phenomenon, guarantee sustained drug, evenly discharge lentamente medicine, have improved the curative effect of producing mouth.
For solving the problems of the technologies described above, technical scheme provided by the invention is as follows: a kind of memantine slow release pill, memantine slow release pill comprises the pastille piller, isolation coat layer and the slow release coatings that comprise memantine from the inside to the outside successively.
In above-mentioned memantine slow release pill, described isolation coat layer comprises isolation coat material 70-95 part, Pulvis Talci 5-30 part by weight; Described isolation coat material is ketopyrrolidine, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl-cellulose, ethyl cellulose, IR, Eudragit RL100, Eudragit RS100, EudragitRL 30D, Eudragit RS 30D, Eudragit NE30D, Aquacoat ECD, Surelease or Kollicoat RS30D.
In aforesaid memantine slow release pill, described isolation coat material is hydroxypropyl methylcellulose.
In aforesaid memantine slow release pill, the quality of described sealing coat is the 3%-20% of pastille piller quality.
In aforesaid memantine slow release pill, described pastille piller comprises celphere, is provided with the principal agent layer of hydrochloric memantine in the outside of celphere.
In aforesaid memantine slow release pill, described principal agent layer comprises memantine 20-50 part, binding agent 7-15 part, diluent 30-50 part and antiplastering aid 5-15 part by weight; Described sustained release coating layer comprises sustained release coating material 70-85 part, Polyethylene Glycol 10-30 part and triethyl citrate 0-5 part by weight; In described sustained release coating material ethyl cellulose, cellulose acetate, Eudragit RL100, Eudragit RS100, Eudragit RL 30D, Eudragit RS 30D, Eudragit NE30D, Aquacoat ECD, Surelease or Kollicoat RS30D one or more.
In aforesaid memantine slow release pill, described binding agent is ketopyrrolidine, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl-cellulose or ethyl cellulose; Described diluent is mannitol, Polyethylene Glycol, sucrose, lactose or tartaric acid; Described antiplastering aid is Pulvis Talci, magnesium stearate, stearic acid or glyceryl monostearate; Described solvent is that one or more of ethanol, water, acetone, methanol, isopropyl alcohol combine.
In aforesaid memantine slow release pill, described binding agent is hydroxypropyl methylcellulose; Described diluent is mannitol; Described antiplastering aid is Pulvis Talci.
The preparation method of aforesaid memantine slow release pill, is characterized in that: comprise the following steps;
(1) getting hypromellose is dissolved in solvent and is mixed with solution A; Polyethylene Glycol and memantine are dissolved in to solvent and are mixed with solution B; Solution A is joined in solution B, then add Pulvis Talci to stir, obtain pastille coating solution;
(2) pastille coating solution is carried out to coating to celphere, after being dried, make the principal agent layer piller of hydrochloric memantine;
(3) get hypromellose and be dissolved in solvent and be mixed with solution C, add solution C to stir Pulvis Talci, obtain isolation coat liquid;
(4) isolation coat liquid is carried out to coating to principal agent layer piller, after being dried, make sealing coat piller;
(5) get triethyl citrate and Polyethylene Glycol and be dissolved in solvent and be mixed with solution D, add solution D to stir ethyl cellulose, obtain sustained release coating liquid;
(6) sustained release coating liquid is carried out to coating to sealing coat piller, after being dried, obtain memantine slow release pill.
In the preparation method of above-mentioned memantine slow release pill, specifically comprise the following steps;
(1), the preparation of principal agent layer piller;
A, get hypromellose and add the container that 80 DEG C～90 DEG C of purified water are housed, stir and make to disperse, then add purified water, limit edged stirs, and obtains A product;
B, Polyethylene Glycol and memantine are put in container, added purified water to dissolve, obtain B product;
C, A product are added in B product, stir, then add while stirring Pulvis Talci, Pulvis Talci is uniformly dispersed, cross 80 mesh sieves, obtain pastille coating solution;
D, by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of celphere, use peristaltic pump by pastille coating solution to celphere hydrojet;
E, pastille coating solution is sprayed completely, controlled temperature of charge between 36 DEG C～40 DEG C, drier about 5-10 minute, obtained the principal agent layer piller of hydrochloric memantine;
(2), the preparation of sealing coat piller;
A, get hypromellose and add the container that 80 DEG C～90 DEG C of purified water are housed, stir and make to disperse, let cool, stir on cold rnning limit, limit, obtains C product;
B, Pulvis Talci is put into C product stir, cross 80 mesh sieves, maintain agitator gentle agitation, obtain isolation coat liquid;
C, by principal agent layer piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of principal agent layer piller, use peristaltic pump by isolation coat liquid to principal agent layer piller hydrojet;
D, isolation coat liquid is sprayed completely, controlled temperature of charge between 36 DEG C～40 DEG C, drier about 5-10 minute, sealing coat piller obtained;
(3), the preparation of memantine slow release pill;
A, take triethyl citrate and Polyethylene Glycol adds in the container that ethanol is housed, be stirred to dissolve, then add purified water, obtain D product;
B, ethyl cellulose is slowly put into D product stir, cross 80 mesh sieves, maintain agitator gentle agitation, obtain sustained release coating liquid;
C, by sealing coat piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of sealing coat piller, use peristaltic pump by sustained release coating liquid to sealing coat piller hydrojet;
D, sustained release coating liquid is sprayed completely, controlled temperature of charge between 36 DEG C～40 DEG C, drier about 5-10 minute, memantine slow release pill obtained.
Compared with prior art, the present invention has increased one deck isolation coat layer between the pastille piller that comprises memantine and slow release coatings, solve the easily prominent problem of releasing of memantine medicine under high humidity environment, improved the stability of product, ensured the curative effect of product.Further, applicant is also further defined component, proportioning and the preparation technology (comprising the parameter of processing step and each step) of each layer, many factor synergism have reduced burst drug release risk minimum level, make the stability of product reach best.It is little that the present invention also has volume, is not subject to the impact of food when drug administration, and production method is simple, is suitable for suitability for industrialized production, has larger using value.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1: be the impact on slow releasing capsule stripping under super-humid conditions of research sealing coat, prepare two kinds of pillers, without sealing coat (or claim isolation coat layer) pastille piller A with there is sealing coat pastille piller B, after pour into and in capsule, become corresponding slow releasing capsule A and slow releasing capsule B, at the hermetic container of putting into relative humidity 92.5%, investigate 5,10 days stripping results simultaneously.
One, the preparation of slow releasing capsule A
(1) the pastille piller of memantine preparation:
1.1 take hypromellose E3 adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, then add cold purified water, and limit edged stirs, and obtains I;
1.2 put polyethylene glycol 6000 and memantine in container, add purified water to dissolve, and obtain II.
1.3 add (I) in (II) again, stir, and then add Pulvis Talci while stirring, and stir and make Pulvis Talci
Be uniformly dispersed.Coating solution is crossed 80 mesh sieves, maintains agitator gentle agitation, for subsequent use.
1.4 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, can open peristaltic pump hydrojet.
1.5 treat that coating solution has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out pastille piller,
(2) sustained release coating process:
3.1 take triethyl citrate, and polyethylene glycol 6000 adds in the container that ethanol is housed, and is stirred to dissolve, and adds purified water, obtains I.
Ethyl cellulose is slowly put into I by 3.2 to be stirred 80 mesh sieves and maintained agitator gentle agitation, for subsequent use.
3.3 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of piller, can open peristaltic pump hydrojet.
3.4 treat that coating solution has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out slow-release pill A.
(3) slow-release pill A is obtained to slow releasing capsule A by intermediate content filled capsules.
Two, the preparation of slow releasing capsule B
(1) the pastille piller preparation that comprises memantine:
1.1 take hypromellose adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, then add cold purified water, and limit edged stirs, and obtains I.
1.2 put Polyethylene Glycol and memantine in container, add purified water to dissolve, and obtain II.
1.3 add (I) in (II) again, stir, and then add Pulvis Talci while stirring, and stir Pulvis Talci is uniformly dispersed.Coating solution is crossed 80 mesh sieves, maintains agitator gentle agitation, for subsequent use.
1.4 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, can open peristaltic pump hydrojet.
1.5 treat that coating solution has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out pastille piller.
(2) sealing coat piller preparation
2.1 take hypromellose E3 adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, and lets cool, and stir on cold rnning limit, limit, obtains I.
I put into by Pulvis Talci by 2.2 stirred 80 mesh sieves and maintained agitator gentle agitation, for subsequent use.
2.3 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, can open peristaltic pump hydrojet.
2.4 treat that coating solution has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out sealing coat piller.
(3) sustained release coating process:
3.1 take triethyl citrate, and Polyethylene Glycol adds in the container that ethanol is housed, and is stirred to dissolve, and adds purified water, obtains I.
Ethyl cellulose is slowly put into I by 3.2 to be stirred 80 mesh sieves and maintained agitator gentle agitation, for subsequent use.
3.3 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of piller, can open peristaltic pump hydrojet
3.4 treat that coating solution has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out slow-release pill.
(4) slow-release pill B is obtained to slow releasing capsule B by intermediate content filled capsules.
Three, above two kinds of slow releasing capsule are put into 92.5% high humidity environment, sampling in 0 day, 5,10 days, according to Chinese Pharmacopoeia dissolution detection method, is used basket method, under 100 revs/min, in 900ml, 37 degree pH1.2 buffer solution, slow releasing capsule is carried out to stripping curve detection.
Result: obviously can find out that slow releasing capsule A and slow releasing capsule B detected stripping curve in the time of 0 day as broad as long; but through the stripping curve of high humidity slow releasing capsule A after 5 days, 10 days obviously faster than 0 day; but the stripping curve of slow releasing capsule B does not almost change, can show thus the protective effect that sealing coat is superior to slow release effect.
Embodiment 2: the preparation method of memantine slow releasing capsule:
(1): principal agent layer piller (the being pastille piller) preparation of hydrochloric memantine:
1.1 take hydroxypropyl cellulose adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, then add cold purified water, and limit edged stirs, and obtains I.
1.2 put Polyethylene Glycol and memantine in container, add purified water to dissolve, and obtain II.
1.3 add (I) in (II) again, stir, and then add Pulvis Talci while stirring, and stir Pulvis Talci is uniformly dispersed, and cross 80 mesh sieves, maintain agitator gentle agitation, obtain pastille coating solution for subsequent use.
1.4 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, use peristaltic pump by pastille coating solution to celphere hydrojet.
1.5 treat that pastille coating solution has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, obtain the principal agent layer piller of hydrochloric memantine.
(2) sealing coat piller preparation
2.1 take hydroxypropyl cellulose EF adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, and lets cool, and stir on cold rnning limit, limit, obtains I.
I put into by Pulvis Talci by 2.2 stirred 80 mesh sieves and maintained agitator gentle agitation, obtained isolation coat liquid for subsequent use.
2.3 by principal agent layer piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, can open peristaltic pump hydrojet, use peristaltic pump by isolation coat liquid to principal agent layer piller hydrojet.
2.4 have sprayed isolation coat liquid completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, obtain sealing coat piller.
(3) preparation process of memantine slow release pill:
3.1 take triethyl citrate, and Polyethylene Glycol adds in the container that ethanol is housed, and is stirred to dissolve, and adds purified water, obtains I.
Ethyl cellulose is slowly put into I by 3.2 to be stirred 80 mesh sieves and maintained agitator gentle agitation, obtained sustained release coating liquid for subsequent use.
3.3 by sealing coat piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of piller, can open peristaltic pump hydrojet, use peristaltic pump by sustained release coating liquid to sealing coat piller hydrojet.
3.4 treat that sustained release coating liquid has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out memantine slow release pill.
(4) memantine slow release pill is obtained to slow releasing capsule by intermediate content filled capsules.
Embodiment 3: the preparation method of memantine slow releasing capsule
(1) preparation of principal agent layer piller:
1.1 take hydroxypropyl cellulose adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, then add cold purified water, and limit edged stirs, and obtains I.
1.2 put Polyethylene Glycol and memantine in container, add purified water to dissolve, and obtain II.
1.3 add (I) in (II) again, stir, and then add Pulvis Talci while stirring, and stir Pulvis Talci is uniformly dispersed.Cross 80 mesh sieves, maintain agitator gentle agitation, obtain pastille coating solution for subsequent use.
1.4 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, can open peristaltic pump hydrojet, use peristaltic pump by pastille coating solution to celphere hydrojet.
1.5 treat that pastille coating solution has sprayed completely, control temperature of charge between 36 DEG C～40 DEG C, drier about 5-10 minute, obtain the principal agent layer piller of hydrochloric memantine.
(2) sealing coat piller preparation
2.1 take hydroxypropyl cellulose EF adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, and lets cool, and stir on cold rnning limit, limit, obtains I.
I put into by Pulvis Talci by 2.2 stirred 80 mesh sieves and maintained agitator gentle agitation, for subsequent use.
2.3 by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, can open peristaltic pump hydrojet, use peristaltic pump by isolation coat liquid to principal agent layer piller hydrojet.
2.4 coating solutions to be isolated have sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, obtain sealing coat piller.
(3) preparation process of memantine slow release pill:
3.1 take triethyl citrate, and Polyethylene Glycol adds in the container that Surelease is housed, and is stirred to dissolve, and adds purified water, obtains I.
I was stirred 80 mesh sieves by 3.2 maintains agitator gentle agitation, obtains sustained release coating liquid, for subsequent use.
3.3 by sealing coat piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of piller, can open peristaltic pump hydrojet, use peristaltic pump by sustained release coating liquid to sealing coat piller hydrojet.
3.4 treat that sustained release coating liquid has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, obtain memantine slow release pill.
(4) will obtain memantine slow release pill and obtain memantine slow releasing capsule by intermediate content filled capsules.
Embodiment 4: the preparation method of memantine slow releasing capsule
(1) preparation of pastille piller:
Extrude round as a ball: memantine, microcrystalline Cellulose, hydroxypropyl methylcellulose are mixed, make wetting agent wet granulation with 25g water, the wet granular making obtains thickness and the suitable bar of length through extruder, bar obtains roundness and the suitable piller of fineness through spheronizator, it is 1% to fix shaping that this piller is dried to moisture through 50 DEG C, crosses 25 mesh sieves and obtains the pastille piller that comprises memantine.
(2) sealing coat piller preparation
2.1 take hydroxypropyl cellulose EF adds the container that 80 DEG C～90 DEG C of purified water are housed, and stirs and makes to disperse, and lets cool, and stir on cold rnning limit, limit, obtains I.
I put into by Pulvis Talci by 2.2 stirred 80 mesh sieves and maintained agitator gentle agitation, for subsequent use.
2.3 by the pastille piller that comprises memantine by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure (1.6BAR), adjust the fluidized state of piller, can open peristaltic pump hydrojet, use peristaltic pump by sustained release coating liquid to sealing coat piller hydrojet.
2.4 coating solutions to be isolated have sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out sealing coat piller.
(3) preparation process of memantine slow release pill:
3.1 take triethyl citrate, and Polyethylene Glycol adds in the container that Surelease is housed, and is stirred to dissolve, and adds purified water, obtains I.
I was stirred 80 mesh sieves by 3.2 maintains agitator gentle agitation, obtains sustained release coating liquid, for subsequent use.
3.3 by sealing coat piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of piller, can open peristaltic pump hydrojet, use peristaltic pump by sustained release coating liquid to sealing coat piller hydrojet.
3.4 treat that sustained release coating liquid has sprayed completely, control temperature of charge and between 36 DEG C～40 DEG C, are dried about 5-10 minute again, take out memantine slow release pill.
(4) memantine slow release pill is obtained to memantine slow releasing capsule by intermediate content filled capsules.
Claims (10)
1. memantine slow release pill, is characterized in that: memantine slow release pill comprises the pastille piller, isolation coat layer and the slow release coatings that comprise memantine from the inside to the outside successively.
2. memantine slow release pill according to claim 1, is characterized in that: described isolation coat layer comprises isolation coat material 70-95 part, Pulvis Talci 5-30 part by weight; Described isolation coat material is ketopyrrolidine, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl-cellulose, ethyl cellulose, IR, Eudragit RL100, Eudragit RS100, Eudragit RL 30D, Eudragit RS 30D, Eudragit NE30D, AquacoatECD, Surelease or Kollicoat RS30D.
3. memantine slow release pill according to claim 2, is characterized in that: described isolation coat material is hydroxypropyl methylcellulose.
4. according to the memantine slow release pill described in claim 2 or 3, it is characterized in that: the quality of described sealing coat is the 3%-20% of pastille piller quality.
5. according to the memantine slow release pill described in claim 1 to 4 any one, it is characterized in that: described pastille piller comprises celphere, be provided with the principal agent layer of hydrochloric memantine in the outside of celphere.
6. memantine slow release pill according to claim 5, is characterized in that: described principal agent layer comprises memantine 20-50 part, binding agent 7-15 part, diluent 30-50 part and antiplastering aid 5-15 part by weight; Described sustained release coating layer comprises sustained release coating material 70-85 part, Polyethylene Glycol 10-30 part and triethyl citrate 0-5 part by weight; In described sustained release coating material ethyl cellulose, cellulose acetate, Eudragit RL100, Eudragit RS100, Eudragit RL 30D, Eudragit RS 30D, Eudragit NE30D, AquacoatECD, Surelease or Kollicoat RS30D one or more.
7. memantine slow release pill according to claim 6, is characterized in that: described binding agent is ketopyrrolidine, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl-cellulose or ethyl cellulose; Described diluent is mannitol, Polyethylene Glycol, sucrose, lactose or tartaric acid; Described antiplastering aid is Pulvis Talci, magnesium stearate, stearic acid or glyceryl monostearate; Described solvent is that one or more of ethanol, water, acetone, methanol, isopropyl alcohol combine.
8. memantine slow release pill according to claim 7, is characterized in that: described binding agent is hydroxypropyl methylcellulose; Described diluent is mannitol; Described antiplastering aid is Pulvis Talci.
9. according to the preparation method of the memantine slow release pill described in claim 1 to 8 any one, it is characterized in that: comprise the following steps;
(1) getting hypromellose is dissolved in solvent and is mixed with solution A; Polyethylene Glycol and memantine are dissolved in to solvent and are mixed with solution B; Solution A is joined in solution B, then add Pulvis Talci to stir, obtain pastille coating solution;
(2) pastille coating solution is carried out to coating to celphere, after being dried, make the principal agent layer piller of hydrochloric memantine;
(3) get hypromellose and be dissolved in solvent and be mixed with solution C, add solution C to stir Pulvis Talci, obtain isolation coat liquid;
(4) isolation coat liquid is carried out to coating to principal agent layer piller, after being dried, make sealing coat piller;
(5) get triethyl citrate and Polyethylene Glycol and be dissolved in solvent and be mixed with solution D, add solution D to stir ethyl cellulose, obtain sustained release coating liquid;
(6) sustained release coating liquid is carried out to coating to sealing coat piller, after being dried, obtain memantine slow release pill.
10. the preparation method of memantine slow release pill according to claim 9, is characterized in that: specifically comprise the following steps;
(1), the preparation of principal agent layer piller;
A, get hypromellose and add the container that 80 DEG C～90 DEG C of purified water are housed, stir and make to disperse, then add purified water, limit edged stirs, and obtains A product;
B, Polyethylene Glycol and memantine are put in container, added purified water to dissolve, obtain B product;
C, A product are added in B product, stir, then add while stirring Pulvis Talci, Pulvis Talci is uniformly dispersed, cross 80 mesh sieves, obtain pastille coating solution;
D, by celphere by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of celphere, use peristaltic pump by pastille coating solution to celphere hydrojet;
E, pastille coating solution is sprayed completely, controlled temperature of charge between 36 DEG C～40 DEG C, drier about 5-10 minute, obtained the principal agent layer piller of hydrochloric memantine;
(2), the preparation of sealing coat piller;
A, get hypromellose and add the container that 80 DEG C～90 DEG C of purified water are housed, stir and make to disperse, let cool, stir on cold rnning limit, limit, obtains C product;
B, Pulvis Talci is put into C product stir, cross 80 mesh sieves, maintain agitator gentle agitation, obtain isolation coat liquid;
C, by principal agent layer piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of principal agent layer piller, use peristaltic pump by isolation coat liquid to principal agent layer piller hydrojet;
D, isolation coat liquid is sprayed completely, controlled temperature of charge between 36 DEG C～40 DEG C, drier about 5-10 minute, sealing coat piller obtained;
(3), the preparation of memantine slow release pill;
A, take triethyl citrate and Polyethylene Glycol adds in the container that ethanol is housed, be stirred to dissolve, then add purified water, obtain D product;
B, ethyl cellulose is slowly put into D product stir, cross 80 mesh sieves, maintain agitator gentle agitation, obtain sustained release coating liquid;
C, by sealing coat piller by hand feed way add in the material barrel of fluid bed, start heating, while remaining on more than 35 DEG C to temperature of charge, open atomizing pressure, adjust the fluidized state of sealing coat piller, use peristaltic pump by sustained release coating liquid to sealing coat piller hydrojet;
D, sustained release coating liquid is sprayed completely, controlled temperature of charge between 36 DEG C～40 DEG C, drier about 5-10 minute, memantine slow release pill obtained.
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| CN105769794A (en) * | 2016-04-03 | 2016-07-20 | 北京化工大学 | Memantine hydrochloride sustained release micro-pill tablets and preparation method thereof |
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| CN108066297A (en) * | 2016-11-16 | 2018-05-25 | 深圳万和制药有限公司 | Treat the positioning release Memantine Orally disintegrating tablet compositions of senile dementia |
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| CN109966269A (en) * | 2017-12-27 | 2019-07-05 | 江苏万邦生化医药集团有限责任公司 | A kind of Memantine hydrochloride slow-release pellet preparation and preparation method thereof |
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| CN104434855A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Memantine hydrochloride tablet and preparation method thereof |
| CN105326837A (en) * | 2015-10-09 | 2016-02-17 | 北京万全德众医药生物技术有限公司 | Memantine hydrochloride sustained release-donepezil quick release compound capsule |
| CN105769794B (en) * | 2016-04-03 | 2019-06-21 | 北京化工大学 | A kind of memantine sustained release pellet tablet and preparation method thereof |
| CN105769794A (en) * | 2016-04-03 | 2016-07-20 | 北京化工大学 | Memantine hydrochloride sustained release micro-pill tablets 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 |
| CN108066297B (en) * | 2016-11-16 | 2022-09-16 | 深圳万和制药有限公司 | Positioning release memantine orally disintegrating tablet composition for treating senile dementia |
| CN108066297A (en) * | 2016-11-16 | 2018-05-25 | 深圳万和制药有限公司 | Treat the positioning release Memantine Orally disintegrating tablet compositions of senile dementia |
| CN106581682A (en) * | 2016-12-09 | 2017-04-26 | 河南中帅医药科技股份有限公司 | Memantine hydrochloride/donepezil slow-release resin composition and preparation method thereof |
| CN106727439A (en) * | 2016-12-21 | 2017-05-31 | 河南中帅医药科技股份有限公司 | A kind of memantine is sustained donepezil quick-release compound capsule |
| CN109966269A (en) * | 2017-12-27 | 2019-07-05 | 江苏万邦生化医药集团有限责任公司 | A kind of Memantine hydrochloride slow-release pellet preparation and preparation method thereof |
| CN108969506A (en) * | 2018-09-11 | 2018-12-11 | 山东鲁抗医药股份有限公司 | A kind of memantine sustained release pellet and preparation method thereof |
| CN111568871A (en) * | 2020-03-23 | 2020-08-25 | 北京华氏开元医药科技有限公司 | Urapidil sustained release preparation 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 |
| CN114748443A (en) * | 2022-04-20 | 2022-07-15 | 北京丰科睿泰医药科技有限公司 | Memantine hydrochloride sustained-release pellet and preparation method thereof |
| CN114748443B (en) * | 2022-04-20 | 2023-05-02 | 北京丰科睿泰医药科技有限公司 | Memantine hydrochloride sustained-release pellets and preparation method thereof |
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