CN101862297B - Water-insoluble medicine sustained-release pellet, sustained-release orally disintegrating tablet thereof and preparation method thereof - Google Patents
Water-insoluble medicine sustained-release pellet, sustained-release orally disintegrating tablet thereof and preparation method thereof Download PDFInfo
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- CN101862297B CN101862297B CN2009100492217A CN200910049221A CN101862297B CN 101862297 B CN101862297 B CN 101862297B CN 2009100492217 A CN2009100492217 A CN 2009100492217A CN 200910049221 A CN200910049221 A CN 200910049221A CN 101862297 B CN101862297 B CN 101862297B
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Abstract
The invention discloses a water-insoluble medicine sustained-release pellet, a sustained-release orally disintegrating tablet thereof and a preparation method thereof. The water-insoluble medicine sustained-release pellet comprises a hollow pellet core, a medicine layer, an insulation layer and a sustained-release layer, wherein the sustained-release layer comprises the following ingredients: 54 to 88 percent of sustained-release materials, 2 to 30 percent of antitackiness agents and 1 to 30 percent of pore-foaming agents, wherein the percentage is the mass percentage in the sustained-release layer, wherein the sustained-release materials are one kind or several kinds of materials selected from ethyl acrylate and methyl methacrylate copolymers, polyvinyl acetate and ethyl cellulose. Through regulating the coating combinations and filling auxiliary materials to be pressed into orally disintegrating tablets, the medicine can be slowly released for more than 8 to 13 hours, so the stable blood medicine concentration can be maintained, the side effect is reduced, the medicine taking times can be reduced, and the medicine taking is convenient. The invention conforms to zero-grade release, has the advantages of high final accumulated medicine release amount, high efficacy, strong selectivity, good mouth feeling, simple production steps and high efficiency, and can be applied to large-scale production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly a kind of slow-release micro-pill of water-insoluble medicine, its slow release oral cavity disintegration tablet and preparation method thereof.
Background technology
The slow release time of the slow releasing preparation of existing water-insoluble medicine is short, can not realize long-acting release, and the longest have only 6 hours.Like ibuprofen slow-release speed disintegrating tablet is blocker with phospholipid; Kollicoat SR 30D is a coating material; Adopt granulating coated prepared slow release speed disintegrating tablet, but because the restriction of granulating process, coating is incomplete; Make slow-release time (the Fast dispersible/slow releasingibuprofen tablets.Adamo Fini that has only 1.5 hours; Valentina Bergamante, Gian Carlo Ceschel, A.Fini et al./European Journal of Pharmaceutics and Biopharmaceutics 69 (2008) 335-341).And in the body slowly release reach the medicine more than 8 hours, blood drug level that can held stationary reduces side effect, and can reduce and take number of times, greatly facilitates taking of medicine, is in particular the crowd who takes medicine for a long time to offer convenience, but fails to realize always.
Summary of the invention
Therefore, it is shorter that the technical problem that the present invention will solve is exactly the slow-release time that exists to existing water-insoluble medicine, generally less than 8 hours deficiency, slow-release micro-pill, its slow release oral cavity disintegration tablet of a kind of water-insoluble medicine and preparation method thereof is provided.This slow release oral cavity disintegration tablet can reach quickly disintegrated requirement in the oral cavity, again can be in vivo slowly release 8～13 hours, the blood drug level of held stationary reduces side effect, reduces and takes number of times.
Because slow release layer is the determiner of the rate of release of slow-release micro-pill, therefore, for the release that makes slow-release micro-pill between 8～13 hours, the inventor has carried out great deal of experimental to slow release layer required composition and content, has accomplished the present invention finally.
One of technical scheme that solves the problems of the technologies described above provided by the invention is; A kind of slow-release micro-pill of water-insoluble medicine; Comprise celphere, medicine layer, sealing coat and slow release layer; Described slow release layer comprises following component: 54～88% slow-release material, 2～30% antiplastering aid and 1～30% porogen, and described percentage ratio is the mass percent that accounts for slow release layer; Wherein, described slow-release material is selected from any or multiple in copolymer, polyvinyl acetate and the ethyl cellulose of ethyl acrylate and methyl methacrylate.
In the slow release layer of the present invention, described slow-release material is selected from any in copolymer, polyvinyl acetate esters and the ethyl cellulose of ethyl acrylate and methyl methacrylate or multiplely all is fit to the present invention.Wherein, preferably EudragitNE30D of the copolymer of described ethyl acrylate and methyl methacrylate.Described polyvinyl acetate is Kollicoat SR30D preferably.The preferably full water ethylcellulose dispersion of described ethyl cellulose.Slow-release material is the main material that forms slow release layer, and its content then can not be controlled drug release rate and repeatability is poor very little, otherwise, then can not reach ideal release effect.The content of described slow-release material is 54～88% (wt), and that preferable is 62～80% (wt).
In the slow release layer of the present invention, the preferable enteric material that also further comprises, described enteric material is selected from the polymer of anionic polymer and methacrylic acid.The polymer of described anionic polymer and methacrylic acid is preferable is selected from Eudragit L30D-55 and Eudragit L100-55.The content of enteric material is 0～8% (wt), and that preferable is 1～8% (wt).Enteric material can quicken the dissolving of slow release layer, participates in the release of control medicine.
In the slow release layer of the present invention, described antiplastering aid can be this area antiplastering aid commonly used, preferably talc powder and/or glyceryl monostearate.The content of antiplastering aid is 2～30% (wt), and that preferable is 15～25% (wt).
In the slow release layer of the present invention; Described porogen can be this area porogen commonly used; Preferable be selected from any in lactose, polyvidone, Polyethylene Glycol, polyoxyethylene sorbitan monoleate and the hydroxypropyl emthylcellulose or multiplely all be fit to the present invention, better is to be selected from lactose, polyvidone and hydroxypropyl emthylcellulose.The content of described porogen is 1～30% (wt), and that preferable is 5～15% (wt).
Conventional like this area, can also add other in the slow release layer of the present invention, preferable like plasticizer.Described plasticizer can be this area common plasticizers; Preferably be selected from any in glycerol, dibutyl phthalate, diethyl phthalate, stearic acid, Polyethylene Glycol, propylene glycol, triethyl citrate and the triacetyl glycerine or multiplely all be fit to the present invention, preferably be selected from glycerol and triethyl citrate.The content of described plasticizer is 1～20% (wt), and that preferable is 2～8% (wt).
Conventional like this area, can also add pigment in the slow release layer of the present invention, color lake and flavoring agent etc.
In the slow-release micro-pill of water-insoluble medicine of the present invention, the content of described slow release layer accounts for 10～80% (wt) of slow-release micro-pill gross mass, preferably 20～50% (wt).
In the slow-release micro-pill of water-insoluble medicine of the present invention, described celphere can be the celphere of all routines in this area, preferable one or more of sucrose ball core, the starch ball heart and the microcrystalline Cellulose ball heart of being selected from.Celphere also can be selected its size according to the required particle diameter that reaches of final micropill as the nuclear core of slow-release micro-pill of the present invention, and all size celphere has commercially available, or makes by oneself according to prior art.The mean diameter of described celphere is preferable in 0.1～0.3 millimeter (mm) scope, and that better is 0.15～0.25mm.Having selected the reason of the little sucrose ball heart of particle diameter is the little crushing resistance that can improve micropill of particle diameter, and processes oral cavity disintegration tablet and reduce grittiness.The content of celphere accounts for 5～50% (wt) of slow-release micro-pill gross mass, preferably 20～40% (wt).
The slow-release micro-pill of water-insoluble medicine of the present invention, described water-insoluble medicine can be acetaminophen, diclofenac sodium, ibuprofen or hydrochlorothiazide.In the slow-release micro-pill of water-insoluble medicine of the present invention; Described medicine layer is made up of active constituents of medicine and auxiliary element, and described active constituents of medicine can be following water-insoluble medicine: acetaminophen, diclofenac sodium, ibuprofen or hydrochlorothiazide.Described auxiliary element comprises binding agent.Binding agent is meant and suitable active constituents of medicine is made into the medicine-feeding suspension, and helps active constituents of medicine to adhere to be coated on the material on the celphere, its content very little, particularly less than 1.5% of micropill weight, then medicine-feeding rate is low; Otherwise too high like content, the suspension viscosity of then adding medicine to is too high and medicine-feeding is uneven.Described binding agent can be the conventional binding agent in medicament field, and any in preferred hydroxypropyl methylcellulose and the polyvinylpyrrolidone or two kinds all are fit to the present invention.The mass ratio of active constituents of medicine and binding agent preferably 3: 1～14: 1.The content of described medicine layer accounts for 5～50% (wt) of slow-release micro-pill gross mass, and that preferable is 10～30% (wt).
In the slow-release micro-pill of water-insoluble medicine of the present invention; Said sealing coat is meant and between medicine layer and slow release layer, forms a kind of barrier; The material of isolating both is in order to avoid medicine layer and slow release layer react or medicine influences the stability of micropill to coatings infiltration; Its content is then isolated heterodyne very little, otherwise, then influence drug release rate.Described sealing coat can be all conventional sealing coats in this area.Preferable can be selected from hydroxypropyl methylcellulose and polyvinylpyrrolidone.The content of sealing coat accounts for 1～5% (wt) of slow-release micro-pill gross mass, preferably 1～3% (wt).
The slow-release micro-pill of water-insoluble medicine of the present invention can be used for tabletting and prepares the slow release oral cavity disintegration tablet, perhaps is used to prepare slow-release suspension.
Two of the technical scheme that solves the problems of the technologies described above provided by the invention is; A kind of method for preparing of slow-release micro-pill of described water-insoluble medicine; May further comprise the steps: adopt and cut the spray fluid bed; Celphere is used medicinal liquid, 2%～8% isolated material aqueous solution, sustained release coating liquid spray coated successively, process slow-release micro-pill of the present invention; The wherein said medicinal liquid of going up contains 10～35% water-insoluble medicine active component and 1.0～5.5% adhesive; Described sustained release coating liquid comprises 20～50% slow-release material, 2～15% antiplastering aid, 1～10% plasticizer, 1～15% porogen, and described percentage ratio is mass percent.
Three of the technical scheme that solves the problems of the technologies described above provided by the invention is; A kind of slow release oral cavity disintegration tablet of water-insoluble medicine; It comprises the described slow-release micro-pill of 20～50% claim 1,5～10% disintegrating agent, 36～70% filler, 0.2～5% lubricant and 0.1～0.5% correctives, and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
In the slow release oral cavity disintegration tablet of water-insoluble medicine of the present invention, described filler is to be selected from any in mannitol, lactose and the microcrystalline Cellulose or multiplely all to be fit to the present invention.Described mannitol is preferable is selected from mannitol 200SD and mannitol 100SD.Described microcrystalline Cellulose is preferable is selected from microcrystalline Cellulose PH102, KG-801 and KG-802 etc.The content of described filler is 36～70% (wt), and that preferable is 48～55% (wt), and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
In the slow release oral cavity disintegration tablet of water-insoluble medicine of the present invention; Described disintegrating agent is to be selected from any in crospolyvinylpyrrolidone, hyprolose, carboxymethyl starch sodium, sodium carboxymethyl cellulose and the alanine or multiplely all to be fit to the present invention; Preferable crospolyvinylpyrrolidone, hyprolose and the alanine of being selected from, best is 3: 1: 1 crospolyvinylpyrrolidone of mass ratio, hyprolose and alanine.The content of disintegrating agent is 5～10% (wt), and that preferable is 5～8% (wt), and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
In the slow release oral cavity disintegration tablet of water-insoluble medicine of the present invention, described lubricant is to be selected from any in differential silica gel, magnesium stearate and the Pulvis Talci or multiplely all to be fit to the present invention, preferable differential silica gel and the magnesium stearate of being selected from.The content of described lubricant is 0.2～5% (wt), and that preferable is 1～2% (wt), and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
In the slow release oral cavity disintegration tablet of water-insoluble medicine of the present invention; Described correctives can be the conventional correctives in this area; Preferable be selected from any in aspartame, Fructus Citri tangerinae essence, Herba Menthae essence and the apple essence or multiplely all be fit to the present invention, preferably be selected from aspartame and Herba Menthae essence.The content of described correctives is 0.1～0.5% (wt), and preferable is 0.1～0.3%, and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
In the slow release oral cavity disintegration tablet of water-insoluble medicine of the present invention, the preferable effervescent that also further comprises, described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.Described effervescent can be the conventional effervescent in this area, the sodium bicarbonate and the citric acid of preferable is mass ratio 1: 1～3: 1.The content of described effervescent is 0～3% (wt), and that preferable is 1～3% (wt), and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
Four of the technical scheme that solves the problems of the technologies described above provided by the invention is; A kind of method for preparing of slow release oral cavity disintegration tablet of described water-insoluble medicine; Comprise the steps: slow-release micro-pill and filler, disintegrating agent, effervescent, correctives and mix lubricant with described water-insoluble medicine; Use the tablet machine tabletting, promptly get.
Raw material that the present invention is used or reagent except that specifying, all commercially available getting.
Than prior art, beneficial effect of the present invention is following: the slow release oral cavity disintegration tablet that the invention provides a kind of water-insoluble medicine.The sucrose ball heart that particularly preferred particle diameter is little and suitable coating material Eudragit NE30D, ethyl cellulose, perhaps Kollicoat SR 30D combination; Realize following effect: the first, the oral cavity disintegration tablet that is pressed into through combination of adjustment coating and filling adjuvant can slowly discharge more than 8-13 hour, thus the blood drug level of held stationary; Reduce side effect, have excellent safety, reduce and take number of times; Taking convenience has improved the patient's compliance of taking medicine.Second: the slow release oral cavity disintegration tablet of water-insoluble medicine of the present invention shows that through external dissolution test more meeting zero level discharges, and finally the cumulative release amount also is higher than common slow-release orally disintegrating tablets, and it is big to have effect, the characteristics that selectivity is strong.The 3rd: because slow-release micro-pill particle diameter of the present invention is little, intensity is stronger, and preferred coating material has certain toughness, when adopting its preparation oral cavity disintegration tablet, can be in less pressure lower sheeting molding, and mouthfeel is good.The 4th: the present invention prepares the method for slow-release micro-pill, can spray at tangent line to realize medicine-feeding and art for coating in the fluid bed simultaneously, and production stage is simple, and efficient is higher, can be applicable to large-scale production.
Description of drawings
Below in conjunction with description of drawings characteristic of the present invention and beneficial effect.
Fig. 1 is the release profiles of acetaminophen slow-release micro-pill oral cavity disintegration tablet in water.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1 preparation acetaminophen slow-release micro-pill
1. ball medicine in the heart
Polyvinylpyrrolidone PVP S630 17g and acetaminophen 100g added among 75% (v/v) ethanol 560ml process medicinal liquid, acetaminophen concentration 15g/100ml wherein, binding agent PVPS630 concentration 2.5% (wt).With mean diameter is that the 0.15mm sucrose ball heart was put in the fluid bed fluidisation 10 minutes, will go up medicinal liquid and slowly be sprayed on ball heart surface.Medicine-feeding weightening finish: 45.0～50.0%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
15g is dissolved in the 300ml pure water with hydroxypropyl methylcellulose (HPMC), with cutting last pill that the spray fluid bed slowly is sprayed on gained in the step 1 in the heart.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
3. bag slow release layer
With You Teqi Eudragit E udragit NE30D 170g; Enteric solubility Eudragit E udragitL30D-5520g; Ethyl cellulose 20g; Pure water 200g crosses thousand order Pulvis Talci 50g and processes coating solution with lactose 4.5g with the high speed shear stirring and evenly mixing, and usefulness is cut and sprayed fluid bed this liquid slowly is sprayed on the micropill surface that step 2 obtains.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
2 preparations of embodiment acetaminophen slow-release micro-pill oral cavity disintegration tablet
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Acetaminophen slow-release micro-pill 225
Mannitol 178
Microcrystalline Cellulose 87
Crospolyvinylpyrrolidone 22
Hyprolose 11
Aspartame 2
Magnesium stearate 1
Differential silica gel 1
Pulvis Talci 15
Method for preparing is following:
The acetaminophen slow-release micro-pill of embodiment 1 gained is crossed 60 mesh sieves; Adjuvant with directly compressible: mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone, hyprolose, magnesium stearate, Pulvis Talci, differential silica gel and Aspartane are used tablet machine direct compression, tablet hardness 3kg.
Getting this slow-release micro-pill oral cavity disintegration tablet, according to the device of the Pharmacopoeia of the People's Republic of China (two appendix of version in 2005) dissolution method slurry method, is dissolution medium with pure water 900mL, and rotating speed is 100r/min; Regularly get dissolution fluid 5mL, filter, and in time add 5mL water; Dilution shakes up, according to ultraviolet spectrophotometry (Pharmacopoeia of the People's Republic of China appendix IV A); Measure absorbance at the 243nm place,, obtain the release degree and draw the release curve according to standard curve Equation for Calculating detected level.The stripping curve of acetaminophen slow-release micro-pill oral cavity disintegration tablet is seen Fig. 1, and vertical coordinate is represented drug release percentage rate (Q) among the figure, abscissa express time (t).It is thus clear that this acetaminophen slow-release micro-pill oral cavity disintegration tablet disintegrate is rapid, disintegrate in 50 seconds, slowly release can reach 13 hours in water.
Embodiment 3 preparation diclofenac sodium slow-release micro-pill
1. ball medicine in the heart
With polyvinylpyrrolidone PVP VA64 17g with diclofenac sodium 100g is added 75% (v/v) ethanol 560ml, diclofenac na concn: 15g/100ml wherein, binder concn: 2.5% (wt).With mean diameter is that 0.10mm sucrose ball core was put in the fluid bed fluidisation 10 minutes, and above-mentioned medicinal liquid slowly is sprayed on ball heart surface.Medicine-feeding weightening finish: 45.0～50.0%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
Hydroxypropyl methylcellulose 13g is dissolved in the 300ml pure water, slowly is sprayed on pill in the heart with cutting the spray fluid bed.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
3. bag slow release layer
With polyvinyl acetate (Kollicoat SR30D BASF) 100g; Ethyl cellulose 20g, pure water 150g, glyceryl monostearate 3g and hypromellose 1.5g use high-speed stirred; Mixing slowly is sprayed on this liquid on the micropill surface that step 2 obtains with cutting the spray fluid bed.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Diclofenac sodium slow-release micro-pill 225
Mannitol 178
Microcrystalline Cellulose 87
Crospolyvinylpyrrolidone 25
Magnesium stearate 1
Differential silica gel 1
Pulvis Talci 15
Method for preparing is following:
Embodiment 3 prepared diclofenac sodium slow-release micro-pill are crossed 60 mesh sieves; Adjuvant with directly compressible: mannitol; Microcrystalline Cellulose; Crospolyvinylpyrrolidone, hyprolose, alanine, differential silica gel, magnesium stearate, Pulvis Talci and Aspartane are used tablet machine direct compression, tablet hardness 3kg.Get this slow-release micro-pill oral cavity disintegration tablet, measure dissolution with the method for embodiment 2.This disintegration of tablet is rapid, and disintegrate in 50 seconds slowly discharges 8 hours in water.
Embodiment 5 preparation ibuprofen slow-release micropill oral cavity disintegration tablets
1. ball medicine in the heart
PVP S630 17g and ibuprofen 60g added among 75% (v/v) ethanol 560ml process medicinal liquid, ibuprofen concentration: 10g/100ml wherein, binding agent PVP S630 concentration: 2.5% (wt).With mean diameter is that the 0.20mm sucrose ball heart was put in the fluid bed fluidisation 10 minutes, will go up medicinal liquid and slowly be sprayed on ball heart surface.Medicine-feeding weightening finish: 45.0～50.0%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
Hydroxypropyl methylcellulose 15g is dissolved in the 300ml pure water, with cutting last pill that the spray fluid bed slowly is sprayed on gained in the step 1 in the heart.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
4. bag slow release layer
With You Teqi acrylic resin (Eudragit NE30D) 170g; Enteric solubility Eudragit E udragit L30D-55 20g; Ethyl cellulose 20g; Pure water 200g crosses thousand order Pulvis Talci 50g and processes coating solution with lactose 4.5g with the high speed shear stirring and evenly mixing, and usefulness is cut and sprayed fluid bed this liquid slowly is sprayed on the micropill surface that step 2 obtains.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Ibuprofen slow-release micropill 225
Mannitol 178
Microcrystalline Cellulose 87
Crospolyvinylpyrrolidone 25
Citric acid 3
Sodium bicarbonate 3
Magnesium stearate 1
Differential silica gel 1
Pulvis Talci 15
Method for preparing is following:
Embodiment 5 prepared ibuprofen slow-release micropills are crossed 60 mesh sieves; Adjuvant with directly compressible: mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone, hyprolose, alanine, differential silica gel, magnesium stearate, Pulvis Talci, sodium bicarbonate, citric acid and Aspartane are used tablet machine direct compression, tablet hardness 3kg.Get this slow-release micro-pill oral cavity disintegration tablet, measure dissolution with the method for embodiment 2.This disintegration of tablet is rapid, and disintegrate in 50 seconds slowly discharges 13 hours in water.
Embodiment 7 preparation hydrochlorothiazide slow-release micro-pill
1. ball medicine in the heart
PVP S630 10g and hydrochlorothiazide 50g added among 75% (v/v) ethanol 440ml process medicinal liquid, hydrochlorothiazide concentration 10g/100ml wherein, binding agent PVP S630 concentration 2% (wt).With mean diameter is that the 0.30mm sucrose ball heart was put in the fluid bed fluidisation 10 minutes, will go up medicinal liquid and slowly be sprayed on ball heart surface.Medicine-feeding weightening finish: 45.0～50.0%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
Hydroxypropyl methylcellulose 15g is dissolved in the 300ml pure water, with cutting last pill that the spray fluid bed slowly is sprayed on gained in the step 1 in the heart.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
3. bag slow release layer
With You Teqi acrylic resin (Eudragit NE30D) 170g; Enteric solubility Eudragit E udragit L30D-55 20g; Ethyl cellulose 20g; Pure water 200g crosses thousand order Pulvis Talci 50g and processes coating solution with lactose 4.5g with the high speed shear stirring and evenly mixing, and usefulness is cut and sprayed fluid bed this liquid slowly is sprayed on the micropill surface that step 2 obtains.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Hydrochlorothiazide slow-release micro-pill 150
Mannitol 178
Microcrystalline Cellulose 87
Crospolyvinylpyrrolidone 25
Citric acid 3
Sodium bicarbonate 3
Magnesium stearate 1
Differential silica gel 1
Pulvis Talci 15
Method for preparing is following:
Embodiment 7 prepared hydrochlorothiazide slow-release micro-pill are crossed 60 mesh sieves; Adjuvant with directly compressible: mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone, hyprolose, alanine, differential silica gel, magnesium stearate, Pulvis Talci, sodium bicarbonate, citric acid and Aspartane are used tablet machine direct compression, tablet hardness 3kg.Get this slow-release micro-pill oral cavity disintegration tablet, measure dissolution with the method for embodiment 2.This disintegration of tablet is rapid, and disintegrate in 50 seconds slowly discharges 13 hours in water.
Embodiment 9 preparation acetaminophen slow-release micro-pill
1. ball medicine in the heart
With processing medicinal liquid among hydroxypropyl methylcellulose 92g and the pure 1700ml of acetaminophen 278g adding 75% (v/v).With mean diameter is that the 0.15mm sucrose ball heart was put in the fluid bed fluidisation 10 minutes, will go up medicinal liquid and slowly be sprayed on ball heart surface.Medicine-feeding weightening finish: 43%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
Polyvinylpyrrolidone 30g is dissolved in the 380ml pure water, with cutting last pill that the spray fluid bed slowly is sprayed on gained in the step 1 in the heart.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
3. bag slow release layer
With full water ethylcellulose dispersion 54g; Eudragit L100-55 10g, pure water 220g, glycerol 1g; Glyceryl monostearate 20g; Pulvis Talci 10g, polyvidone 3g and Polyethylene Glycol 2g process coating solution with the high speed shear stirring and evenly mixing, with cutting the spray fluid bed this liquid slowly are sprayed on the micropill surface that step 2 obtains.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Slow-release micro-pill acetaminophen slow-release micro-pill 250
Filler mannitol 126
Filler microcrystalline Cellulose 54
Disintegrating agent carboxymethyl base Starch Sodium 50
Correctives Herba Menthae essence 0.2
Correctives aspartame 0.3
Magnesium stearate lubricant 15
Lubricant Pulvis Talci 4.5
Method for preparing is following:
The acetaminophen slow-release micro-pill of embodiment 9 gained is crossed 60 mesh sieves; Adjuvant with directly compressible: mannitol, microcrystalline Cellulose, carboxymethyl starch sodium, Herba Menthae essence, Aspartane, magnesium stearate and Pulvis Talci are used tablet machine direct compression, tablet hardness 3kg.Get this slow-release micro-pill oral cavity disintegration tablet, measure dissolution with the method for embodiment 2.This disintegration of tablet is rapid, and disintegrate in 50 seconds slowly discharges 11 hours in water.
Embodiment 11 preparation acetaminophen slow-release micro-pill
1. ball medicine in the heart
With processing medicinal liquid among hydroxypropyl methylcellulose 2.6g and acetaminophen 18.4g adding 75% (v/v) ethanol 53ml.With mean diameter is that the 0.15mm sucrose ball heart was put in the fluid bed fluidisation 10 minutes, will go up medicinal liquid and slowly be sprayed on ball heart surface.Medicine-feeding weightening finish: 20%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
Polyvinylpyrrolidone 4g is dissolved in the 70ml pure water, with cutting last pill that the spray fluid bed slowly is sprayed on gained in the step 1 in the heart.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
3. bag slow release layer
With full water ethylcellulose dispersion 88g, pure water 180g, glyceryl monostearate 5g, polyoxyethylene sorbitan monoleate 2g and glycerol 5g process coating solution with the high speed shear stirring and evenly mixing, with cutting the spray fluid bed this liquid slowly are sprayed on the micropill surface that step 2 obtains.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Slow-release micro-pill acetaminophen slow-release micro-pill 150
Filler mannitol 147
Filler microcrystalline Cellulose 147
Disintegrating agent carboxymethyl base sodium cellulosate 25
Correctives aspartame 1
Correctives Herba Menthae essence 0.5
Magnesium stearate lubricant 15
Lubricant differential silica gel 10
Effervescent sodium bicarbonate 3.8
Effervescent citric acid 1.3
Method for preparing is following:
The acetaminophen slow-release micro-pill of embodiment 11 gained is crossed 60 mesh sieves; Adjuvant with directly compressible: mannitol, microcrystalline Cellulose, sodium carboxymethyl cellulose, Aspartane, Herba Menthae essence, magnesium stearate, differential silica gel, sodium bicarbonate and citric acid are used tablet machine direct compression, tablet hardness 3kg.Get this slow-release micro-pill oral cavity disintegration tablet, measure dissolution with the method for embodiment 2.This disintegration of tablet is rapid, and disintegrate in 50 seconds slowly discharges 9 hours in water.
Embodiment 13 preparation acetaminophen slow-release micro-pill
1. ball medicine in the heart
With processing medicinal liquid among hydroxypropyl methylcellulose 9g and acetaminophen 117g adding 75% (v/v) ethanol 550ml.With mean diameter is that the 0.15mm sucrose ball heart was put in the fluid bed fluidisation 10 minutes, will go up medicinal liquid and slowly be sprayed on ball heart surface.Medicine-feeding weightening finish: 99%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
Polyvinylpyrrolidone 0.8g is dissolved in the 40ml pure water, with cutting last pill that the spray fluid bed slowly is sprayed on gained in the step 1 in the heart.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
3. bag slow release layer
With full water ethylcellulose dispersion 60g; Eudragit L30D 1g, pure water 200g, glyceryl monostearate 4g; Hypromellose 15g and triethyl citrate 20g process coating solution with the high speed shear stirring and evenly mixing, with cutting the spray fluid bed this liquid slowly are sprayed on the micropill surface that step 2 obtains.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Slow-release micro-pill acetaminophen slow-release micro-pill 200
Filler mannitol 128
Disintegrating agent crospolyvinylpyrrolidone 30
Disintegrating agent hyprolose 10
Disintegrating agent alanine 10
Correctives aspartame 2.5
Method for preparing is following:
The acetaminophen slow-release micro-pill of embodiment 13 gained is crossed 60 mesh sieves; Adjuvant with directly compressible: mannitol, crospolyvinylpyrrolidone, hyprolose, alanine, magnesium stearate and Aspartane are used tablet machine direct compression, tablet hardness 3kg.Get this slow-release micro-pill oral cavity disintegration tablet, measure dissolution with the method for embodiment 2.This disintegration of tablet is rapid, and disintegrate in 50 seconds slowly discharges 12 hours in water.
Embodiment 15 preparation acetaminophen slow-release micro-pill
1. ball medicine in the heart
With processing medicinal liquid among hydroxypropyl methylcellulose 0.6g and acetaminophen 5.7g adding 75% (v/v) ethanol 57ml.With mean diameter is that the 0.15mm sucrose ball heart was put in the fluid bed fluidisation 10 minutes, will go up medicinal liquid and slowly be sprayed on ball heart surface.Medicine-feeding weightening finish: 26%.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
2. bag sealing coat
Polyvinylpyrrolidone 1.3g is dissolved in the 30ml pure water, with cutting last pill that the spray fluid bed slowly is sprayed on gained in the step 1 in the heart.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 33～35 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 12～15g/min.
3. bag slow release layer
With full water ethylcellulose dispersion 60g; Eudragit L30D 4g, pure water 200g, glyceryl monostearate 4g; Lactose 30g and triethyl citrate 2g process coating solution with the high speed shear stirring and evenly mixing, with cutting the spray fluid bed this liquid slowly are sprayed on the micropill surface that step 2 obtains.The operating condition of tangent line spray fluid bed is: the blower fan frequency is 20～23Hz; Temperature of charge is 23～25 ℃; The rotational frequency of rotating disk is 100～150rpm; The atomizing pressure of atomizing lance is 0.10～0.15MPa; The hydrojet speed of coating solution is 6～10g/min.The gained slow-release micro-pill is crossed 60 mesh sieves.
Embodiment 16 tablettings prepare acetaminophen slow-release micro-pill oral cavity disintegration tablet
Tabletting prepares oral cavity disintegration tablet, a slice amount (mg)
Slow-release micro-pill acetaminophen slow-release micro-pill 100
Filler microcrystalline Cellulose 50
Disintegrating agent carboxymethyl base Starch Sodium 40
Correctives aspartame 1
Magnesium stearate lubricant 1
Effervescent sodium bicarbonate 5.33
Effervescent citric acid 2.67
Method for preparing is following:
The acetaminophen slow-release micro-pill of embodiment 15 gained is crossed 60 mesh sieves, and with the adjuvant of directly compressible: microcrystalline Cellulose, carboxymethyl starch sodium, Aspartane, magnesium stearate, sodium bicarbonate and citric acid are used tablet machine direct compression, tablet hardness 3kg.Get this slow-release micro-pill oral cavity disintegration tablet, measure dissolution with the method for embodiment 2.This disintegration of tablet is rapid, and disintegrate in 50 seconds slowly discharges 12 hours in water.
Further specify beneficial effect of the present invention through Test Example below.
The experiment of effect embodiment 1 medicine accelerated stability
Embodiment 1 prepared acetaminophen oral cavity disintegration tablet is packaged in the double-deck aluminium plastic bag of sealing; Under 40 ℃ ± 2 ℃, the condition of RH 75% ± 5%; Placed 3 months; Took a sample respectively in 0,1,2,3 month, carry out the mensuration of tablet character, disintegration time, hardness, content, release degree, the result sees table 1.
Table 1. acetaminophen oral cavity disintegration tablet accelerated stability experiment (n=3)
Can be found out that by the accelerated stability experimental result 3 months character of the sample of in double-deck aluminium plastic bag, preserving, content are compared basic no change during with 0 day, disintegration time slightly prolongs, and hardness slightly descends.These article should seal and be kept in the shady and cool exsiccant environment.
Claims (14)
1. the slow-release micro-pill of a water-insoluble medicine; Form by celphere, medicine layer, sealing coat and slow release layer; It is characterized in that the mass percent that they account for the slow-release micro-pill gross mass is respectively 5～50% celphere, 5～50% medicine layers, 1～5% sealing coat and 10～80% slow release layers; The mean diameter of celphere is 0.1～0.3 millimeter; Described slow release layer comprises following component: 54～88% slow-release material, 2～30% antiplastering aid and 1～30% porogen, and described percentage ratio is the mass percent that accounts for slow release layer; Wherein, described slow-release material is selected from any or multiple in Eudragit NE30D, Kollicoat SR30D and the ethyl cellulose.
2. slow-release micro-pill as claimed in claim 1 is characterized in that, described ethyl cellulose is full water ethylcellulose dispersion.
3. slow-release micro-pill as claimed in claim 1; It is characterized in that; Described slow release layer also further comprises 1～8% enteric material, and described enteric material is selected from the polymer of anionic polymer and methacrylic acid, and described percentage ratio is the mass percent that accounts for slow release layer.
4. slow-release micro-pill as claimed in claim 3 is characterized in that, the polymer of described anionic polymer and methacrylic acid is selected from Eudragit L30D-55 and Eudragit L100-55.
5. slow-release micro-pill as claimed in claim 1 is characterized in that, described antiplastering aid is Pulvis Talci and/or glyceryl monostearate; Described porogen is selected from any or multiple in lactose, polyvidone, Polyethylene Glycol, polyoxyethylene sorbitan monoleate and the hydroxypropyl emthylcellulose.
6. slow-release micro-pill as claimed in claim 1 is characterized in that, described slow release layer also further comprises 1～20% plasticizer, and described plasticizer is selected from glycerol and triethyl citrate, and described percentage ratio is the mass percent that accounts for slow release layer.
7. slow-release micro-pill as claimed in claim 1 is characterized in that the content of described slow release layer accounts for 10～80% of slow-release micro-pill gross mass; The mean diameter of described celphere is 0.1～0.3 millimeter, and the content of celphere accounts for 5～50% of slow-release micro-pill gross mass; Described medicine layer is made up of active constituents of medicine and auxiliary element; Described active constituents of medicine is acetaminophen, diclofenac sodium, ibuprofen or hydrochlorothiazide; Described auxiliary element comprises adhesive; Described adhesive is selected from any in hydroxypropyl methylcellulose and the polyvinylpyrrolidone or two kinds, and the mass ratio of active constituents of medicine and binding agent is 3: 1～14: 1, and the content of medicine layer accounts for 5～50% of slow-release micro-pill gross mass; Described sealing coat is selected from hydroxypropyl methylcellulose and polyvinylpyrrolidone, and the content of described sealing coat accounts for 1～5% of slow-release micro-pill gross mass.
8. method for preparing like the slow-release micro-pill of each described water-insoluble medicine of claim 1～7; May further comprise the steps: adopt and cut the spray fluid bed; Celphere is used medicinal liquid, 2%～8% isolated material aqueous solution, sustained release coating liquid spray coated successively, process slow-release micro-pill; The mean diameter of wherein said celphere is 0.1～0.3 millimeter; The described medicinal liquid of going up contains 10～35% water-insoluble medicine active component and 1.0～5.5% adhesive; Described sustained release coating liquid comprises 20～50% slow-release material, 2～15% antiplastering aid, 1～10% plasticizer, 1～15% porogen; Described percentage ratio is mass percent; Wherein, described slow-release material is selected from any or multiple in Eudragit NE30D, Kollicoat SR30D and the ethyl cellulose.
9. the slow release oral cavity disintegration tablet of a water-insoluble medicine; It is characterized in that; It comprises each described slow-release micro-pill of 20～50% claim 1～7,5～10% disintegrating agent, 36～70% filler, 0.2～5% lubricant and 0.1～0.5% correctives, and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
10. slow release oral cavity disintegration tablet as claimed in claim 9 is characterized in that, described filler is selected from any or multiple in mannitol, lactose and the microcrystalline Cellulose; Described disintegrating agent is selected from any or multiple in crospolyvinylpyrrolidone, hyprolose, carboxymethyl starch sodium, sodium carboxymethyl cellulose and the alanine; Described lubricant is selected from any or multiple in micropowder silica gel, magnesium stearate and the Pulvis Talci; Described correctives is selected from any or multiple in aspartame, Fructus Citri tangerinae essence, Herba Menthae essence and the apple essence.
11. slow release oral cavity disintegration tablet as claimed in claim 10 is characterized in that, described mannitol is selected from mannitol 200SD and mannitol 100SD; Described microcrystalline Cellulose is selected from microcrystalline Cellulose PH102, KG-801 and KG-802; Described disintegrating agent is 3: 1: 1 crospolyvinylpyrrolidone of mass ratio, hyprolose and alanine.
12. slow release oral cavity disintegration tablet as claimed in claim 9 is characterized in that, it also further comprises effervescent, and the content of described effervescent is 1～3%, and described percentage ratio is the mass percent that accounts for the slow release oral cavity disintegration tablet.
13. slow release oral cavity disintegration tablet as claimed in claim 12 is characterized in that, described effervescent is the sodium bicarbonate and the citric acid of mass ratio 1: 1～3: 1.
14. the method for preparing of the slow release oral cavity disintegration tablet of a water-insoluble medicine as claimed in claim 12; May further comprise the steps: with the slow-release micro-pill of each described water-insoluble medicine of claim 1～7; With filler, disintegrating agent, effervescent, correctives and mix lubricant; Use the tablet machine tabletting, promptly get.
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| CN102228441B (en) * | 2011-06-23 | 2013-01-30 | 湖北舒邦药业有限公司 | Dexibuprofen sustained-release pellet and preparation method thereof |
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