CN1839846A - Levofloxacin slow release micropill, its preparation method and uses - Google Patents
Levofloxacin slow release micropill, its preparation method and uses Download PDFInfo
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- CN1839846A CN1839846A CN 200610037700 CN200610037700A CN1839846A CN 1839846 A CN1839846 A CN 1839846A CN 200610037700 CN200610037700 CN 200610037700 CN 200610037700 A CN200610037700 A CN 200610037700A CN 1839846 A CN1839846 A CN 1839846A
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Abstract
The invention relates to a slow release micro-pellet preparation containing Levofloxacin, its preparation process and therapeutic use, wherein the micro-pellet preparation contains 0-40% of conventional medicinal particles and 60-100% of slow release medicinal micro-pellet, the micro-pellet contains medicinal core including Levofloxacin, and slow release coating layer whose content being 4-100% of the pellet core.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to contain sustained-release pellet preparation, its preparation method and the therapeutic use thereof of levofloxacin.
Background technology
Levofloxacin (levofloxacin) is the L type optical activity isomer of ofloxacin, is third generation fluoroquinolones broad spectrum antibiotic, and its antibacterial activity is the twice of ofloxacin, and adverse reaction rate is lower.Be widely used at present clinical, clinical commonly used be levofloxacin lactate and levofloxacin hydrochloride, its drug effect of different salt is suitable.Because the levofloxacin biological half-life is less than 6h, the ordinary preparation clinical treatment of levofloxacin needs every day to be taken 2～3 times.For reducing medicining times, keep the concentration of blood medicine treatment stably, the controlled release agent type of existing report has: the dry powder pulmonary that CN03111151.9 discloses levofloxacin sucks microball preparation; CN03137240.6 discloses oral levofloxacin controlled release pharmaceutical compositions, mainly adopts cellulose esters or esters etc. to make matrix tablet; CN200410020412.5 discloses the levofloxacin lactate sustain-released ophthalmic gels has report that it is prepared into the levofloxacin slow release preparation.Traditional slow releasing preparation exists medicine to dash forward to release, cause patient's blood medicine too high, increases the hidden danger of side effect.
Summary of the invention
The invention discloses the sustained-release pellet preparation of levofloxacin.Slow-release micro-pill is a kind of divided dose decentralized dosage form, a dosage often is made up of dispersive a plurality of unit, a common dosage by tens so that more than 100 slow-release micro-pill form, compare with dosage form such as common slow releasing preparation that single dose is made up of a unit, has following advantage: can be extensively after 1, micropill is taken, be evenly distributed in the intestinal, since dosage incline decentralized, medicine increases at the gastrointestinal tract distribution area, bioavailability is improved and reduces or eliminates medicine to the gastrointestinal zest; 2, the influence of the transhipment unable to take food thing conveying rhythm and pace of moving things of micropill in gastrointestinal tract; 3, the drug release behavior of slow release or controlled release micro pill is a summation of forming each micropill drug release behavior of a dosage, error or the defective unlikely drug release behavior generation to whole preparation of indivedual pillers in preparation has a strong impact on, therefore, levofloxacin is prepared into behind the sustained-release pellet preparation and is better than existing levofloxacin slow release preparation aspect repeatability in the release rule, the concordance, and by determining that dosage is designed to be administered once in one day.
The present invention is achieved through the following technical solutions:
The slow-release micro-pill that contains levofloxacin of the present invention; it is characterized in that forming by 0%～40% common (rapid release) medicine-containing particle or the slow release pastille micropill of rapid release pastille micropill and 60%～100%; wherein slow release pastille micropill is to contain pill core (the ball core that promptly contains levofloxacin) and membrane layers also is the sustained release coating layer from inside to outside successively, and wherein the weight of sustained release coating layer is to contain 4～100% of pill core.Weightening finish 4～100% during the coating that also promptly is commonly called as.Coating increases weight preferred 5～40%.The key of controlling slow release micropill release profiles is the weightening finish that parcel contains the sustained release coating layer of pill core among the present invention, i.e. the weightening finish of extended release coatings film.When the coating weightening finish was lower than 4%, 2 hours cumulative release percentage rate did not reach the effect of slow release greater than 90%.And too many when coating weightening finish, surpass at 100% o'clock, discharge too slowly, 12 hours cumulative release percentage rate are less than 30%, and are as seen too slow owing to drug release, are not suitable for clinical practice.
Containing pill core can directly spray the levofloxacin layer on celphere, spray again on celphere after also can mixing by levofloxacin and pharmaceutic adjuvant, can also be round as a ball by levofloxacin and pharmaceutic adjuvant mixing, wherein ball core or pharmaceutic adjuvant can be selected from starch, lactose, dextrin, sucrose, microcrystalline Cellulose, pregelatinized Starch, inorganic salts, mannitol, sorbitol, cellulose derivative, hydroxypropyl emthylcellulose, Polyethylene Glycol, polyvidone, acrylic resin, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, magnesium stearate, micropowder silica gel, Pulvis Talci, in the sodium lauryl sulphate one or more.
If by spraying on celphere after levofloxacin and the pharmaceutic adjuvant mixing, then the weight of levofloxacin and pharmaceutic adjuvant mixture is preferably 20～500% of celphere weight again.More preferably 50～200%.
Levofloxacin micropill of the present invention can also have a sealing coat containing between pill core and the coatings, and insolated layer materials is selected from one or more in hydroxypropyl emthylcellulose, acrylic resin (You Teqi), Opadry, the low-substituted hydroxypropyl cellulose.Sealing coat can prevent the migration of medicine, improves the stability of slow-release micro-pill.
The preferred weight of sealing coat is to contain pill core 1～50%.Preferred weight is 2～20%.
Above-mentioned slow-release micro-pill, coatings are preferably from cellulose esters or acrylic resin (Youteqi, Eudragit), ethyl cellulose, Opadry, Aquacoat
RIn ECD-30, Su Lisi (Surelease), hydroxypropyl emthylcellulose, polyvinyl alcohol, polyolefin, polyester, cellulose acetate, polrvinyl chloride, Merlon, vinyl alcohol, vinylacetate, ethylene-propylene polymer, ethylene-vinyl acetate copolymer, hyprolose phthalate ester, the Hydroxypropyl Methyl Cellulose Phthalate one or more.Preferred acrylic resins (Youteqi, Eudragit), Opadry, Aquacoat
RIn ECD-30, Su Lisi (Surelease), ethyl cellulose, the hydroxypropyl emthylcellulose one or more.
Coatings is except containing above-mentioned membrane material, also contain in plasticizer, antiplastering aid, porogen, the opacifier one or more, described plasticizer is selected from one or more in dibutyl sebacate, citrate, acetoglyceride, citron acid esters, glyceride, phthalic acid ester, polyethylene glycols, cochin oil, Oleum Ricini, Polysorbate, glyceride, succinate, benzoate, phosphate ester, adipate ester, the tartrate; Described antiplastering aid is selected from one or more in Pulvis Talci, magnesium stearate, glyceryl monostearate, the micropowder silica gel; Described porogen is selected from one or more among Polyethylene Glycol, polyvidone, sucrose, lactose, salt, HPMC, the HPC; Described opacifier is a titanium dioxide.The amount of plasticizer is with respect to 0～200% of coating material weight, and more preferably 20～100%.The amount of antiplastering aid is preferred 0～200%, and more preferably 20～100%.In addition, issuable bubble in the time of in membrane material, can also adding defoamer with the removal preparation, the preferred simethicone of defoamer, methyl-silicone oil.The methyl-silicone oil addition is 0.1～0.5% of a polymer volume.Can also be in the membrane material according to being routinely added to color lake, ferrum oxide, titanium dioxide.Because levofloxacin is a photosensitizer, meets light and degrades easily, therefore, adds the stability that an amount of opacifier can improve levofloxacin.Color lake and titanium dioxide consumption are 5～100% of polymer.
Plasticizer can improve the pliability of thin film, helps spray droplet and sprawls and mutually combine at micropill, helps the formation of complete thin film.Plasticizer is indispensable especially to aqueous dispersion, and it can reduce the film-forming temperature of polymer, makes the polyalcohol emulsion particle in the aqueous dispersion be fused into fine and close thin film under the coating operative temperature or in coating after-baking process.
The coating solution that is sprayed at the micropill surface in the coating process becomes sticky with solvent evaporates, adds an amount of antiplastering aid in the coating solution and can reduce viscosity, avoids inter-adhesive between the micropill.Amount of talc is 25～200% of a polymer, and preferable amount is 25～50%.The consumption of glyceryl monostearate is 2～10% of an amount of polymers.
Levofloxacin slow release micropill of the present invention more preferably consists of and contains: contain one or more in medicinal adjuvant preferred starch, lactose, dextrin, sucrose, microcrystalline Cellulose, pregelatinized Starch, inorganic salts, mannitol, sorbitol, cellulose derivative, Polyethylene Glycol, polyvidone, acrylic resin, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, magnesium stearate, micropowder silica gel, Pulvis Talci, the sodium lauryl sulphate in the pill core; In the preferred hydroxypropyl emthylcellulose of sealing coat, Opadry, acrylic resin, the low-substituted hydroxypropyl cellulose one or more preferably contain 2～20% of pill core weight; Coatings preferred acrylic resins, Opadry, Aquacoat
RIn ECD-30, Su Lisi, ethyl cellulose, the hydroxypropyl emthylcellulose one or more, preferred weight are to contain 4～100% of pill core.Preferred weight is 5～50%.
The preparation method of levofloxacin slow release micropill of the present invention, comprise: celphere is placed fluid bed, the aqueous solution of preparation levofloxacin, the words that need adjuvant are added medicine to after with levofloxacin and auxiliary materials and mixing, micropill is increased weight to desired value, promptly get and contain pill core, bag extended release coatings film must contain the slow-release micro-pill of levofloxacin.Wrap contagion gown if desired, then behind last intact levofloxacin layer with quadrat method bag contagion gown, and then bag extended release coatings film.In order to improve the stability of micropill surface extended release coatings film, can the slow-release micro-pill of gained is aging, place 40～80 ℃ to wear out 1～48 hour.
Another kind of preparation method comprises: preparation levofloxacin granule, place spheronizator round as a ball,, must contain the slow-release micro-pill of levofloxacin with quadrat method bag extended release coatings film, micropill directly is filled in the capsulae vacuus, or micropill is added other pharmaceutic adjuvant repress makes slow releasing tablet.Wrap contagion gown if desired, then behind last intact levofloxacin layer with quadrat method bag contagion gown, and then bag extended release coatings film.If micropill need wear out, the slow-release micro-pill for preparing places 40～80 ℃ to wear out 1～48 hour.
The present invention's common (rapid release) medicine-containing particle can be with conventional method with levofloxacin and pharmaceutic adjuvant mixing granulation, also the levofloxacin layer can be sprayed on celphere, or contain pill core by spraying again on celphere, to make after levofloxacin and the pharmaceutic adjuvant mixing.For consistent with slow-release micro-pill, preferred for preparation becomes to contain pill core in preparation, standby (for the common pill core that contains).Part contains pill core and wraps the extended release coatings film again, makes slow-release micro-pill.
Further above-mentioned micropill directly is filled in the capsulae vacuus, or micropill is added other pharmaceutic adjuvant repress makes slow releasing tablet.Common if desired medicine-containing particle, then can be in proportion with common medicine-containing particle or pastille micropill with directly be filled in the capsulae vacuus after slow-release micro-pill mixes, or blended micropill added the pharmaceutic adjuvant repress make slow releasing tablet.Can also be prepared into other dosage forms as required.
Can control the release of medicine by sustained release coating; in addition; in slow-release micro-pill, add common (rapid release) granule of part or micropill again; medicine discharges rapidly after can making medicine arrive human body; reach required blood drug level; slow-released part slowly discharges again then, makes blood drug level keep a steady state value substantially, brings into play best curative effect.
Simultaneously, the present invention also can not add common (rapid release) medicine-containing particle or micropill, can wrap different thickness during extended release coatings at bag, and the micropill with different extended release coatings thickness has different release curves, reasonably combinedly reaches required preferably release profiles.
Levofloxacin described in the present invention can be its episome, also can be the acid-addition salts of levofloxacin, and preferred acid-addition salts is levofloxacin hydrochloride or levofloxacin lactate, and the levofloxacin of different salt all is fit to technical scheme of the present invention.
The present invention preferably adopts rapid release and slow-release micro-pill combined effect, medicine absorbed rapidly after immediate release section was taken the patient, reach certain blood drug level, slow-release micro-pill slow release medicine more then, utilize the levofloxacin pellet preparations of technology preparation of the present invention, its release in vitro curve display, 0.5～2 hour release be 20～50%, 2～12 hours be 40～70%, 6～24 hours greater than 70%.Drug release rate is mild, has reached 24 hours slow release effects substantially.
In vivo test proves that also levofloxacin slow release micropill preparation of the present invention can discharge gently in 24 hours.
Be the test data of the pharmacokinetics of part preparation of the present invention below:
Method in the body
Chromatographic condition:
Chromatographic column: Diamonsil C18 post 5 μ m-150mm * 4.6mm;
Detect wavelength: 290nm;
Flow velocity: 1.0ml/min;
Sensitivity: 0.01AUFs
Column temperature: 30 ℃
Get blank plasma 0.5ml, totally 7 parts, the pharmaceutical standards solution 50 μ l that add variable concentrations respectively, make plasma concentration be respectively 0.20,0.50,2.0,5.0,10.0,20.00,30.00 μ g/ml, in each pipe, add inner mark solution 50 μ l, by the operation of plasma treatment method, obtain analysis result.With the concentration C is abscissa, and medicine and interior target peak area ratio (mark in A principal agent/A) are vertical coordinate, carry out linear regression.
Article six, beagle dog, ♂ ♀ half and half is as animal subject.3 of the levofloxacin tablets (100mg/ sheet, reference preparation) of 1 of the oral levofloxacin slow release micropill capsule of the present invention of dual crossing (the 300mg/ grain is subjected to test preparation, the preparation of embodiment 11 methods) and commercially available Yangzijiang Pharmaceutical Group Co., Ltd's production at random.Fasting 12h before taking medicine.In 8 administrations on an empty stomach in morning, extract blank blood before the administration.The ordinary tablet group is in back 0.5,1,1.5,2,3,4,6,8,10,24,36, the 48h of taking medicine; The sustained-release micro-pill capsules group in 1,2,3,4,6,8,12,16,20,24,36,48h gets veins of upper extremity blood 3ml and puts in the anticoagulant heparin pipe, the centrifugal 10min of 3000rpm gets upper plasma, it is standby to put-20 ℃ of freezing preservations.
Plasma treatment method: get pastille blood plasma 0.5ml, add inner mark solution (200 μ g/ml) 50 μ l, vortex 30s, the perchloric acid 0.5ml of adding 5% behind the mixing, vortex 1min is transferred in the 1.5ml centrifuge tube, the centrifugal 10min of 10000rpm, get supernatant, the centrifugal 10min of the same 10000rpm gets supernatant 20 μ l sample introductions.
Data result is seen Fig. 1.
Levofloxacin slow release micropill of the present invention can be used for antibacterial action.
Description of drawings
Fig. 1 is a release profiles in the levofloxacin slow release micropill body of the present invention
Fig. 2 is embodiment 1 a levofloxacin slow release micropill release in vitro curve
Fig. 3 is embodiment 2 levofloxacin slow release micropill release profiles
Fig. 4 is embodiment 3 levofloxacin slow release micropill release profiles
Fig. 5 is embodiment 4 levofloxacin slow release micropill release profiles
Fig. 6 is embodiment 5 levofloxacin slow release micropill release profiles
Fig. 7 is embodiment 6 levofloxacin slow release micropill release profiles
Fig. 8 is embodiment 7 levofloxacin slow release micropill release profiles
Fig. 9 is embodiment 8 levofloxacin slow release micropill release profiles
Figure 10 is embodiment 9 levofloxacin slow release micropill release profiles
Figure 11 is embodiment 10 levofloxacin slow release micropill release profiles
Figure 12 is embodiment 11 levofloxacin slow release micropill release profiles
Figure 13 is embodiment 12 levofloxacin slow release micropill release profiles
Figure 14 is embodiment 13 levofloxacin slow release micropill release profiles
Figure 15 is embodiment 14 levofloxacin slow release micropill release profiles
Figure 16 is embodiment 15 levofloxacin slow release micropill release profiles
The specific embodiment
The drug release determination method:
By " 2000 editions two appendix XD first methods of Chinese pharmacopoeia adopt the device of dissolution method (appendix XC first method), get levofloxacin slow release micropill, with the 1000ml distilled water is solvent, rotating speed is that per minute 100 changes, get solution 5ml respectively at certain hour, add the distilled water of uniform temp, equal volume simultaneously, institute's sample thief filters immediately, gets subsequent filtrate and measures.
Embodiment 1
The preparation of levofloxacin slow release micropill
The prescription of celphere is formed:
Starch: dextrin 4: 1 (weight ratio)
The sealing coat coating material: 2% hydroxypropyl emthylcellulose (HPMCE5) aqueous solution wherein also contains 5% Polyethylene Glycol, 2% polyoxyethylene sorbitan monoleate
The slow release layer coating material: 20% Aquacoat, also contain 10% polyvidone, 5% diethyl phthalate, 10% titanium dioxide
Preparation technology:
Starch, dextrin are pressed 4: 1 weight ratio mixing, are binding agent system soft material with an amount of 30% ethanol, the round as a ball celphere of making of coated pot, and the celphere of getting between the 20-40 order is standby.
Celphere is placed fluid bed, the aqueous solution of preparation levofloxacin, medicine-feeding, it is about 100% that micropill is increased weight, and adopts the aqueous solution bag contagion gown of HPMC, makes to contain pill and increase weight about 2%, adopt the aqueous dispersion bag extended release coatings film of ethyl cellulose again, make it to increase weight 6%.With slow-release micro-pill fill capsule, promptly get the levofloxacin slow release micropill capsule.The release curve is seen Fig. 2.
Embodiment 2
Sealing coat coating material: 5% Opadry aqueous solution (Shanghai Colorcon company)
Slow release layer coating material: 10% Su Lisi aqueous dispersion (Shanghai Colorcon company)
Preparation technology:
Microcrystalline Cellulose, levofloxacin are mixed by 3: 7 weight ratios, make wet feed with 40% alcoholic solution, wet feed is extruded the preparation granule through the extruder sieve plate, place spheronizator round as a ball, adopt Opadry aqueous solution bag contagion gown, make to contain pill and increase weight approximately 6%, adopt Su Lisi aqueous dispersion bag extended release coatings film again, make it to increase weight 5%, get slow-release micro-pill.The slow-release micro-pill for preparing places 80 ℃ to wear out 1 hour.The release curve is seen Fig. 3.
Embodiment 3
Starch
Dextrin
Levofloxacin
Sealing coat coating material: 10% Opadry, 50% ethanol water
Slow release layer coating material: 15% Su Lisi aqueous dispersion
Preparation technology:
With starch, dextrin, levofloxacin is mixing in 3: 3: 4 by weight, make wet feed with the 3%HPMC50% alcoholic solution, wet feed is extruded the preparation granule through the extruder sieve plate, place spheronizator round as a ball, adopt Opadry ethanol water bag contagion gown, make to contain pill and increase weight approximately 8%, adopt Su Lisi aqueous dispersion bag extended release coatings film again, make it to increase weight 7%, get slow-release micro-pill.The release curve is seen Fig. 4.
Slow release layer coating material: 10% Aquacoat (containing 5% polyvidone, 100% dibutyl phthalate, 50% lemon yellow color lake)
Preparation technology:
Starch, dextrin were put in the coating pan by 1: 1, made wetting agent, the general ball of molding with Diluted Alcohol.When ball core circle arrives to a certain degree, in 55 ℃ of oven dry, the ball core of dry back screening 24～30 order sizes is standby.Get an amount of ball core, put in the coating pan, squirt the ball wicking surface with the Diluted Alcohol liquid of PVP, it is an amount of to be spilled into levofloxacin+talcous mixed powder, makes to adhere to the ball wicking surface so repeated multiple times operation, finish until preparation, dry, filter out the micropill of 22～18 order sizes after the taking-up.Adopt Aquacoat bag extended release coatings film, make it to increase weight 9%, get slow-release micro-pill.The slow-release micro-pill for preparing places 60 ℃ to wear out 24 hours.The release curve is seen Fig. 5.
Embodiment 5
Starch
Sucrose
Levofloxacin
Sealing coat coating material: the strange E100 of 10% You Te (Degussa China Investment Ltd.) 50% ethanol water (containing 4% magnesium stearate, 8% Polyethylene Glycol)
Slow release layer coating material: 8% Su Lisi aqueous dispersion
Preparation technology:
Starch, sucrose, levofloxacin are made wet feed by weight 1: 1: 3 usefulness 70% alcoholic solution, wet feed is extruded the preparation granule through the extruder sieve plate, place spheronizator round as a ball, adopt You Teqi ethanol water bag contagion gown, make and contain pill and increase weight about 10%, adopt Su Lisi aqueous dispersion bag extended release coatings film again, make it to increase weight 7.5%, get slow-release micro-pill.Add 25% not coating pastille micropill, 75% weightening finish, 7.5% micropill in the capsule, its release the results are shown in Figure 6.
Pregelatinized Starch
Carboxymethyl starch sodium
Levofloxacin
Slow release layer coating material: 10% Su Lisi aqueous dispersion
Preparation technology:
Pregelatinized Starch, carboxymethyl starch sodium, levofloxacin are made wet feed by 10: 1: 39 weight ratios with the 5%PVP50% alcoholic solution, wet feed is extruded the preparation granule through the extruder sieve plate, place spheronizator round as a ball, adopt Su Lisi aqueous dispersion bag extended release coatings film, make it to increase weight 8.9%, get slow-release micro-pill.The slow-release micro-pill for preparing places 50 ℃ to wear out 48 hours.Add 25% not coating pastille micropill, 75% weightening finish, 8.9% micropill in the capsule, its release the results are shown in Figure 7.
Embodiment 7
Starch
Microcrystalline Cellulose
Carboxymethyl starch sodium
Levofloxacin
Sealing coat coating material: 20% Opadry, 50% ethanol water
Slow release layer coating material: 7% Su Lisi aqueous dispersion
Preparation technology:
Starch, microcrystalline Cellulose, carboxymethyl starch sodium, levofloxacin were pressed 20: 10: 5: 65 weight ratios are mixed, make wet granular with 5% polyvidone, 70% alcoholic solution, place the coating pan of rotation round as a ball, adopt Opadry ethanol water bag contagion gown, make and contain pill and increase weight about 8%, adopt Surelease aqueous dispersion bag extended release coatings film again, make it to increase weight 6.5%, get slow-release micro-pill.Add 10% not coating pastille micropill, 90% weightening finish, 6.5% micropill in the capsule, its release the results are shown in Figure 8.
Sealing coat coating material: 10% low-substituted hydroxypropyl cellulose solution
Slow release layer coating material: 15% Su Lisi aqueous dispersion
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, the aqueous solution of preparation levofloxacin, add medicine to by end spray method, it is about 30% that micropill is increased weight, and adopts Opadry ethanol water bag contagion gown, make and contain pill and increase weight about 8%, adopt Su Lisi aqueous dispersion bag extended release coatings film again, make it to increase weight 9.9%, get slow-release micro-pill.Add 20% not coating pastille micropill, 80% weightening finish, 9.9% micropill in the capsule, its release the results are shown in Figure 9.
Embodiment 9
Starch: dextrin: the levofloxacin weight ratio is 4: 1: 5
Slow release layer coating material: 15% ethyl cellulose aqueous solution (containing 5% polyvinylpyrrolidone, 10% diethyl phthalate)
Preparation technology:
Starch, dextrin are crossed 100 mesh sieves respectively, and mixing is a binding agent system soft material with an amount of 30% ethanol, the round as a ball celphere of making of coated pot, and the celphere of getting between the 20-40 order is standby.
Celphere is placed the high-efficiency coating pot, the aqueous solution of preparation levofloxacin, medicine-feeding, it is about 30% that micropill is increased weight, and gets the aqueous solution bag extended release coatings film that a part wherein adopts ethyl cellulose, makes it to increase weight 8%, slow-release micro-pill.Do not incapsulate after the slow-release micro-pill of coating pastille micropill, 80% weightening finish 8% mixes with 20%.The release curve is seen Figure 10.
Embodiment 10
Sealing coat coating material: 20% Gonak (containing 5% Polyethylene Glycol, 10% dimethyl phthalate)
Slow release layer coating material: the strange NE30D aqueous dispersion of 40% You Te (containing 12% superfine talcum powder, a small amount of simethicone)
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, the aqueous solution of preparation levofloxacin is added medicine to by end spray method, makes micropill increase weight about 50%, adopt HPMC bag contagion gown, make to contain pill and increase weight approximately 20%, adopt the strange NE30D bag of You Te extended release coatings film again, make it to increase weight 10%, the slow-release micro-pill for preparing places 40 ℃ to wear out 24 hours.The release curve is seen Figure 11.
Embodiment 11
Sealing coat coating material: 15% Opadry aqueous solution (containing 5% Polyethylene Glycol, 20% triethyl citrate)
Slow release layer coating material: the strange NE30D aqueous dispersion of 40% You Te (containing 18% superfine talcum powder, a small amount of methyl-silicone oil)
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, the aqueous solution of preparation levofloxacin, add medicine to by end spray method, it is about 100% that micropill is increased weight, and adopts Opadry bag contagion gown, make and contain pill and increase weight about 50%, adopt You Teqibao extended release coatings film again, make it to increase weight 15%, the release curve is seen Figure 12.
Sealing coat coating material: the strange EPO aqueous dispersion of 8% You Te (containing 5% sodium lauryl sulphate, 2% dibutyl sebacate, 8% Pulvis Talci)
Slow release layer coating material: the strange NE30D aqueous dispersion of 40% You Te (containing 5% superfine talcum powder, a small amount of simethicone)
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, prepare the 5%HPMCE5 aqueous solution of 20% levofloxacin, add medicine to, make micropill increase weight about 200% by end spray method, adopt the strange EPO bag of You Te contagion gown, make to contain pill and increase weight approximately 30%, adopt the strange NE30D bag of You Te extended release coatings film again, make it to increase weight 15%, add 25% not coating pastille micropill, 75% weightening finish, 15% micropill in the capsule, its release the results are shown in Figure 13.
Embodiment 13
Sealing coat coating material: 5% Gonak (containing 5% Polyethylene Glycol, triethyl citrate)
Slow release layer coating material: the strange NE30D aqueous dispersion of 40% You Te (containing 5%PEG, 10% superfine talcum powder, a small amount of simethicone)
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, the aqueous solution of preparation levofloxacin is added medicine to by end spray method, makes micropill increase weight about 20%, adopt HPMC bag contagion gown, make to contain pill and increase weight approximately 10%, adopt the strange NE30D bag of You Te extended release coatings film again, make it to increase weight 19%, add 30% not coating pastille micropill, 70% weightening finish, 19% micropill in the capsule, its release the results are shown in Figure 14.
Sealing coat coating material: 20% Gonak (containing 5% tributyl citrate)
Slow release layer coating material: the strange NE30D aqueous dispersion of 30% You Te (containing 5%HPMC solution, 30% superfine talcum powder, a small amount of simethicone)
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, prepare the 5%PVP aqueous solution of 25% levofloxacin, add medicine to by end spray method, it is about 100% that micropill is increased weight, and adopts HPMC bag contagion gown, makes to contain pill and increase weight about 15%, adopt You Teqibao extended release coatings film again, make it to increase weight 13%.Slow-release micro-pill places 40 ℃ to wear out 48 hours.
With the slow-release micro-pill 60%, microcrystalline Cellulose 20%, carboxymethyl starch sodium 3%, micropowder silica gel 0.2%, the magnesium stearate 0.5% mix homogeneously tabletting that make, its release curve is seen Figure 15.
Embodiment 15
Sealing coat coating material: the strange E10095% alcoholic solution of 2% You Te (containing 4% Pulvis Talci, 0.5% Polyethylene Glycol)
Slow release layer coating material: the You Te strange RL30D of strange RS30D/ You Te (10: 1) (containing 20% Oleum Ricini, 20% triethyl citrate, 10% magnesium stearate)
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, the 2%HPMCE15 aqueous solution of preparation levofloxacin, add medicine to by end spray method, it is about 500% that micropill is increased weight, and adopts the strange E100 bag of You Te contagion gown, makes to contain pill and increase weight about 5%, adopt the strange RL30D bag of the strange RS30D/ You Te of You Te extended release coatings film again, make it to increase weight 40%.Its release curve is seen Figure 16.
Slow release layer coating material: the strange RS10095% ethanol of 6% You Te aqueous dispersion (containing 20% dibutyl sebacate, 5% Pulvis Talci, 5% lactose)
Preparation technology:
Ball core preparation method is with embodiment 1, celphere is placed fluid bed, prepare the 2%HPMC aqueous solution of 15% levofloxacin, add medicine to by end spray method, it is about 200% that micropill is increased weight, and adopts the strange E100 bag of You Te contagion gown, makes to contain pill and increase weight about 5%, adopt the strange RS100 bag of You Te extended release coatings film again, make it to increase weight 40%.
Embodiment 17
Slow release layer coating material: Aquacoat
RECD-30 aqueous dispersion (containing 30% triethyl citrate)
Preparation technology:
Ball core preparation method places fluid bed with embodiment 1 with celphere, prepares the 1%HPMC aqueous solution of 10% levofloxacin, adds medicine to by end spray method, and it is about 100% that micropill is increased weight, and adopts Aquacoat
RECD-30 bag extended release coatings film makes it to increase weight 12%.
Slow release layer coating material: 35% cellulose acetate butyl ester aqueous dispersion (containing 1% polyvinyl alcohol, 20% acetoglyceride)
Preparation technology:
Ball core preparation method places fluid bed with embodiment 1 with celphere, prepares the aqueous solution of 20% levofloxacin, adds medicine to by end spray method, and it is about 100% that micropill is increased weight, and adopts cellulose acetate butyl ester bag extended release coatings film, makes it to increase weight 10%.
Claims (10)
1, a kind of sustained-release pellet preparation that contains levofloxacin; it is characterized in that forming by 0%～40% the common medicine-containing particle or the slow release pastille micropill of micropill and 60%～100%; wherein slow release pastille micropill be successively from inside to outside contain levofloxacin contain pill core, sustained release coating layer, wherein the weight of sustained release coating layer is to contain 4～100% of pill core weight.
2, the sustained-release pellet preparation of claim 1, it is characterized in that containing pill core and be made up of levofloxacin and pharmaceutic adjuvant, wherein pharmaceutic adjuvant is selected from one or more in starch, lactose, dextrin, sucrose, microcrystalline Cellulose, pregelatinized Starch, inorganic salts, mannitol, sorbitol, cellulose derivative, hydroxypropyl emthylcellulose, Polyethylene Glycol, polyvidone, acrylic resin, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, magnesium stearate, micropowder silica gel, Pulvis Talci, the sodium lauryl sulphate.
3, the sustained-release pellet preparation of claim 1 is characterized in that the sustained release coating layer material is selected from cellulose esters or acrylic resin, ethyl cellulose, Opadry, AquacoatR
EIn CD-30, Su Lisi, hydroxypropyl emthylcellulose, polyvinyl alcohol, polyolefin, polyester, cellulose acetate, polrvinyl chloride, Merlon, vinyl alcohol, vinylacetate, ethylene-propylene polymer, ethylene-vinyl acetate copolymer, hyprolose phthalate ester, the Hydroxypropyl Methyl Cellulose Phthalate one or more.
4, the sustained-release pellet preparation of claim 3, wherein the sustained release coating layer material is selected from acrylic resin, Opadry, AquacoatR
EIn CD-30, Su Lisi, ethyl cellulose, the hydroxypropyl emthylcellulose one or more.
5, claim 3 or 4 sustained-release pellet preparation, feature is that the sustained release coating material also contains one or more in plasticizer, antiplastering aid, porogen, the opacifier, and described plasticizer is selected from one or more in dibutyl sebacate, citrate, acetoglyceride, citron acid esters, glyceride, phthalic acid ester, polyethylene glycols, cochin oil, Oleum Ricini, Polysorbate, glyceride, succinate, benzoate, phosphate ester, adipate ester, the tartrate; Described antiplastering aid is selected from one or more in Pulvis Talci, magnesium stearate, glyceryl monostearate, the micropowder silica gel; Described porogen is selected from one or more among Polyethylene Glycol, polyvidone, sucrose, lactose, salt, HPMC, the HPC; Described opacifier is a titanium dioxide.
6, the sustained-release pellet preparation of claim 1 wherein contains between pill core and the slow release coatings and to also have a sealing coat, and sealing coat contains one or more in hydroxypropyl emthylcellulose, acrylic resin, Opadry, the low-substituted hydroxypropyl cellulose.
7, the sustained-release pellet preparation of claim 6, wherein the weight of sealing coat is to contain 1～50% of pill core.
8, the preparation method of each sustained-release pellet preparation in the claim 1 to 7 comprises: preparation contains pill core, bag extended release coatings film, the slow-release micro-pill that must contain levofloxacin, wrap contagion gown if desired, then before bag extended release coatings film, wrap contagion gown earlier, wrap the extended release coatings film again; Slow-release micro-pill directly is filled in the capsulae vacuus, or micropill is added the pharmaceutic adjuvant repress makes slow releasing tablet; Or will not be filled in the capsulae vacuus after pill core or medicine-containing particle and slow-release micro-pill are mixed in proportion containing of coating, or adding pharmaceutic adjuvant repress is made sustained-release pellet tablet.
9, each sustained-release pellet preparation is used to prepare the purposes for the treatment of antibacterials in the claim 1 to 7.
10, each sustained-release pellet preparation in the claim 1 to 7, wherein said levofloxacin is the acid-addition salts of levofloxacin episome or levofloxacin.
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| CNB2006100377003A CN100361660C (en) | 2006-01-10 | 2006-01-10 | Levofloxacin slow release micropill, its preparation method and uses |
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| CNB2006100377003A CN100361660C (en) | 2006-01-10 | 2006-01-10 | Levofloxacin slow release micropill, its preparation method and uses |
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| CN1839846A true CN1839846A (en) | 2006-10-04 |
| CN100361660C CN100361660C (en) | 2008-01-16 |
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| CNB2006100377003A Expired - Fee Related CN100361660C (en) | 2006-01-10 | 2006-01-10 | Levofloxacin slow release micropill, its preparation method and uses |
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