CN101703482B - Galanthamine long-acting release injectable microsphere composite and preparation method thereof - Google Patents
Galanthamine long-acting release injectable microsphere composite and preparation method thereof Download PDFInfo
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- CN101703482B CN101703482B CN2009102302927A CN200910230292A CN101703482B CN 101703482 B CN101703482 B CN 101703482B CN 2009102302927 A CN2009102302927 A CN 2009102302927A CN 200910230292 A CN200910230292 A CN 200910230292A CN 101703482 B CN101703482 B CN 101703482B
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Abstract
The invention discloses galanthamine microspheres which contain 5-40wt% of basic group of galanthamine and 60-95wt % of polylactic acid/hydroxyacetic acid copolymer. The invention also provides a galanthamine long-acting release injectable microsphere composite which comprises the following components by weight percent: 60-90% of galanthamine microspheres, 5-25% of frozen dry proppant, 0.5-5% of suspending agent, 0.5-5% of wetting agent and 1-25% of osmotic pressure regulator. The invention combines the vibration nozzle method with the emulsion process (O/W)-solvent evaporation method so that the method has the advantage that the droplet-generating speed is fast, the efficiency is high, the containers used in preparation are easy to use in the aseptic operation, the production process can be carried out continuously, the technology is applicable to scale-up application, etc.
Description
Technical field
The present invention relates to a kind of injectable microsphere composite and method for preparing, more particularly, relate to a kind of biodegradable galanthamine long-acting injection sustained-release microspherical composition and method for preparing.
Background technology
Galantamine belongs to the competitive cholinesterase inhibitor of the second filial generation, can see through blood brain barrier, and interrupted neuromuscular conduction is recovered, and improves the palsy of various peripheral nerve muscular disorders.Be used to treat myasthenia gravis in early days; The discovered in recent years galantamine can significantly improve gerontal patient's memory; Be mainly used in that treatment is slight, moderate and severe Alzheimer's disease (AD); Medication 6～8 week, the back was evident in efficacy, and these article are applicable to benign memory deficits, improved that the patient points to that memory, learning by association, image are recalled, random shape is re-recognized and ability such as portrait memory.The dysmnesia that dementia patients and brain organic pathological changes the are caused effect that also has clear improvement.The common formulations of galantamine has tablet (5mg/ sheet), capsule (5mg/ grain) and injection (1mg, 2.5mg, 5mg/ml).Because the dissolubility of galantamine is relatively poor, thus be made into hydrobromate usually, to increase its dissolubility.The dosage form of having studied has oral liquid, injection, ordinary tablet, dispersible tablet, slow releasing tablet, capsule, ointment etc.Usages such as the dosage of common formulations, the course of treatment are following: (capsule, tablet) 5mg/ grain, 4 times/day; Injection: intramuscular injection or subcutaneous injection, each 2.5-10mg, 1 time/day, 1 the 2-6 week course of treatment.Therefore, because the biological half-life of galantamine is shorter, be about 5 hours; Oral administration every day needs 4 times, and administration is frequent, and clinical application is very inconvenient; And AD patient's memory, judgement, ability of thinking decline, forfeiture; Multiple dosing, the compliance of treatment can not get ensureing, the phenomenon that patient misses or obeys more often occurs.Injection intramuscular injection or subcutaneous administration, 1 time/day, the course of treatment is long, and drug administration by injection treatment inconvenience causes more misery to the patient.Conventional formulation such as oral formulations and injection of solution agent, except the frequent inconvenience of administration, the drug level peak valley phenomenon also is a problem.It is reported that because blood drug level is too high, excessively acetylcholine esterase inhibition will cause untoward reaction such as tangible digestive tract and vascular smooth muscle, its untoward reaction strengthens along with the increase of dosage.
Therefore, the slow releasing preparation of preparation galantamine can reduce administration number of times, improves compliance of patients, reduces the untoward reaction that the fluctuation of blood medicine causes.The research of the slow releasing preparation of galantamine at present, bibliographical information is a slow releasing tablet, as Liu Wei (Liu Wei, flat its ability. the development of Galantamin hydrobromide sustained-release sheet [J]. Jiangsu pharmacy and clinical research, 2006; 14 (4): be main slow-release material 215-217) with glyceryl monostearate, Eudragit E udragit L100-55, the preparation slow releasing tablet, the Galantamin hydrobromide sustained-release sheet presents the good slow release characteristic in 24h as a result.Chen Ang, He Fen (Chen Ang; He Fen. the pastille resin surface is modified legal system and is equipped with galantamine oral sustained release suspension [J]. Chinese Journal of Pharmaceuticals; 2007,38 (3): 227-232) adopt ion exchange absorption technology, modify the resin surface that is combined with galanthamine hydrobromide with acrylic resin RS100; Process slow-release suspension, but slow release 12h.Oral slow releasing preparation slow-release time is generally 12-24h, and concerning patient AD, administration number of times still is more, the phenomenon that misses or obey more easily.Therefore, relatively, long-acting slow-release preparation reaches the preparation of two weeks to month like the slow release cycle; Should be used for saying from actual therapeutic, can greatly reduce frequency, improve patient's treatment compliance; Reduce the treatment cost, can finely satisfy the clinical treatment demand of AD, have good application potential.
Biodegradable material is the new material that obtains broad research and application in recent years at home and abroad, comprises polylactic acid (PLA), polylactic acid/hydroxy acetate multipolymer (PLGA), polycaprolactone (PCL) etc.Polylactic acid series material is good long-acting slow-release material, has certain mechanical strength, and histocompatibility is good; No immunoreation; Therefore biodegradable in vivo is lactic acid, hydroxyacetic acid, and final degradation is carbon dioxide and water, implants or inject to need not operation behind subcutaneous, the muscle and take out.Adopt PLGA 1 month the leuprorelin acetate long-acting slow-release microsphere (trade name: enantone of slow release of successfully developing and go on the market from Japan military field drugmaker; LeupDepot) since, polylactic acid-based material has obtained increasingly extensive application in the continuous release microsphere drug-supplying system.Long-acting slow-release microsphere technology is the sophisticated technology in the pharmaceutical preparation, has become the focus of domestic and international preparation research and development.The technological means that adopts Biodegradable material PLGA to prepare the continuous release microsphere of drug administration by injection is admitted widely.
Adopt biodegradable polymer, packaging medicine is prepared into micro-balloon injection, and the size of microsphere is generally at 100 μ m; With the form packing of lyophilized injectable powder, adding sterilized water for injection or normal saline are made disperse medium before using, slight jolting; Can form stable suspensoid; Adopt conventional syringe approach drug administration by injection subcutaneous or intramuscular to get final product, syringeability is good, the implantation of need not performing the operation.Microsphere is after subcutaneous, intramuscular injection administration; Along with slow corrosion, the biodegradation of material at the drug administration by injection position; Drug release comes out, absorbs the entering blood circulation; Therefore infiltration rate is slow, and can come control drug release speed according to material chosen such as the degree of polymerization of material, molecular weight, monomeric ratios, thereby can play the administration purpose of long-acting slow-release in vivo.At present, do not see the research report of galanthamine long-acting release micro-balloon injection as yet, therefore research and develop this novel form and have excellent research value.
The preparation technology of long-acting slow-release micro-balloon injection uses stirring and emulsifying (O/W, W/O or W/O/W)-solvent evaporation method (Emulsion-solvent evaporation method), spray drying method (Spray drying method), supercritical fluid technology sedimentation (Supercritical fluid CO always
2Anti-solvent method) etc.But the method for preparing of these microspheres commonly used exists one of common shortcoming: the particle diameter of microsphere can not be well controlled, so the volume difference in size of microsphere is big, and particle size distribution is wide.To this problem; Conventional method is the screening method that adopts final microsphere; Screen out the excessive or too small microsphere of particle diameter, therefore the microsphere of choosing OK range can cause waste to a certain degree as certified products; And the microsphere after the screening distributes and still to let broad, has a certain proportion of small particle diameter microsphere like this in the finished product.Because the little microsphere surface of particle diameter is long-pending big, the prominent phenomenon of releasing of medicine in the dispose procedure in too high external, the body that causes the long-acting slow-release micro-balloon injection easily of small particle diameter microsphere ratio in the injection.If prominent release excessively, release amount of medicine is excessive, can cause untoward reaction to strengthen.In general, it is little that the medicine that microsphere is sealed is generally dosage, and the medicine of strong drug action is therefore prominently released phenomenon and caused the odd-numbered day dosage too high easily, produces intoxicating phenomenon.In addition; Microsphere preparation technology commonly used can not comparatively accurately control the size and the distribution of microsphere in the preparation process; This can cause the differences between batches of size and distribution of microspheres product big, and external, the intravital release of medicine can not be controlled preferably.Therefore, method for preparing microsphere commonly used at present is necessary to reform, thereby is able to evenly control the purpose of microspherulite diameter.
It is more that microsphere prominent released the phenomenon reason, except particle diameter difference is big, also has dissolubility, the preparation technology of medicine self, the quality (ratio of molecular weight ranges, oligomer) of encapsulating material etc.; One of them major reason of ignoring easily is exactly to note the polylactic acid-based material that the suitable end group of employing is modified according to the characteristics of entrapped drug, reports like patent (CN1723895A); Employing terminal residues such as the flat field of invention population do not have esterification to modify, be with carboxyl (PLGA COOH); Adopt traditional emulsifying (O/W)-solvent evaporation method, preparation huperzine A microsphere, the result shows; Adopting end is the PLGA material of carboxyl; Can improve the drug loading and the envelop rate of huperzine A, release in vitro shows simultaneously, but adopts prominent the releasing of the PLGA better controlled microsphere of this kind specification.The PLGA material of not analyzing terminal band carboxyl in this patent can improve drug loading, envelop rate and reduce the prominent reason of releasing.In fact, these physics and chemistry characteristics with medicine self are relevant.Huperzine A is an alkaloid; Basic group in the molecular structure is a primary amine, and polarity is big, so huperzine A has certain water solublity (0.8mg/ml; 25 ℃); The envelop rate of emulsifying (the O/W)-solvent evaporation method that therefore usually adopts is low, drug loading is low, and medicine spreads the microsphere surface that is caused in Emulsion micropore is many, so medicine is prominent, and to release phenomenon serious.When utilizing PLGA to seal to contain the medicine of amine groups; Can utilize end not have esterification to modify; Band carboxyl (COOH) material; Can utilize microsphere Chinese medicine and carrier interactions, promptly the amido of medicine forms hydrogen bond with the carboxyl of material, thereby can play stable entrapped drug, raising drug loading, envelop rate.The rate of release of microsphere Chinese medicine is also owing to the hydrogen bond action of medicine with carrier material is controlled better.The leuprorelin long-acting release injectable microsphere that goes on the market the earliest utilizes the amido in the medicine to follow the hydrogen bond action of the carboxyl of material just; Material selection PLGA-COOH (Okada H; One-and three-month release injectable microspheres ofLH-RH superagonist leuporelin acetate [J] .Advanced Drug Delivery Review; 1997,28 (1): 43-47).Galantamine is an alkaloid, in the molecular structure tertiary amine is arranged, and also can utilize this construction features, improves drug loading, envelop rate and the sustained release of microsphere.
The prominent problem of releasing to the huperzine A microsphere; The inventor Chen Qing China of patent (CN1981744A) etc. start with through method for preparing, adopt emulsifying (W/O)-solvent evaporation method to prepare microsphere; External release test shows; Prominent the releasing preferably of microsphere controlled, but release 1d is released to 16% in the body, and dashing forward, it is still more obvious to release phenomenon.The method of emulsifying (W/O) prepares microsphere, and subsequent treatment comparatively bothers, and generally is of little use.This method for preparing foreign minister is a corn wet goods vegetable oil; Emulsifying agent is Span80; Therefore the cleaning of microsphere needs organic solvents such as petroleum ether, is unfavorable for the large-scale production preparation of microsphere, and the control of residual Span80 emulsifying agent also is a considerable problem in the microsphere.
External long-acting slow-release micro-balloon injection such as the leuprorelin acetate microsphere that has gone on the market, the technology that adopts in the production is stirring and emulsifying (W/O/W)-solvent evaporation method, this kind of domestic imitation also is to adopt this production technology; This production technology is through the mechanical agitation work done; The dichloromethane solution that disperses PLGA forms W/O/W, after the solvent evaporates; Emulsion droplet solidifies, and promptly forms microsphere.Though having certain production application, production technology is worth; But adopt this method to prepare microsphere; Exist prepared in laboratory and excessively arrive pilot-scale, a production-scale technology amplification difficult problem, reason just is that along with preparative scale increase the emulsifying effectiveness of stirring and emulsifying is not easy control.In addition; Size and distribution depends on the prepared emulsion droplet of stirring and emulsifying size and distributes in this production technology; But because the inhomogeneities of mechanical agitation force distribution; The emulsion droplet size difference that causes forming is big, thus the microspherulite diameter of this prepared size with distribute all wayward.
Prepare the technology amplification difficult problem that microsphere exists to stirring and emulsifying (O/W)-solvent evaporation method; (CN2719296Y) designing and preparing such as patent inventor marquis's Huimin special equipment can utilize this method to prepare the device of microsphere continuously; Improved production efficiency, and can continuous production.This equipment can solve emulsifying (O/W)-volatility process microsphere preparation technology's an amplification difficult problem preferably.But this equipment can not carry out size and distribute that to control be bigger sorry microsphere.Another shortcoming is exactly sealing of suitable water-insoluble drug only, is not suitable for water soluble drug and seals the multi-emulsion method of employing (W/O/W)-solvent evaporation method.Vibrating nozzle method (Vibrating nozzle breakup method) can reach the size droplet diameter size that accurate control is produced through nozzle diameter, dither and high-voltage electrostatic field.This method preparation of successfully applying to APA microcapsule (APA microcapsule) in cell biological engineering field in recent years comes encapsulation of cells and tissue.Have production efficiency height, microcapsule diameter size evenly, the technology advantage that is easy to amplify.External existing laboratory, pilot scale, production-scale microvibrograph are commercially produced equipment (Switzerland Inotech Biosystem company, Inotech Encapsulator series microvibrograph).But Shang Weiyou utilizes this legal system to be equipped with the application report of long-acting release injectable microsphere.Reason is that the purpose of design of microvibrograph is a preparation APA microcapsule; It is more than 300～500 μ m that size requires; And the particle diameter of injectable microsphere is much smaller, and about mean diameter 100 μ m, generally is less than 200 μ m; Otherwise the syringeability of micro-balloon injection clinical injection administration can be affected.Therefore must designing and preparing meet the vibrating nozzle that the injectable microsphere size requires.In addition; What microvibrograph sprayed is sodium alginate aqueous solution; And microsphere preparation is adopted is organic solvent or the W/O colostrums such as dichloromethane of PLGA, and therefore both must carry out big groping and adjusting to technological parameters such as frequency of vibration, voltage of electric field at aspect significant differences such as surface activity, viscositys.
Summary of the invention
To the deficiency of prior art, the technical issues that need to address of the present invention are to disclose a kind of novel form of galanthamine long-acting release injectable microsphere composite and new method for preparing microsphere.Employed galantamine (Galanthamine) is a kind of phenanthridine alkaloid that comes from lycoris plants snowflake (Leucojum aestivum) among the present invention, chemistry 11-methyl by name-3-methoxyl group-4 α, 5; 9; 10,11,12-six hydrogen-6H-benzofuran [3 α; 3,2-ef] [2] benzazepine-6-alcohol.
The inventor furthers investigate to existing technology status, finds through lot of experiment results, adopts following technical proposals to achieve the above object, thereby has accomplished the present invention.Technical scheme of the present invention is following:
A kind of galantamine microsphere comprises galantamine base that accounts for microsphere gross weight 5-40% and the polylactic acid/hydroxy acetate multipolymer that accounts for total microsphere gross weight 60-95%.
Aforesaid galantamine microsphere, optimized technical scheme are that microspherulite diameter is 25-200 μ m, is more preferably 50-150 μ m.Aforesaid galantamine microsphere; Optimized technical scheme is; Lactic acid (LA) is 30 with the mol ratio of hydroxyacetic acid (GA) in the said polylactic acid/hydroxy acetate multipolymer: 70-70: 30; The molecular weight of said polylactic acid/hydroxy acetate multipolymer is 5000-50000 dalton, is preferably 10000-30000 dalton.Aforesaid galantamine microsphere, optimized technical scheme are that the end group of said polylactic acid/hydroxy acetate multipolymer is-the COOH group.
The present invention also provides a kind of galanthamine long-acting release injectable microsphere composite, and its component and weight percentage are: galantamine microsphere 60-90%, lyophilizing proppant 5-25%, suspending agent 0.5-5%, wetting agent 0.5-5%, osmotic pressure regulator 1-25%.Aforesaid galanthamine long-acting release injectable microsphere composite, preferred scheme be, said lyophilizing proppant is a kind of in mannitol, sucrose, trehalose, the lactose and more than one.Aforesaid galanthamine long-acting release injectable microsphere composite, preferred scheme be, said suspending agent is a kind of in sodium carboxymethyl cellulose, hypromellose, dextran, hetastarch, the polyvinylpyrrolidone and more than one.Aforesaid galanthamine long-acting release injectable microsphere composite, preferably scheme is, and said wetting agent is a Tween 80, and said osmotic pressure regulator is a sodium chloride.
The present invention also provides the method for preparing of aforementioned galanthamine long-acting release injectable microsphere composite, comprises following two steps: the preparation of galantamine microsphere and the preparation of lyophilized injectable powder:
The preparation of said galantamine microsphere: adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method, step is following: galantamine base, polylactic acid/hydroxy acetate multipolymer are dissolved in organic solvent, as decentralized photo; Adopting diameter is 25 or 50 μ m nozzles, frequency of vibration 2000-5000Hz, voltage of electric field 500-1500V; The concentration 0.05-0.5g/ml of polylactic acid/hydroxy acetate multipolymer forms symmetrical liquid drop with decentralized photo in the decentralized photo, is added drop-wise in the polyvinyl alcohol water solution that concentration is 0.1-5wt%; Emulsifying is condensed into microsphere, after microsphere solidifies; Isolate the galantamine microsphere, washing;
The preparation of said freeze-dried powder: suspending agent, lyophilizing proppant, osmotic pressure regulator, wetting agent are dissolved with sterilized water for injection, and antibacterial and the impurity in the reagent is removed in aseptic filtration, as the suspensoid medium of micro-balloon injection; The galantamine microsphere of preparation is suspended in the suspensoid medium; Stir, promptly get the microsphere suspensoid, the settling ratio 15min of suspensoid is greater than 0.8; This suspensoid is sub-packed in the cillin bottle under stirring condition; Lyophilization rapidly, moisture is controlled at 0.1-5wt%, promptly gets final finished.
The method for preparing of aforementioned galanthamine long-acting release injectable microsphere composite, optimized technical scheme be, is in dichloromethane, ethyl acetate, the acetone one or more at organic solvent described in the preparation of galantamine microsphere.
Main creative contribution of the present invention is embodied in provides a kind of long-acting sustained-release injection based on the galantamine microsphere and preparation method thereof, promptly shows following two aspects:
(1) vibrating nozzle method (Vibrating nozzle breakup method) preparation galantamine microsphere.
This method for preparing is that traditional emulsifying (O/W)-solvent evaporation method is innovated; Through changing the nozzle of different-diameter size; The factors such as concentration of PLGA in adjustment frequency of vibration, voltage of electric field, the decentralized photo; The particle diameter of the decentralized photo when accurately control Emulsion prepares, thereby the emulsion droplet particle diameter that control is produced finally reach the purpose that the control microspherulite diameter is concentrated relatively.This method have microspherulite diameter size evenly, the clear superiority of narrow distribution range, in addition, it is fast that the vibrating nozzle method generates the speed of drop, efficient is high, the preparation tank capacity carries out the sterile working, production process can be carried out continuously, technology is easy to amplify advantages such as application.The application inventor finds that through a large amount of tests this method is specially adapted to the formation of the organic solvent dispersed phase drop of polymeric material.Therefore, the present invention adopts the base of galantamine to prepare microsphere, and does not adopt water miscible hydrobromate.Because receive the restriction of the viscosity factor of decentralized photo, the application inventor repeatedly attempts to utilize colostrum (W/O) as decentralized photo, the sustained-release micro-spheres for preparing water soluble drug through multi-emulsion method (W/O/W) does not obtain the comparatively effect of ideal control microspherulite diameter.Therefore, this method for preparing is applicable to the preparation of poorly water soluble drugs microsphere.Those skilled in the art understand easily, to some water-soluble organic acid bases medicines, can utilize its base, characteristics that the acidic group water solublity is low, combine emulsifying (the O/W)-base of this type of solvent evaporation method preparation medicine or the microsphere of acidic group through vibrating nozzle.
(2) formation of galanthamine long-acting release injectable microsphere composite.
Above-mentioned galantamine microsphere can be used for preparing galanthamine long-acting release injectable microsphere; Be the lyophilized injectable powder of a kind of embedding in cillin bottle, comprising the galantamine microsphere of therapeutic dose and suspending agent, proppant, wetting agent, osmotic pressure regulator, its preferred ingredients and weight percent content comprise: galantamine microsphere 60～90%; Lyophilizing proppant 5～25%; Suspending agent 0.5～5%, wetting agent 0.5～5%, osmotic pressure regulator 1～25%.Described suspending agent is a sodium carboxymethyl cellulose, hypromellose, polyvinylpyrrolidone.Described proppant is mannitol, sucrose, lactose etc., and it mainly acts on is when lyophilization, to play peptizaiton, prevents the adhesion between the microsphere.Described wetting agent is a Tween 80, and it mainly acts on is to make the easy moistening of microsphere surface, thereby microsphere is dispersed in the injection preferably.
Galanthamine long-acting injection sustained-release microspherical composition of the present invention can be used for the syndromic medicine of preparation treatment Alzheimer's; Microsphere composition is added sterilized water for injection (addition of water for injection is 1～5 times of galanthamine long-acting injection sustained-release microspherical composition weight); Jolting gently; Mixing, the intramuscular injection administration.An every two weeks or an injection in month are once.Galantamine in the microsphere discharges through biodegradation, the corrosion of diffusion and PLGA material, and slow-release time can be kept two weeks or one month.
Description of drawings
Fig. 1 is the galantamine PLGA microsphere microphotograph of embodiment 3 preparations.
Fig. 2 is the release in vitro curve of the galantamine PLGA microsphere of embodiment 3 preparations.
Fig. 3 is the release in vitro curve of the galantamine PLGA microsphere of embodiment 7 preparations.
Fig. 4 is the interior release profiles of body of the galantamine PLGA microsphere of embodiment 3 preparations.
Fig. 5 is the interior release profiles of body of the galantamine PLGA microsphere of embodiment 7 preparations.
The specific embodiment
Come technical characterictic of the present invention is done further to specify below in conjunction with specific embodiment.But the present invention does not receive the restriction of these specific embodiments.
Raw materials used or equipment all can obtain from market among the embodiment.Wherein, galantamine is available from ChangZhou TianPu Pharmacy Co., Ltd; Polylactic acid/hydroxy acetate multipolymer (PLGA) is available from the Shandong Prov. Medical Apparatus & Instrument Research Inst; Polyvinyl alcohol 17-88,05-88 is available from Beijing Organic Chemical Plant; Polyvinyl alcohol 1750 is available from chemical reagent purchasing station, Chinese Medicine group Shanghai; Dichloromethane, ethyl acetate, acetone are all available from chemical reagent purchasing station, Chinese Medicine group Jinan; Mannitol is available from Qingdao Mingyue Marine Alga Group Corp., Ltd.; Sucrose is available from Distributions in Liaocheng of Shandong Province peace letter pharmaceutic adjuvant company limited; Trehalose is available from Wuhan Yuancheng Technology Development Co., Ltd.; Sodium carboxymethyl cellulose is available from the mountains and rivers, Huainan, Anhui pharmaceutic adjuvant company limited; Dextran is available from Shanghai Huamao Pharmaceutical Co; Tween 80 is available from Qingdao Tian Liyuan bio tech ltd; Inotech IE50R microvibrograph is available from Switzerland Inotech Biosystem company; Vibrating nozzle ( aperture 25,50 μ m) is available from Switzerland Inotech Biosystem company; Vacuum pump (Xiamen Jim Maclaren Science and Technology Ltd.); The water bath with thermostatic control agitator is available from the suitable magnificent Instr Ltd. in Jintan City; Bag filter (the molecular retention quality is 8000-14400u) is available from Beijing Xia Si biotech company.
The vibrating nozzle method combines emulsifying (O/W)-solvent evaporation method to prepare the preparation of microsphere:
(1) the vibrating nozzle method combines emulsifying (O/W)-solvent evaporation method to prepare the technical study of microsphere: the technological factors such as voltage of concentration, frequency of vibration, electric field of mainly investigating PLGA in the pore size, decentralized photo of vibrating nozzle are to the influence of rounding property, size and distribution, drug loading and the envelop rate of microsphere preparation.(2) prescription research: (LA: GA=50: 50,75: 25) factor such as ratio is to the influence of microsphere drug loading, envelop rate, external release mainly to investigate the ratio, PLGA polymerization single polymerization monomer of medicine and carrier PLGA.
With Inotech IE50R microvibrograph prototype (available from Switzerland Inotech Biosystem company) is that the vibrating nozzle method combines emulsifying (O/W)-solvent evaporation method to prepare the microsphere appearance technology platform of microsphere.Prepare the requirement of microsphere according to instrument own characteristic and emulsifying (O/W)-solvent evaporation method; This instrument has been done following improvement: the critical component of (1) control size is the diameter of vibrating nozzle, and the original nozzle fittings of manufacturer, diameter is respectively 100; 150; 200,300 μ m do not have the vibrating nozzle below the 100 μ m.Existing vibrating nozzle diameter is excessive, therefore must change the vibrating nozzle of existing instrument.The application inventor is through getting in touch with producer, and producer agrees to provide diameter to be respectively the vibrating nozzle of two kinds of diameter specifications of 25,50 μ m according to original jet size size.(2) adopt vacuum pump to bleed, promote the volatilization of organic solvent in the microsphere.
Through above measure, Inotech IE50R microvibrograph is improved to the equipment that can be used for the microsphere preparation, inventor's called after: vibrating nozzle method microsphere appearance.Utilize vibrating nozzle method of the present invention successfully to prepare galantamine PLGA microsphere.Technological parameter is controlled as follows: vibrating nozzle diameter 25 or 50 μ m; The theoretical drug loading 5～50% (percentage by weight) of galantamine; The concentration 5～50% (concentration expressed in percentage by weight) of PLGA in the decentralized photo; Frequency of vibration 2000～5000Hz, voltage of electric field 500～1500V can prepare the galantamine PLGA microsphere of size 25～200 μ m.
Embodiment 1: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
The about 55mg of precision weighing galantamine base, the about 1000mg of PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) adds in the 5ml dichloromethane, and vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere.Apparatus for preparation adopts improved vibrating nozzle method microsphere appearance, and technological parameter is following: the aperture 50 μ m of nozzle, frequency of vibration 2000Hz; Voltage of electric field: 500V, the flow velocity 1ml/min of decentralized photo liquid makes nozzle can produce even, successive drop; Splash in the continuous phase of getting 5%PVA17-88 aqueous solution 200ml middling speed magnetic agitation 1h, low speed magnetic agitation 4h then; Decompression promotes the organic solvent performance, centrifugal collection microsphere, and washing, vacuum drying promptly get.
Embodiment 2: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
The about 130mg of precision weighing galantamine base, the about 1000mg of PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) adds in the 20ml ethyl acetate, and vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere.The system apparatus for preparation adopts improved vibrating nozzle method microsphere appearance, and technological parameter is following: the aperture 25 μ m of nozzle, frequency of vibration 3000Hz; Voltage of electric field: 1000V, the flow velocity 2ml/min of decentralized photo liquid makes nozzle can produce even, successive drop; Splash in the continuous phase of getting 2%PVA17-50 aqueous solution 200ml middling speed magnetic agitation 1h, low speed magnetic agitation 4h then; Decompression promotes the organic solvent performance, centrifugal collection microsphere, and washing, vacuum drying promptly get.
Embodiment 3: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
The about 300mg of precision weighing galantamine base, the about 1000mg of PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) adds in the 10ml dichloromethane, and vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere.Technological parameter is following: the aperture 50 μ m of nozzle, frequency of vibration 2000Hz, voltage of electric field: 1500V; The flow velocity 1ml/min of decentralized photo liquid makes nozzle can produce even, successive drop, splashes in the continuous phase of getting 1.0%PVA17-88 aqueous solution 200ml; Middling speed magnetic agitation 1h, low speed magnetic agitation 4h then, decompression promotes the organic solvent performance; Centrifugal collection microsphere, washing, vacuum drying promptly get.
The microscopic examination photo of the microsphere of embodiment 3 preparations is seen Figure of description 1, and is visible by figure, adopts vibrating nozzle legal system of the present invention to be equipped with the galantamine microsphere, can effectively control the microspherulite diameter size, distributes and concentrates, and microspherulite diameter concentrates on 75～150 μ m.
Embodiment 4: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
The about 550mg of precision weighing galantamine base, the about 1000mg of PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) adds in the 5ml acetone, and vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere, technological parameter is following: the aperture 25 μ m of nozzle, frequency of vibration 3000Hz; Voltage of electric field: 500V, the flow velocity 1ml/min of decentralized photo liquid makes nozzle can produce even, successive drop; Splash in the continuous phase of getting 0.5%PVA17-88 aqueous solution 200ml middling speed magnetic agitation 1h, low speed magnetic agitation 4h then; Decompression promotes the organic solvent performance, centrifugal collection microsphere, and washing, vacuum drying promptly get.
Embodiment 5: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
The about 750mg of precision weighing galantamine base, the about 1000mg of PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) adds in the 10ml ethyl acetate, and vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere, technological parameter is following: the aperture 50 μ m of nozzle, frequency of vibration 5000Hz; Voltage of electric field: 1000V, the flow velocity 1ml/min of decentralized photo liquid makes nozzle can produce even, successive drop; Splash in the continuous phase of getting 0.5%PVA17-88 aqueous solution 200ml middling speed magnetic agitation 1h, low speed magnetic agitation 4h then; Decompression promotes the organic solvent performance, centrifugal collection microsphere, and washing, vacuum drying promptly get.
Embodiment 6: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
Precision weighing galantamine base 130 about mg, the about 1000mg of PLGA (monomer ratio LA: GA 75: 25, molecular weight 15000) add in the 2ml organic solvent (dichloromethane 1ml, acetone are 1ml), and vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere, technological parameter is following: the aperture 50 μ m of nozzle, frequency of vibration 3000Hz; Voltage of electric field: 1000V, the flow velocity 0.5ml/min of decentralized photo liquid makes nozzle can produce even, successive drop; Splash in the continuous phase of getting 5%PVA17-88 aqueous solution 300ml middling speed magnetic agitation 1h, low speed magnetic agitation 4h then; Decompression promotes the organic solvent performance, and centrifugal collection microsphere is washed, is drying to obtain.
Embodiment 7: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
Precision weighing galantamine base 300 about mg, the about 1000mg of PLGA (monomer ratio LA: GA 75: 25, molecular weight 15000) adds in the 10ml dichloromethane, and vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere, technological parameter is following: the aperture 50 μ m of nozzle, frequency of vibration 3000Hz; Voltage of electric field: 1500V, the flow velocity 1ml/min of decentralized photo liquid makes nozzle can produce even, successive drop; Splash in the continuous phase of getting 1%PVA05-88 aqueous solution 300ml middling speed magnetic agitation 1h, low speed magnetic agitation 4h then; Decompression promotes the organic solvent performance, and centrifugal collection microsphere is washed, is drying to obtain.
Embodiment 8: the vibrating nozzle legal system is equipped with galantamine PLGA microsphere.
Precision weighing galantamine base 550 about mg, and the about 1000mg of PLGA (monomer ratio LA: GA75: 25, molecular weight 15000) add in the 5ml dichloromethane, vortex makes its dissolving fully, makes decentralized photo.Decentralized photo is transferred in the 20ml glass syringe.Adopt the vibrating nozzle method to combine emulsion process (O/W)-solvent evaporation method to prepare microsphere, technological parameter is following: the aperture 25 μ m of nozzle, frequency of vibration 2000Hz; Voltage of electric field: 500V, the flow velocity 1ml/min of decentralized photo liquid makes nozzle can produce even, successive drop; Splash in the continuous phase of getting 2%PVA17-88 aqueous solution 300ml middling speed magnetic agitation 1h, low speed magnetic agitation 4h then; Decompression promotes the organic solvent performance, and centrifugal collection microsphere is washed, is drying to obtain.
Embodiment 9: the preparation of galanthamine long-acting release micro-balloon injection (slow release cycle two weeks).
Prescription is formed: (with 100 radiacmeters)
Galantamine base 15g
PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) 50g
Mannitol 20g sodium carboxymethyl cellulose 1.5g
Sodium chloride 1.5g Tween 80 0.5g
Preparation technology: prepare microsphere according to embodiment 3 said methods.Mannitol, sodium carboxymethyl cellulose, sodium chloride and Tween 80 are dissolved with sterilized water for injection, and antibacterial and impurity in the reagent are removed in 0.22 μ m microporous filter membrane aseptic filtration, as the suspensoid substrate of micro-balloon injection.Microsphere is suspended in the suspensoid substrate, stirs, promptly get the microsphere suspensoid.This suspensoid is sub-packed under stirring condition in the 10ml cillin bottle, simultaneously freezing rapidly, the sample that freezes is placed freezer dryer, add the lyophilizing plug, lyophilization 72h, moisture meets the requirements, and the aluminium lid sealing promptly gets final finished.
Embodiment 10: the preparation of galanthamine long-acting release micro-balloon injection (slow release cycle two weeks).
Prescription is formed: (with 100 radiacmeters)
Galantamine base 15g
PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) 50g
Trehalose 25g sodium carboxymethyl cellulose 1.5g
Sodium chloride 2g Tween 80 0.5g
Preparation technology: prepare microsphere according to embodiment 3 said methods.Mannitol, sodium carboxymethyl cellulose, sodium chloride and Tween 80 are dissolved with sterilized water for injection, and antibacterial and impurity in the reagent are removed in 0.22 μ m microporous filter membrane aseptic filtration, as the suspensoid substrate of micro-balloon injection.Microsphere is suspended in the suspensoid substrate, stirs, promptly get the microsphere suspensoid.This suspensoid is sub-packed under stirring condition in the 10ml cillin bottle, simultaneously freezing rapidly, the sample that freezes is placed freezer dryer, add the lyophilizing plug, lyophilization 72h, moisture meets the requirements, and the aluminium lid sealing promptly gets final finished.
Embodiment 11: the preparation of galanthamine long-acting release micro-balloon injection (slow release cycle two weeks).
Prescription is formed: (with 100 radiacmeters)
Galantamine base 15g
PLGA (monomer ratio LA: GA 50: 50, molecular weight 12000) 50g
Sucrose 40g sodium carboxymethyl cellulose 5g
Sodium chloride 1.5g Tween 80 1.5g
Preparation technology: prepare microsphere according to embodiment 3 said methods.Mannitol, sodium carboxymethyl cellulose, sodium chloride and Tween 80 are dissolved with sterilized water for injection, and antibacterial and impurity in the reagent are removed in 0.22 μ m microporous filter membrane aseptic filtration, as the suspensoid substrate of micro-balloon injection.Microsphere is suspended in the suspensoid substrate, stirs, promptly get the microsphere suspensoid.This suspensoid is sub-packed under stirring condition in the 10ml cillin bottle, simultaneously freezing rapidly, the sample that freezes is placed freezer dryer, add the lyophilizing plug, lyophilization 72h, moisture meets the requirements, and the aluminium lid sealing promptly gets final finished.
Embodiment 12: the preparation of galanthamine long-acting release micro-balloon injection (1 month slow release cycle).
Prescription is formed: (with 100 radiacmeters)
Galantamine base 15g
PLGA (monomer ratio LA: GA 75: 25, molecular weight 15000) 50g
Mannitol 20g dextran 1 .5g
Sodium chloride 1.5g Tween 80 0.5g
Make each technology: prepare microsphere according to embodiment 7 said methods.Mannitol, sodium carboxymethyl cellulose, sodium chloride and Tween 80 are dissolved with sterilized water for injection, and antibacterial and impurity in the reagent are removed in 0.22 μ m microporous filter membrane aseptic filtration, as the suspensoid substrate of micro-balloon injection.Microsphere is suspended in the suspensoid substrate, stirs, promptly get the microsphere suspensoid.This suspensoid is sub-packed under stirring condition in the 10ml cillin bottle, simultaneously freezing rapidly, the sample that freezes is placed freezer dryer, add the lyophilizing plug, lyophilization 72h, moisture meets the requirements, and the aluminium lid sealing promptly gets final finished.
Embodiment 13: the preparation of galanthamine long-acting release micro-balloon injection (1 month slow release cycle).
Prescription is formed: (with 100 radiacmeters)
Galantamine base 15g
PLGA (monomer ratio LA: GA 75: 25, molecular weight 15000) 50g
Sucrose 25g sodium carboxymethyl cellulose 1.5g
Sodium chloride 1.5g Tween 80 0.5g
Preparation technology: prepare microsphere according to embodiment 7 said methods.Mannitol, sodium carboxymethyl cellulose, sodium chloride and Tween 80 are dissolved with sterilized water for injection, and antibacterial and impurity in the reagent are removed in 0.22 μ m microporous filter membrane aseptic filtration, as the suspensoid substrate of micro-balloon injection.Microsphere is suspended in the suspensoid substrate, stirs, promptly get the microsphere suspensoid.This suspensoid is sub-packed under stirring condition in the 10ml cillin bottle, simultaneously freezing rapidly, the sample that freezes is placed freezer dryer, add the lyophilizing plug, lyophilization 72h, moisture meets the requirements, and the aluminium lid sealing promptly gets final finished.
Experimental example 1:HPLC-UV method is measured the drug loading and the envelop rate of galantamine microsphere.
Chromatographic condition: Shimpack ODS C
18Post (150mm * 5mm, 5 μ m); Mobile phase: methanol-water-glacial acetic acid (75: 925: 10); UV detects wavelength: 289nm; Flow velocity: 1.0ml/min; Sample size: 20 μ l.Under this chromatographic condition, the galantamine retention time is 6.7min, and number of theoretical plate is calculated as 1800 by the galantamine peak.
Content assaying method: precision takes by weighing galantamine microsphere an amount of (containing galantamine 5mg approximately) and puts in the 10ml measuring bottle, adds acetonitrile 2ml, and vortex is used methanol constant volume to dissolving, shakes up.Filter with 0.22 μ m nylon leaching film, get subsequent filtrate with 10 times of mobile phase dilutions, centrifugal (behind 17000 * g) 10min, get supernatant 20 μ l sample introductions, the HPLC method is measured content.The calculating of drug loading and envelop rate:
Drug loading (%)=(contained drug quality in the microsphere)/(gross mass of microsphere) * 100%
Envelop rate (%)=(the actual drug loading of microsphere)/(the theoretical drug loading of microsphere) * 100%
The drug loading and the entrapment efficiency determination result of experimental result and discussion: embodiment 1～8 microsphere see table 1.Can find that by table 1 the PLGA material of two kinds of different monomers ratios does not have significant difference to drug loading, the envelop rate of galantamine.Along with the rising of theoretical drug loading, the envelop rate of microsphere reduces gradually, is reduced to 68.1% by the highest 93.2%.Theoretical medicine carrying dose is 23% o'clock, and envelop rate still can keep higher level, 86.7%, meet pharmacopeia to the envelop rate requirement in the microparticle formulation guideline.
The drug loading and the entrapment efficiency determination of table 1 galanthamine long-acting release microsphere
| Sample | PLGA (LA: GA) monomer ratio | Theoretical drug loading (%) | Actual drug loading (%) | Envelop rate (%) |
| Embodiment 1 | 50∶50 | 5.40 | 5.03 | 93.2 |
| |
50∶50 | 11.49 | 10.05 | 87.5 |
| Embodiment 3 | 50∶50 | 23.13 | 20.05 | 86.7 |
| |
50∶50 | 34.71 | 26.52 | 76.4 |
| |
50∶50 | 42.63 | 29.11 | 68.3 |
| |
75∶25 | 11.79 | 10.39 | 88.1 |
| Embodiment 7 | 75∶25 | 23.19 | 19.92 | 85.9 |
| |
75∶25 | 35.32 | 26.38 | 74.7 |
Experimental example 2: the outer release test of the microsphere of galantamine microsphere.
Experimental technique: precision takes by weighing galantamine microsphere an amount of (containing galantamine 10mg approximately), puts in the bag filter, adds 0.01mol/L physiology isotonic phosphate buffer liquid (pH7.4; Containing 0.02%NaN3,0.1% Tween 80) 0.5ml is with dispersion microsphere, then bag filter put among 0.01mol/L physiology isotonic phosphate buffer liquid (pH7.4) 50ml; In 37 ℃ of constant temperature shaking tables, 50 times/min, jolting is apart from 4cm/ time; Regularly change whole media; Discharge liquid through 0.22 μ m filtering with microporous membrane, get subsequent filtrate 20 μ l sample introductions and measure, the HPLC-UV method is measured dissolution medium Chinese medicine content.
The external release curve of experimental result and discussion: embodiment 3 said microspheres is seen Figure of description 2, and visible by figure, the microsphere release in vitro of embodiment 3 is comparatively constant; 1d discharges 10.1%, the not prominent phenomenon of releasing, and 7d discharges 52.3%; 14d discharges 92.1%, and the sustainable release of microsphere reaches 14d.The release curve is seen accompanying drawing 3 in the body of embodiment 7 said microspheres, and visible by figure, the microsphere release in vitro of embodiment 7 is comparatively constant, and 1d discharges 8.3%, the not prominent phenomenon of releasing, and 14d discharges 45.1%, and 28d discharges 89.6%, and the sustainable release of microsphere reaches 30d.
Experimental example 3: release test in the microsphere of galantamine microsphere.
Test objective: investigate said preparation release performance in animal body.
Test specimen: according to the galanthamine long-acting release microsphere of the embodiment of the invention 3 and 7 described method preparations.
Experimental animal: the SD rat, 36, male and female half and half are divided into 6 groups at random, 6 every group.
Test method: it is subcutaneous that the galantamine microsphere is injected rat abdomen, carefully cuts the microsphere and the muscular tissue of injection site in different time intervals, measures residual dose behind the homogenization, reflects drug release rate in the body of microsphere indirectly.Precision takes by weighing microsphere and puts in right amount in the ampoule, with the sterilized water for injection solution suspendible that contains 0.5% carmethose and 0.1% Tween 80.Every rat is in abdominal part hypodermic 0.5ml (being equivalent to 12mg).With remaining microsphere in an amount of acetonitrile dissolving syringe and the ampoule, measure remaining dose simultaneously, calculate actual dosage.
Sampling method and time point: rat is steam again and raises, and respectively at d1,3,5,7,10,14 behind the injectable microsphere (embodiment 3 described microspheres), d1,7,14,21,35 (embodiment 7 said microspheres) puts to death 1 group; Cut the epidermis of injection site open, carefully take off microsphere and surrounding tissue, thinly slice after freezing; Put in the glass homogenizer, add acetonitrile-water (9: 1) 2ml, grind 5min repeatedly; Be diluted to 10ml with mobile phase, the vortex mixing, centrifugal (behind 17000 * g) 10min; Get supernatant 50 μ l sample introductions, the content of galantamine in the HPLC-UV method working sample.
The release curve is seen Figure of description 4 in the body of experimental result and discussion: embodiment 3 described microspheres.Visible by figure, discharge comparatively constantly in the body of embodiment 3 described microspheres, 1d discharges 12.1%, and 7d discharges 58.3%, and 14d discharges 94.7% and has almost released whole medicines with the drug release rate of every day 6.6%.This release pattern and the cycle galantamine slow releasing injection as the slow release two weeks is more rational.The release curve is seen Figure of description 5 in the body of embodiment 7 described microspheres.Visible by figure, the interior release of the body of embodiment 7 described microspheres is comparatively constant, and 1d discharges 10.4%, does not significantly dash forward and releases phenomenon.14d discharges 52.1%, and 28d discharges 86.1%.Drug release rate with every day 3.1% has almost been released whole medicines.This release pattern and cycle are more rational as one month injection of galantamine slow release.
Experimental example 4: galanthamine long-acting release injectable microsphere pharmacodynamic experiment.
Experiment purpose: rat memory acquisition disturbance modelling verification galanthamine long-acting release injectable microsphere improves the learning and memory effect to rat due to the employing scopolamine.
Laboratory animal: 40 of SD rats, male and female are not limit.
Medicine and instrument: scopolamine hydrobromide injection (Shanghai Hefeng Pharmaceutical Co., Ltd., specification: 0.3mg:1ml); Galanthamine hydrobromide injection (Shanghai Xudong Hipu Medicine Co., Ltd, specification: 1mg:1ml); Galanthamine long-acting release micro-balloon injection (embodiment 3, the actual drug loading 20.05% of microsphere).
Experimental technique:
The foundation of Morris water maze method: adopt literature method (Duan Xin, Ma Guangyu. naloxone and galantamine are to the intervention effect [J] of rat space working memory obstacle due to the scopolamine. Chinese clinical rehabilitation, 2005; 9 (16): the 110-111. section is new, Ma Guangyu. and naloxone improves the neuromechanism research [J] of rat space working memory obstacle due to the scopolamine. mental sickness and mental health, 2004; 4 (6): 413-413.).Through training every rat performance to appear stable.
Medication: the SD rat is divided into normal control group, scopolamine group, galantamine injection group treatment group, galanthamine long-acting release injectable microsphere treatment group at random.Every group 10.
Dosage and route of administration: scopolamine is pressed 0.4mg/kg, intraperitoneal injection, and be administered once every day, successive administration 14 days; The galantamine injection is pressed 2mg/kg, intraperitoneal injection, and be administered once every day, successive administration 14 days; The normal control group gives the equal-volume normal saline, and be administered once every day, successive administration 14 days; Galanthamine long-acting release injectable microsphere is pressed 28mg/kg, the smart microsphere of claiming, and the suspensoid suspendible, the abdominal part hypodermic administration is in 0d administration 1 time.
Experimental record and MAIN OUTCOME MEASURES: in 1d, 7d, 14d, 16d, the escape latency of every rat is write down in the operation of beginning water maze delay coupling after the 20d administration, and data t inspection statistics is analyzed.
Experimental result: the result shows; To in by the rat memory acquisition disturbance model test due to the scopolamine; The galanthamine long-acting release micro-balloon injection has significant curative effect to rat memory acquisition disturbance model; Efficacy strength and conventional galantamine injection (same dose, be administered once every day) are suitable.Galanthamine long-acting release micro-balloon injection administration 1d is a produce effects, and this effect can be maintained until 16d, and the 20d effect disappears.Results of pharmacodynamic test shows that the galanthamine long-acting release injectable agent has tangible medicament slow release, drug effect long-acting.
Claims (8)
1. a galantamine microsphere is characterized in that, comprises galantamine base that accounts for microsphere gross weight 5-40% and the polylactic acid/hydroxy acetate multipolymer that accounts for total microsphere gross weight 60-95%; Microspherulite diameter is 25-200 μ m; The mol ratio of lactic acid and hydroxyacetic acid is 30 in the said polylactic acid/hydroxy acetate multipolymer: 70-70: 30; The molecular weight of said polylactic acid/hydroxy acetate multipolymer is 5000-50000 dalton.
2. galantamine microsphere according to claim 1 is characterized in that, microspherulite diameter is 50-150 μ m.
3. galantamine microsphere according to claim 1 is characterized in that, the molecular weight of said polylactic acid/hydroxy acetate multipolymer is 10000-30000 dalton.
4. galantamine microsphere according to claim 1 is characterized in that, the end group of said polylactic acid/hydroxy acetate multipolymer is-the COOH group.
5. a galanthamine long-acting release injectable microsphere composite is characterized in that, component and weight percentage are: galantamine microsphere 60-90% as claimed in claim 1; Lyophilizing proppant 5-25%; Suspending agent 0.5-5%, wetting agent 0.5-5%, osmotic pressure regulator 1-25%; Said lyophilizing proppant is a kind of in mannitol, sucrose, trehalose, the lactose and more than one; Said suspending agent is a kind of in sodium carboxymethyl cellulose, hypromellose, dextran, hetastarch, the polyvinylpyrrolidone and more than one.
6. galanthamine long-acting release injectable microsphere composite according to claim 5 is characterized in that, said wetting agent is a Tween 80, and said osmotic pressure regulator is a sodium chloride.
7. the method for preparing of the arbitrary said galanthamine long-acting release injectable microsphere composite of claim 5-6 is characterized in that, comprises following two steps: the preparation of galantamine microsphere and the preparation of lyophilized injectable powder:
The preparation of said galantamine microsphere: adopt the vibrating nozzle method to combine emulsion process-solvent evaporation method, step is following: galantamine base, polylactic acid/hydroxy acetate multipolymer are dissolved in organic solvent, as decentralized photo; Adopting diameter is 25 or 50 μ m nozzles, frequency of vibration 2000-5000Hz, voltage of electric field 500-1500V; The concentration 0.05-0.5g/ml of polylactic acid/hydroxy acetate multipolymer forms symmetrical liquid drop with decentralized photo in the decentralized photo, is added drop-wise in the polyvinyl alcohol water solution that concentration is 0.1-5wt%; Emulsifying is condensed into microsphere, after microsphere solidifies; Isolate the galantamine microsphere, washing;
The preparation of said freeze-dried powder: suspending agent, lyophilizing proppant, osmotic pressure regulator, wetting agent are dissolved with sterilized water for injection, and antibacterial and the impurity in the reagent is removed in aseptic filtration, as the suspensoid medium of micro-balloon injection; The galantamine microsphere of preparation is suspended in the suspensoid medium; Stir, promptly get the microsphere suspensoid, the settling ratio 15min of suspensoid is greater than 0.8; This suspensoid is sub-packed in the cillin bottle under stirring condition; Lyophilization rapidly, moisture is controlled at 0.1-5wt%, promptly gets final finished.
8. the described method for preparing of claim 7 is characterized in that, is in dichloromethane, ethyl acetate, the acetone one or more at organic solvent described in the preparation of galantamine microsphere.
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| CN103622971B (en) * | 2013-12-16 | 2016-02-17 | 中国药科大学 | A kind of medical composition and its use being used for the treatment of and/or preventing Alzheimer |
| CN107320770A (en) * | 2017-07-12 | 2017-11-07 | 江苏西宏生物医药有限公司 | One kind injection implant |
| CN108096212B (en) * | 2017-12-25 | 2020-06-09 | 河北科技大学 | Preparation method of drug microspheres with hydroxyethyl starch 200/0.5 as carrier |
| CN112823792B (en) * | 2019-11-20 | 2023-07-14 | 鲁南制药集团股份有限公司 | Sustained release microsphere of galanthamine pamoate for injection and preparation method thereof |
| CN113384536B (en) * | 2020-03-14 | 2024-04-02 | 鲁南制药集团股份有限公司 | Sustained release galanthamine pamoate particles for injection and preparation method thereof |
| CN111728957B (en) * | 2020-07-06 | 2022-04-19 | 济南大学 | Tolterodine long-acting sustained-release microsphere and preparation method thereof |
| CN111643483B (en) * | 2020-07-06 | 2022-03-29 | 济南大学 | Method for preparing galanthamine sustained-release microspheres |
| CN113440597A (en) * | 2021-07-02 | 2021-09-28 | 山东谷雨春生物科技有限公司 | Method for preparing leuprorelin microspheres |
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