CN102697726A - Liposome combined medicament of alprostadil and like and large-scale industrial production technology and application thereof - Google Patents

Liposome combined medicament of alprostadil and like and large-scale industrial production technology and application thereof Download PDF

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CN102697726A
CN102697726A CN2011102121399A CN201110212139A CN102697726A CN 102697726 A CN102697726 A CN 102697726A CN 2011102121399 A CN2011102121399 A CN 2011102121399A CN 201110212139 A CN201110212139 A CN 201110212139A CN 102697726 A CN102697726 A CN 102697726A
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蔡海德
***
刘会梅
张连印
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Abstract

The invention relates to a liposome combined medicament of alprostadil and the like, large-scale industrial production technology and applications thereof, and is characterized in that a raw material molar ratio of components of the liposome combined medicament of alprostadil and the like of the invention is disclosed; the invention also provides a large-scale industrial preparation method of the liposome combined medicament, which is characterized in that according to pharmaceutically-allowable dosages, freeze-dried injection, or oral preparations, or sprays, or suppositories of the liposome combined medicament of alprostadil and the like are prepared; the liposome combined medicament of alprostadil and the like is characterized in that the applications comprise virus resistance, tumor resistance, angina resistance, and blood pressure reduction.

Description

Liposome composite medicine and big industrialized producing technology and purposes such as Alprostadil
The application is for enjoying the domestic priority application.Formerly applicant country is a China, is 201010240184.0 at the application number of first to file, and the applying date is on 07 29th, 2010, and name is called " dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine ".
Technical field
The present invention relates to a kind of big suitability for industrialized production liposome composite medicine method for preparing; It is characterized in that; Subject matter is with dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze-drying; With unified prescription, technology, equipment both suitability for industrialized production liposomal body composition injection greatly, suitability for industrialized production liposomal body composition oral preparation greatly again.
Background technology
China's pharmaceutical technology, crude drug technology of preparing and international most advanced level gap be only in 5 years, and what have meets or exceeds international most advanced level, and preparation technique will fall behind international most advanced level 20 years.Existing a large amount of be to produce secondary ordinary preparation, and three generations's slow release, controlled release agent, especially four generation targeting preparation such as liposome only be in the laboratory research stage at present.Reason has:
1, existingly produce, scientific research prepares liposome medicament technology injection and oral formulations prescription, technology, equipment disunity, both wasted resource, the energy, investment is greatly, and is of low quality again, contaminated environment.
2, the method for liposome medicament suitability for industrialized production is had: high pressure homogenization method, supercritical ultrasonics technology, organic solvent seasoning, spray drying method, fluidized bed coating, single phase soln freeze-drying.High pressure homogenization method and supercritical ultrasonics technology particle diameter are controlled, but high energy is broken, and crude drug is had destruction; The four kinds of methods in back to particle diameter uncontrollable and particle size distribution do not concentrate, organic solvent residual has quality problems such as leakage, deposition, cohesion, phospholipid corruption;
3, existing method for preparing lipidosome makes the envelop rate of lipidosome drug carrier can not reach 100%, and each batch fluctuation, variation are greatly; Slip is big, loses the liposome medicament meaning;
4, production process is turned from side to side manyly, and during energy charge, equipment investment is big, and prescription, technology be unstable to be leaned on, immature, causes that the quality of the pharmaceutical preparations is uncontrollable, unstable, poor reproducibility;
5, sterilization, depyrogenation method are improper, and omnidistance aseptic, apyrogeneity operation is difficult to ensure, liposome medicament is lacked the height aseptic concept; Cause liposome medicament corrupt under antibacterial corrodes, envelop rate falls progressively, and slip increases progressively; Effect duration is extremely short, almost loses medical value;
6, injection indissolubility population and particle diameter exceed standard;
7, crude drug, phospholipid and adjuvant, solvent selection do not have the national drug quality standard mostly, have patent to criticize not New Drug Certificate and production certification yet, and the registration difficulty is very big, chronic;
8, break away from Chinese truth, obtain liposome new drug production certification, spend nearly 10 years from developing to, expensive more than 2,000 ten thousand yuan, good again medicine patent of invention, exhausted big multiple enterprises dare not be invested and developed.It is thus clear that; Carry out medical reform and national system for basic pharmaceutical period in country; From get into the secondary preparation of national essential drugs, select the big product of sales volume to rise to the Liposomal formulation in the 4th generation, carry out the preparation technique innovation, eliminate its side effect and untoward reaction; The medicine sales volume is big like this, and the investment recovery time is short.Reach safety, effectively, high-quality, economic this basic principle.
Summary of the invention
The present invention seeks to overcome the defective of above-mentioned prior art.Theme of the present invention is: with dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze-drying; With unified prescription, technology, equipment both suitability for industrialized production liposomal body composition injection greatly, suitability for industrialized production liposomal body composition oral preparation greatly again.The standard prescription and the normalized process for preparing of dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-lyophilization suitability for industrialized production liposome composite medicine are provided.Form secondary pharmaceutical preparation innovation rise to four generation targeting preparation.
The present invention realizes through following technical scheme:
The each component feed molar number of the standard of suitability for industrialized production liposome composite medicine of the present invention is such as following:
Figure BSA00000545503400021
Said crude drug is strong fat-soluble strong or water solublity powerful feature, and prescription dosage is 1/3rd to 1/5th of the oral or injection preparation minimum gauge amount of formulation of existing secondary correspondence.Preferably: Alprostadil and 1: 30 compositions of indapamide mole ratio, or CEFUROXIME AXETIL and 2500: 1 compositions of Alprostadil mole ratio, or fluconazol; Or voriconazole, or sorbide nitrate, or ribavirin and 1: 1 compositions of cefadroxil mole ratio; Or paclitaxel and 333: 1 compositions of Alprostadil molal quantity, or clindamycin phosphate, or ganciclovir; Or noroxylin, or tanshinone IIA, or prostaglandin A 1, or meropenem, or pioglitazone, or rosiglitazone, or simvastatin; Or cytosine arabinoside, or hydroxy camptothecin, or sodium nitroprusside, or valaciclovir; Or doxorubicin, or etoposide, or adefovir ester, or ribavirin and 1000: 1 compositionss of Alprostadil weight ratio; Or ligustrazine microcosmic salt or Pazufloxacin Mesilate, or cefpiramide sodium, or mitoxantrone, or Ondansetron Hydrochloride.
The mean molecule quantity of said phospholipid raw material all defines with 800D and calculates, and the phospholipid raw material is the compositions of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine, and mole ratio is 1-5: 0.5 compositions.
The antioxidant of said phospholipid is reduced glutathion.
Said immobilized artificial membrane molecular state diluent is again an antioxidant, is dimercaprol.
Said liposome medicine carrying body dispersant is again an excipient, is xylitol.
Said surfactant is a sodium dehydrocholate.
The each component raw material of liposome composite medicine all should have national standard, and all is the national standard of pharmaceutical injection agent level.Both met national GMP standard, met the regulation of country's " medicine registration management way " again, in order to industrialization development.
The present invention also provides the normalized process for preparing of said group of plastid composition of medicine:
1, in dissolving tank; The xylitol dosage is dissolved into 10% percentage by weight solution of xylitol in the injection phosphorus phthalate buffer; With this solution 121 ℃ of steam sterilizations 20 minutes, when solution temperature is 20-25 ℃, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D; Remove pyrogen and pyrogen molecule fragment in the solution, get the solution that ultrafiltration obtains; Again at room temperature; The solution that the five equilibrium ultrafiltration obtains; Be divided into A, B solution, A, B solution used the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8% respectively, with A, B solution respectively through the membrane filtration mistake in the following aperture of 0.05 μ m; Remove the precipitate of insoluble particle, high volence metal ion, metal ion, use 8% analytically pure hydrochloric acid solution adjust pH to be 5.0-8.0 respectively A, B solution again.If the crude drug that water solublity is strong is complete with an amount of water for injection dissolving; With the membrane ultrafiltration of molecular cut off 1000D, depyrogenation, gained ultrafiltration solution merges in the B solution and stirs; The following membrane filtration mistake through 0.05 μ m aperture is removed bacterium in the raw material medicine solution, insoluble particle again.The raw material medicinal liquid requires check pyrogen and qualified could the permission of insoluble particle to add in the B solution.If fat-soluble crude drug dissolving is then handled by following the 3rd step.
2, with A solution in the spray dryer of preparation pharmaceutical injection agent level; By the spray drying well-established law; A solution is by mixing ejection with 100 grades of compressed airs of cleanliness factor (being come room temperature by compressor) in the spraying nozzle at equipment top, and 150 ℃ of-190 ℃ of 100 grades of pure airs of temperature that get into device bottom (are attracted by air-introduced machine; High temperature) gas-liquid counter current mixes, and is spray dried to 120-150 order left and right sides porous granule dry powder.Drying finishes, and it is subsequent use that dried material leaves this device bottom in.
3, it is complete to add fat-soluble crude drug, phospholipid, phospholipid dispersant stirring and dissolving in the ethanol respectively; Process proportion at 1.0 to 1.2 solution; Through the membrane ultrafiltration of molecular cut off 1000D, the membrane filtration mistake through the following aperture of 0.05 μ m is removed pyrogen, antibacterial, insoluble particle again.
4, with the composition dries granule of the A solution of the 2nd step preparation, be put in the boiling coating machine, by boiling coating and the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume with the preparation of the 3rd step divides three parts earlier.Device bottom change into introduce anhydrous, aseptic, do not have oil, do not have the room temperature purity nitrogen air-flow of the particle of the above particle diameter of 0.001 μ m, under 40 ℃ of-65 ℃ of temperature, the dry thing particle of xylose that the 2nd step the was made coating under the fluidized state that seethes with excitement: earlier with (1/3rd volumes) phospholipid alcoholic solution of first part; Being transported in the coating nozzle at equipment middle part with clean rank through compression by pump is that 100 grades of pure nitrogen gas mix; Be spray form and be sprayed onto the thick that boiling is highly flowed for 400mm-450mm material (xylitol) in the machine, at boiling material particle surface coating, the mixed equably and dispersion of the material simultaneous altitude under the boiling; And make solvent evaporates as quick as thought; Form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide is accomplished, airpillow-dry 15 minutes; Again with three parts of the B solution of first step preparation also five equilibrium; With 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, do not have oil, do not have in 100 grades of purity nitrogen air-flows of particle of the above particle diameter of 0.001 μ m, press the aforesaid operations coating, behind the coating; Airpillow-dry 20 minutes has carried out coating-drying process for the first time like this; Repeat above-mentioned coating-drying process, the solution that carries out second part, the 3rd part 1/3rd volumes of two kinds of solution of second, third time respectively carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.The outermost layer coatings is the dry thing layer of xylitol micropore, or the dry thing layer of micropore of the compositions of water-soluble crude drug, xylitol, for the third time behind the coating, and residual moisture content≤1.0% in the coating dried material that obtains, residual dimercaprol≤0.2%.Note,, do not contain crude drug in its alcoholic solution if water miscible crude drug then is crude drug and xylitol three coatings of dried particles to A solution in B solution.
5, in material-compound tank, add the isopyknic water for injection of using with the first step of injection phosphorus acid salt solution, inflated with nitrogen maintains an equal level with jar external pressure in jar, under 100 rev/mins of mixing speeds, is heated to 60 ± 5 ℃; Transferring speed of agitator is 500-700 rev/min, and under the inflated with nitrogen, the dry thing of the coating that in 30 minutes to 60 minutes, made for the 4th step joins in the material-compound tank in jar; After adding the dry thing of coating, in jar, under the inflated with nitrogen environment, keep 60 ± 5 ℃ of temperature, and under 100 rev/mins of stirrings, kept 60-120 minute; Under 100 rev/mins of stirrings, be cooled to 30-40 ℃ to a jar inner liquid medicine again; Under 100 rev/mins of stirrings, add the dissolving of antioxidant glutathion and sodium dehydrocholate respectively fully again, and adjustment medicinal liquid pH value 5.0-8.0.
6, hold temperature in 30 ± 5 ℃ of scopes at guarantor's medicinal liquid, under the 0.1-0.2Mpa nitrogen pressure, cross the medicinal liquid that the 5th step made, get filterable medicinal liquid, obtain the liposome medicinal liquid of particle diameter less than 150nm with 0.15 μ m membrane filtration.The dosage packing liposomal body liquid of pressing this medicine of pharmaceutics permission is in cillin bottle, and the false add plug, well-established law lyophilization in the freeze drying box of lyophilization unit.To medicine solid residue moisture be less than 2%, the dimercaprol residual quantity is less than 0.2%.Lid is rolled in the vacuum tamponade, and laggard storehouse is up to the standards.Process the lyophilized injection of the nanometer particle size of liposome medicine carrying body.This lyophilized injection also can be made into aseptic spray.
7, under 100 grades of aseptic ranks; The lipid drug particles that the 6th step was held back on the filterable filter membrane greater than 150nm wash 10% by in the operation sterilization of the 1st step, freshly prepd 10% xylitol solution of depyrogenation; Measure the content of total phospholipids raw material in the medicinal liquid; And, reach in the control medicinal liquid total phospholipids content at 40-80mg/ml with the qualified freshly prepd 10% xylitol solution adjustment of sterilization depyrogenation medicine liquid volume; Join this medicinal liquid during another batching irritates, under nitrogen, 100 rev/mins of mixing speeds, 30-60 minute internal heating to 50 ± 5 ℃ keep this temperature range to stir 60-120 minute; Keep again under nitrogen, 100 rev/mins of rotating speeds, the cooling medicinal liquid installs to the medicinal liquid branch in the rustless steel pallet of 316L to 20-25 ℃, is put in the freeze drying box of another lyophilizing unit, the well-established law lyophilization, moisture is less than 2% to the medical solid.The dimercaprol residual quantity is less than 0.2%.Obtain the liposome medicament solid, under 100 grades of aseptic ranks, be crushed to the 80-100 order to the liposome medicament solid, press the dosage that pharmaceutics allows, well-established law is processed the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
8, all operations all should carry out in strict accordance with the aseptic requirement of injection in the national GMP standard.Oral formulations also must be undertaken by the aseptic requirement of injection.
Liposome medicament of the present invention; Aseptic freeze-dried injection in use; When using the dissolving of transfusion aquation in the cillin bottle; The phospholipid dispersant disperses liposome medicine carrying body rapidly, and under xylitol liquid surface tension and Action of Surfactant, forms the liposome medicine carrying particle dispersed system of particle diameter 50nm-150nm scope single chamber nanometer particle size; Oral formulations forms 150-1000nm particle diameter particle at enteral.Envelop rate is all 100%.Liposome medicine carrying body is dispersed in the transfusion 6 hours internal leakage rates below 5%, does not precipitate, does not condense, not stratified, is uniformly dispersed.In gastrointestinal fluid, disperse to form single chamber and multicell mixing liposome medicament behind the drug oral of the present invention, improve the therapeutic index of medicine.
Advantage of the present invention has:
1, with unified prescription, technology, equipment both suitability for industrialized production liposomal body composition injection greatly, suitability for industrialized production liposomal body composition oral preparation greatly again.
2, with the innovative combination of innovation of the equipment of secondary preparation and secondary preparation process prepare four generation targeting preparation, make mysterious liposome medicament from laboratory implementation industrialization steady production.Standard prescription, the normalized process for preparing of liposome composite medicine have been opened up; And be that injection, oral formulations, other route of administration preparation have unified core prescription and method for preparing; In cheap apparatus, produce; Greatly save Factory Building, equipment, manpower, time, the energy, also can realize zero emission.
3, the present invention focuses on theory innovation and brings innovative technology to break through: with safety, effectively, high-quality, economic this basic principle; The invention medicine all is high request ground from the beginning of selecting materials, to the preparation process, to using final liposome medicament to be distributed to the transfusion omnidistance aseptic, pyrogen to medicine, particle diameter, particle size distribution, envelop rate, slip, corrupt rate, the rate of settling, cohesion rate, effect duration or the like, perfect meets this basic principle, make the medicine industrialization development of the present invention risk of going on the market little.
4, the medicine core technology among the present invention has: the phospholipid feed molar is counted input amount and is broken through the prior art consumption; Be 5 times of prior art consumption; Be 10 times of crude drug; And crude drug is to select fat-soluble or water solublity to be better than the medicine of dispersant xylitol, and widely greater than the envelop rate to xylitol, envelop rate reaches 100% to phospholipid to the envelop rate of medicine; Phospholipid raw material consumption is big simultaneously, has a large amount of blank liposomes, and blank liposome is engulfed the few quilt of drug-loaded liposome by macrophage phagocytic in vivo, and curative effect is higher; Surfactant is dissolved in the liposome phospholipid rete, and the liposome bilayer is played " shutoff ", reinforcement effect; This is because the surface of liposome activating agent is a sodium salt; In pH value such as dissolving normal saline and glucose were infused less than 6, its sodium salt of part became water-fast acid molecule, and gets in the phospholipid bilayer; Replace cholesterol also to play " shutoff ", reinforce the liposome particles effect; Make slip very little, surfactant also has deposition, the cohesion of lipotropism plastid in transfusion, strengthens liposome in addition and is dispersed into uniform liposome transfusion effect; Owing to add immobilized artificial membrane dispersant dimercaprol; When coating is dry; The solid-state dispersion of micropore that makes immobilized artificial membrane be molecular state replaces broken, the broken immobilized artificial membrane particle of ultrasound waves of high pressure bump, and than the broken little thousands of times of phospholipid raw material particle of high pressure bump, xylitol replaces evaporable dimercaprol position when coating; Form phospholipid and xylitol molecules attitude microporous solids dispersion, make xylitol become the dispersant of liposome; Originally discover, xylitol also with mannitol appearance have protection liposome medicine carrying body when the lyophilization not by the destructive protective effect of little ice slag, but mannitol has stimulation to blood vessel when intravenous drip; Dimercaprol is antioxidation when coating, and protection glutathion, phospholipid, crude drug are not oxidized, make glutathion play antioxidation and anti-peroxidation group usefulness in vivo, and the liver protecting are not damaged by medicine; Phospholipid material originally discovers, this saturated phospholipid of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine compositions process that liposome is stable, slip is low, and phospholipid does not have antigen and harmless to liver to human body; Lipidosome freeze-dried injection of the present invention is to have processed the lyophilization again of liposome dispersed system, when aquation again, keeps liposome physics and chemical property constant.
5, because particle diameter, the particle size distribution of above-mentioned effect medicine of the present invention in transfusion is constant; Envelop rate 100%, slip≤5%, corrupt rate are 0%, sedimentation rate is 0%, the cohesion rate is 0%; Eliminated the accumulating of liposome medicament refrigerator, content and envelop rate falls progressively, slip is risen progressively, effect duration is shorter than four big world property difficult problems of crude drug.Become satisfactorily good can be practical four generation preparation.
6, the liposome medicament of the present invention's preparation, phospholipid is to become solid solution to be scattered in the immobilized artificial membrane suction with molecularity to release in agent and the surfactant in the immobilized artificial membrane, and than supercritical ultrasonics technology, the little thousands of times of the broken phospholipid particle of high-pressure uniform matter; The volatilization of solvent and dimercaprol makes the phospholipid rete form countless micro hole layers when coating-drying; It is much bigger that this forms the RF specific surface area than freeze-drying; Because in the freeze-drying process in the solid hydrone distillation volatilization distance RF is dissolved condenses than the long thousands of times of coatings distance; Again because phospholipid rete and xylitol layer are the immobilized artificial membrane dispersant layers, rapid, high degree of dispersion phospholipid when aquation.These three kinds of advantages more stablize, more form the nanometer particle size scope to favorable reproducibility than the liposome particles particle diameter that prior art forms, and particle diameter are normal distribution.
7, composition of medicine of the present invention is because the phospholipid of choosing is natural phospholipid; Be human body and microbial cell film component; There is better targeting drug release function at pathogenic bacteria, virocyte, tumor cell and blood vessel wall destruction place, and therapeutic index is high, so the crude drug consumption only is 1/3rd to 1/5th of a secondary medicine; Add sealing of phospholipid, the untoward reaction of crude drug has not almost had.The consumption of crude drug reduces, and strengthens the phospholipid consumption, guarantees that envelop rate reaches 100%, and has " shutoff " to reinforce the surfactant of liposome effect, so slip is zero.
8, the immobilized artificial membrane dispersant of composition of medicine of the present invention is again the proppant of immobilized artificial membrane coating.Be again the material of liposome particles size when controlling the proliposome aquation jointly with surfactant, they are by due to the surface tension effects that in aqueous solution, forms certain limit.Xylitol can be ideal immobilized artificial membrane dispersant and excipient to diabetes, hepatopath's energize.
9, the immobilized artificial membrane diluent of composition of medicine of the present invention; By not only being dissolved in ethanol but also water-soluble, when spray drying, volatilize, form the micropore phospholipid rete that immobilized artificial membrane becomes the molecular state solid dispersion system; When aquation in the immobilized artificial membrane phospholipid be with the molecular state degree of crushing and and surface dispersant be distributed to phospholipid in the water; Form uniform nanoparticle liposome medicine carrying body, dimercaprol wherein is again the antioxidant of good liposome, protection phospholipid and medicine when coating.
10, the Action of Surfactant of composition of medicine of the present invention first is when the phospholipid aquation, to be distributed to phospholipid in the water; Second in the transfusion that gets into pH value 4.0-6.0; It is the molecular structure organic acid by the sodium salt acidify again; Get into again that liposome is two to be divided in the fat layer, play liposome " shutoff " reinforcement effect, the 3rd plays Action of Surfactant at surface of liposome.
11, the present invention can make liposome medicament effect duration reach 1 year, adopts four effective measures: the one, added antioxidant, protection immobilized artificial membrane and not oxidation of crude drug; The 2nd, in immobilized artificial membrane coatings outside, bag protects the phospholipid rete in phospholipid dispersant coatings; The 3rd, oral formulations also is by injection selection, sterilization and sterile working, eliminates antibacterial the corruption of phospholipid is decomposed, and this is the place of all existing liposome oral formulations and even injection technology significant error; The 4th, be scattered in the transfusion at liposome; Metal ion in 0.2% the dimercaprol complexation transfusion is arranged; Make the metal ion that brings in the transfusion can not destroy phospholipid and liposome medicine carrying body; At vitamin C-glutathion-dimercaprol combination antioxidant, under surface of liposome activating agent, dispersant combined effect, do not leak, do not precipitate, not stratified, do not condense, not oxidation, not corrupt, thereby make liposome carry that about body is real has crossed actual use value difficulty.Liposome medicine carrying body is dispersed in the transfusion, owing under the effect of defective of liposome own and transfusion, make liposome composite medicine produce qualitative change, also is the significant error part that the present invention remedies prior art.
12, liposome medicament of the present invention is in the preparation process; Phospholipid liquid and phospholipid dispersant liquid are all crossed (the injection preparation all is to cross through 0.22 μ m membrane filtration usually) through the membrane filtration below the 0.05 μ m aperture; Make the indissolubility particle diameter reduce to 1/4th of permissible value, make that particle diameter 50nm to 150nm particle is liposome particles entirely after the liposome aquation.Can accurately measure the particle diameter and the particle size distribution of liposome medicine carrying body.This also is the place that the present invention remedies the prior art significant error.
The specific embodiment:
Embodiment 1
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400081
The standard preparation process and the method for present embodiment:
1, in dissolving tank; The xylitol dosage is dissolved into 10% percentage by weight solution of xylitol in the injection phosphorus phthalate buffer; With this solution 121 ℃ of steam sterilizations 20 minutes; When solution temperature is 20-25 ℃, remove pyrogen and pyrogen molecule fragment in the solution with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D, get the solution that ultrafiltration obtains; Again at room temperature; The solution that the five equilibrium ultrafiltration obtains is A, B solution; A, B solution are used the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8% respectively; A, B solution respectively through the membrane filtration mistake in 0.05 μ m following aperture, are removed the precipitate of insoluble particle, high volence metal ion, metal ion, use 8% analytically pure hydrochloric acid solution adjust pH to be 5.0-8.0 respectively A, B solution again.Material solution requirement check pyrogen and insoluble particle are qualified.
2, with A solution in pharmaceutical injection agent level spray-type fluidized bed dryer; By the spray drying well-established law; A solution is by mixing ejection with 100 grades of compressed airs of cleanliness factor (being come room temperature by compressor) in the spraying nozzle at equipment top, and 150 ℃ of-190 ℃ of 100 grades of pure airs of temperature that get into device bottom (are attracted by air-introduced machine; High temperature) gas-liquid counter current mixes, and is spray dried to 120-150 order left and right sides porous granule dry powder.Drying finishes, and it is subsequent use that dried material leaves this device bottom in.
3, it is complete to add fat-soluble crude drug, phospholipid, phospholipid dispersant stirring and dissolving in the ethanol respectively, if the crude drug dissolving is undesirable, can in ethanol, add a spot of dichloromethane; Till crude drug dissolubility ideal; Do not add as far as possible and add methylene chloride less as far as possible, process proportion at 1.0 to 1.2 solution, through the politef material membrane ultrafiltration of molecular cut off 1000D; Titanium film filters through the following aperture of 0.05 μ m again, removes pyrogen, antibacterial, insoluble particle.
4, with the composition dries granule of the A solution of the 2nd step preparation, being put in spraying boiling coating-boiling drier, by boiling coating, the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume with the preparation of the 3rd step divides three parts earlier.Device bottom change into introduce anhydrous, aseptic, do not have oil, do not have the room temperature purity nitrogen air-flow of the particle of the above particle diameter of 0.001 μ m, under 40 ℃ of-65 ℃ of temperature, the dry thing particle of xylose that the 2nd step the was made coating under the fluidized state that seethes with excitement: earlier with (1/3rd volumes) phospholipid alcoholic solution of first part; Be transported to by pump in the coating nozzle at equipment middle part and be that 100 grades of pure nitrogen gas mix through the clean rank of compression; Spray form is sprayed onto the thick that boiling is highly flowed for 400mm-450mm material (fructose and mannitol compositions) in the machine, at boiling material particle surface coating, and the mixed equably and dispersion of the material simultaneous altitude under the boiling; And make solvent evaporates as quick as thought; Form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide is accomplished, airpillow-dry 15 minutes; Again with three parts of the B solution of first step preparation also five equilibrium; With 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, do not have oil, do not have in 100 grades of purity nitrogen air-flows of particle of the above particle diameter of 0.001 μ m, press the aforesaid operations coating, behind the coating; Airpillow-dry 20 minutes has carried out coating-drying process for the first time like this; Repeat above-mentioned coating-drying process, the solution that carries out second part, the 3rd part 1/3rd volumes of two kinds of solution of second, third time respectively carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.The outermost layer coatings is the dry thing layer of xylitol micropore; Or the dry thing layer of the micropore of the compositions of water-soluble crude drug, xylitol; For the third time behind the coating; Residual moisture content≤1.0% in the coating dried material that obtains, residual dichloromethane and ethanol are 0%, residual dimercaprol≤0.2%.
5, in material-compound tank, add the isopyknic water for injection of using with the first step of injection phosphorus acid salt solution, inflated with nitrogen maintains an equal level with jar external pressure in jar, under 100 rev/mins of mixing speeds; Be heated to 60 ± 5 ℃; Transferring speed of agitator is 500-700 rev/min, and under the inflated with nitrogen, the dry thing of the coating that in 30 minutes-60 minutes, made for the 4th step joins in the material-compound tank in jar; After adding the dry thing of coating; In jar, under the inflated with nitrogen environment, keep 60 ± 5 ℃ of temperature, and under 100 rev/mins of stirrings, kept 60-120 minute.Under 100 rev/mins of stirrings, be cooled to 30-40 ℃ to a jar inner liquid medicine again.Under 100 rev/mins of stirrings, add the dissolving of antioxidant glutathion and sodium dehydrocholate respectively fully again, and adjustment medicinal liquid pH value 5.0-8.0.
6, hold temperature in 30 ± 5 ℃ of scopes at guarantor's medicinal liquid, under the 0.1-0.2Mpa nitrogen pressure, cross the medicinal liquid that the 5th step made, get filterable medicinal liquid, obtain the liposome medicinal liquid of particle diameter less than 150nm with 0.15 μ m membrane filtration.The dosage packing liposomal body liquid of pressing this medicine of pharmaceutics permission is in cillin bottle, and the false add plug, well-established law lyophilization in the freeze drying box of lyophilization unit.To medicine solid residue moisture be less than 2%, the dimercaprol residual quantity is less than 0.2%, ethanol and dichloromethane are residual all to be 0%.Lid is rolled in the vacuum tamponade, and laggard storehouse is up to the standards.Process lyophilized injection.This lyophilized injection can be made into aseptic spray.
7, under 100 grades of aseptic ranks; The lipid drug particles that the 6th step was held back on the filterable filter membrane greater than 150nm wash 10% by in the qualified xylitol solution of the 1st step operation sterilization depyrogenation; Measure the content of total phospholipids raw material in the medicinal liquid; And, reach in the control medicinal liquid total phospholipids content at 40-80mg/ml with qualified 10% xylitol solution of sterilization depyrogenation adjustment medicine liquid volume.Join medicinal liquid in another batching filling, under nitrogen, 100 rev/mins of mixing speeds; 30-60 minute internal heating to 50 ± ℃, keep this temperature range to stir 60-120 minute, keep again under nitrogen; 100 rev/mins of rotating speeds, the cooling medicinal liquid installs to the Pharmaceutical branch in the rustless steel pallet of 316L to 20-25 ℃; Be put in the freeze drying box of another lyophilizing unit, the well-established law lyophilization, the moisture entrapment amount is less than 2% to the medical solid; The dimercaprol residual quantity is little by 0.2%, and ethanol and dichloromethane are residual to be 0%.Obtain the liposome medicament solid, the liposome medicament solid under 100 grades of aseptic ranks: be crushed to the 80-100 order, press the dosage that pharmaceutics allows, well-established law is processed the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
8, all operations all should carry out in strict accordance with the aseptic requirement of injection in the national GMP standard.Oral formulations also must be undertaken by the aseptic requirement of injection.
Embodiment 2
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400101
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 3
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400111
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 4
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400112
Figure BSA00000545503400121
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 5
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400122
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 6
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400131
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 7
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400132
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 8
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400133
Figure BSA00000545503400141
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 9
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400142
The standard preparation process of present embodiment and method are with embodiment 1.
Embodiment 10
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine standard is following:
Figure BSA00000545503400143
Figure BSA00000545503400151
The standard preparation process of present embodiment and method are with embodiment 1.
The said fat-soluble crude drug of above embodiment, or CEFUROXIME AXETIL and 2500: 1 compositions of Alprostadil mole ratio, or fluconazol, or voriconazole; Or sorbide nitrate, or ribavirin and 1: 1 compositions of cefadroxil mole ratio, or paclitaxel China fir alcohol and 333: 1 compositions of Alprostadil molal quantity; Or clindamycin phosphate, or the hydrogen artemisic succinate, or noroxylin; Or Alprostadil, or tanshinone IIA, or prostaglandin A 1, or dihomo-gamma-linolenic acid or hydroxy camptothecin, or simvastatin, or pioglitazone, or rosiglitazone, or adefovir ester, or ribavirin and 1000: 1 compositionss of Alprostadil weight ratio, or mitoxantrone.
Embodiment 11
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
The standard preparation process and the method for present embodiment:
1, in dissolving tank; The xylitol dosage is dissolved into 10% percentage by weight solution of xylitol in the injection phosphorus phthalate buffer; With this solution 121 ℃ of steam sterilizations 20 minutes; When solution temperature is 20-25 ℃, remove pyrogen and pyrogen molecule fragment in the solution with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D, get the solution that ultrafiltration obtains; Again at room temperature; The solution that the five equilibrium ultrafiltration obtains is A, B solution; A, B solution are used the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8% respectively; A, B solution respectively through the membrane filtration mistake in 0.05 μ m following aperture, are removed the precipitate of insoluble particle, high volence metal ion, metal ion, use 8% analytically pure hydrochloric acid solution adjust pH to be 5.0-8.0 respectively A, B solution again.The crude drug that water solublity is strong with the dissolving of an amount of water for injection fully, with the membrane ultrafiltration of molecular cut off 1000D, depyrogenation merges in the B solution and stirs, the following membrane filtration mistake through 0.05 μ m aperture is again removed bacterium in the crude drug, except that insoluble particle.The raw material medicinal liquid requires check pyrogen and qualified could the permission of insoluble particle to add in the B solution.
2, with A solution in preparation pharmaceutical injection agent level spray dryer; By the spray drying well-established law; A solution is by mixing ejection with 100 grades of compressed airs of cleanliness factor (being come room temperature by compressor) in the spraying nozzle at equipment top, and 150 ℃ of-190 ℃ of 100 grades of pure airs of temperature that get into device bottom (are attracted by air-introduced machine; High temperature) gas-liquid counter current mixes, and is spray dried to 120-150 order left and right sides porous granule dry powder.Drying finishes, and it is subsequent use that dried material leaves this device bottom in.
3, it is complete to add phospholipid, phospholipid dispersant stirring and dissolving in the ethanol respectively, processes proportion at 1.0 to 1.2 solution, and through the membrane ultrafiltration of molecular cut off 1000D, the membrane filtration mistake through the following aperture of 0.05 μ m is removed pyrogen, antibacterial, insoluble particle again.
4, with the composition dries granule of the A solution of the 2nd step preparation, being put in spraying boiling coating-boiling drier, by boiling coating, the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume with the preparation of the 3rd step divides three parts earlier.Device bottom change into introduce anhydrous, aseptic, do not have oil, do not have the room temperature purity nitrogen air-flow of the particle of the above particle diameter of 0.001 μ m, under 40 ℃ of-65 ℃ of temperature, the dry thing particle of xylitol that the 2nd step the was made coating under the fluidized state that seethes with excitement: earlier with (1/3rd volumes) phospholipid alcoholic solution of first part; Being transported in the coating nozzle at equipment middle part with clean rank through compression by pump is that 100 grades of pure nitrogen gas mix; Spray form is sprayed onto the thick that boiling is highly flowed for 400mm-450mm material (fructose and mannitol compositions) in the machine, at boiling material particle surface coating, and the mixed equably and dispersion of the material simultaneous altitude under the boiling; And make solvent evaporates as quick as thought; Form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide is accomplished, airpillow-dry 15 minutes; Again with three parts of the B solution of first step preparation also five equilibrium; With 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, do not have oil, do not have in 100 grades of purity nitrogen air-flows of particle of the above particle diameter of 0.001 μ m, press the aforesaid operations coating, behind the coating; Airpillow-dry 20 minutes has carried out coating-drying process for the first time like this; Repeat above-mentioned coating-drying process, the solution that carries out second part, the 3rd part 1/3rd volumes of two kinds of solution of second, third time respectively carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.The outermost layer coatings is the dry thing layer of micropore of the compositions of water-soluble crude drug, xylitol, for the third time behind the coating, and residual moisture content≤1.0% in the coating dried material that obtains, residual dimercaprol≤0.2%, the ethanol residual quantity is 0%.
5, in material-compound tank, add the isopyknic water for injection of using with the first step of injection phosphorus acid salt solution, inflated with nitrogen maintains an equal level with jar external pressure in jar, under 100 rev/mins of mixing speeds; Be heated to 60 ± 5 ℃; Transferring speed of agitator is 500-700 rev/min, and under the inflated with nitrogen, the dry thing of the coating that in 30 minutes-60 minutes, made for the 4th step joins in the material-compound tank in jar; After adding the dry thing of coating; In jar, under the inflated with nitrogen environment, keep 60 ± 5 ℃ of temperature, and under 100 rev/mins of stirrings, kept 60-120 minute.Under 100 rev/mins of stirrings, be cooled to 30-40 ℃ to a jar inner liquid medicine again.Under 100 rev/mins of stirrings, add the dissolving of antioxidant reduced glutathion and sodium dehydrocholate respectively fully again, and adjustment medicinal liquid pH value 5.0-8.0.
6, keeping fluid temperature in 30 ± 5 ℃ of scopes, under the 0.1-0.2Mpa nitrogen pressure, cross the medicinal liquid that the 5th step made with 0.15 μ m membrane filtration, get filterable medicinal liquid, obtain the liposome medicinal liquid of particle diameter less than 150nm.The dosage packing liposomal body liquid of pressing this medicine of pharmaceutics permission is in cillin bottle, and the false add plug, well-established law lyophilization in the freeze drying box of lyophilization unit.To medicine solid residue moisture be less than 2%, the dimercaprol residual quantity is less than 0.2%, the ethanol residual quantity is 0%.Lid is rolled in the vacuum tamponade, and laggard storehouse is up to the standards.Process lyophilized injection.This lyophilized injection maybe can be made into aseptic spray.
7, under 100 grades of aseptic ranks; The lipid drug particles that the 6th step was held back on the filterable filter membrane greater than 150nm wash 10% by in the qualified freshly prepd xylitol solution of the 1st step operation sterilization depyrogenation; Measure the content of total phospholipids raw material in the medicinal liquid; And, reach in the control medicinal liquid total phospholipids content at 40-80mg/ml with qualified 10% xylitol solution of sterilization depyrogenation adjustment medicine liquid volume.Join medicinal liquid in another batching filling, under nitrogen, 100 rev/mins of mixing speeds; 30-60 minute internal heating to 50 ± ℃, keep this temperature range to stir 60-120 minute, keep again under nitrogen; 100 rev/mins of rotating speeds, the cooling medicinal liquid installs to the Pharmaceutical branch in the rustless steel pallet of 316L to 20-25 ℃; Be put in the freeze drying box of another lyophilization unit, the well-established law lyophilization, moisture is less than 2% to the medical solid; The dimercaprol residual quantity is 0.2%, and the ethanol residual quantity is 0%.Obtain the liposome medicament solid, under 100 grades of aseptic ranks, be crushed to the 80-100 order to the liposome medicament solid, press the dosage that pharmaceutics allows, well-established law is processed the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
8, all operations all should carry out in strict accordance with the aseptic requirement of injection in the national GMP standard.Oral formulations also must be undertaken by the aseptic requirement of injection.
Embodiment 12
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400171
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 13
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400182
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 14
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400191
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 15
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 16
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400201
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 17
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400202
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 18
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400211
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 19
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400212
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 20
Crude drug is that each material component mole ratio of the strong liposome composite medicine standard of water solublity is following:
Figure BSA00000545503400221
The standard preparation process of present embodiment and method are with embodiment 11.
Embodiment 11 to embodiment 20 said water miscible crude drug: preferred ganciclovir or cytosine arabinoside or sodium nitroprusside or valaciclovir or doxorubicin or etoposide or ligustrazine microcosmic salt or levofloxacin hydrochloride or a born of the same parents amine sodium or Ondansetron Hydrochloride or meropenem.
Technological Economy and quality index contrast
Figure BSA00000545503400231
Conclusion: the present invention's technology preparation liposome medicine carrying body and existing even matter freeze-drying, fluidized bed coating law technology system liposome medicine carrying bulk phase ratio; Technological Economy of the present invention and main quality index all are superior to even matter freeze-drying, and quality index all is superior to fluidized bed coating.
The pharmacodynamics demonstration test:
1, medicament for anti-gastric ulcer pharmacodynamics demonstration test: laboratory animal is selected the Jiankang rat, male or female, body weight 200-250g, 8 every group.Make medicament and dosage see the result of the test table.Before the experiment, rat fasting 24 hours is freely drunk water; Under etherization open the abdominal cavity, the glass tubing of internal diameter 5mm, long 30mm vertically is positioned on the body of stomach serosal surface, in tube chamber, add glacial acetic acid 0.2ml; 1.5 dip in out glacial acetic acid with cotton swab after minute, the suture operation otch.The postoperative normal diet; Set up 1 group of 1 group of blank group and positive controls in second day at random, the blank group is used normal saline administration, 0.5ml/ time; Intraperitoneal injection; Positive controls is used physiological saline solution with famotidine, gets 0.5ml/ time, and liposome medicament administration group of the present invention is established drug administration by injection, oral administration group.The liposome medicament drug administration by injection is used the physiological saline solution liposome medicament, gets 0.5ml/ time.Administration 15 days, administration every day 2 times, 12 hours are once.Be divided into drug administration by injection and oral administration.Every embodiment makes sample and connected administration respectively 3 days.After the administration 15 days, dissect and take out stomach, and use formaldehyde fixed, measure ulcer area mm 2, calculate and respectively organize average ulcer area.
The results of pharmacodynamic test table:
Figure BSA00000545503400232
It is thus clear that said medicine comparison of the present invention is high according to the positive drug curative effect.
2, anti-infectives pharmacodynamics test:
(1) animal is selected: select the mice by the infection animal experimental model of Experimental Animal Center preparation, body weight 18-22g, male and female half and half, random packet, 50 of every treated animals.
(2) infection bacteria species: staphylococcus aureus causes the model mice of pneumonia, two groups of model mice that streptococcus pneumoniae causes pneumonia.
(3) infection dosage: measure 100% minimum lethal dose (100%MLD) of the bacterial strain that tries by Experimental Animal Center, as sense
Figure BSA00000545503400241
The microbiological contamination amount.
(4) route of infection: bacterium stock solution is diluted to desired concn (Experimental Animal Center is confirmed) with 5% gastric Mucin, through tail vein injection.
(5) test method: with the mice branch: the A. staphylococcus aureus causes the model mice group of pneumonia, two groups of model mice group that the B. streptococcus pneumoniae causes pneumonia.Carry out the clindamycin phosphate for injection contrast of not administration contrast, prior art for preparing, medicine of the present invention contrast.50 of every group model animals.Quiet immediately notes administration or oral after the infection whenever was administered once at a distance from 6 hours again.Observe the reaction of animal thing, continuous 7 days, record dead mouse number.Institute's medicament and dosage, effect are seen the result of the test table:
Figure BSA00000545503400242
Figure BSA00000545503400251
3,1 myocardial ischemic antagonist pharmacodynamics demonstration test:
Select healthy mice for use, male or female, body weight 18-20g, 10 every group.Cause mouse cardiac muscle ischemia (preparing the myocardial ischemia mouse model) with isoproterenol by Experimental Animal Center.If blank and positive drug matched group.The positive control medicine is defined as nitroglycerin, and be administered once every day, administration 10 days.Carry out the double staining of ischemia or infarcted myocardium after 10 days, i.e. N-BT or TTC dyeing; Quantitative myocardial ischemia of microscopically and infarct size, calculate every cell mean and positive control cell mean and with the percent of the ratio of blank cell mean.Institute's medicament, dosage, administering mode are seen the results of pharmacodynamic test table:
Figure BSA00000545503400252
Figure BSA00000545503400261
3, the pharmacodynamics test of 2 hypotensors:
Select spontaneous hypertensive rat (SHR) for use, 10 every group, kidney angiostenosis type rat, 10 every group.Survey the control period blood pressure and the rhythm of the heart earlier, administration behind blood pressure stabilization was measured blood pressure respectively in 3 hours after preceding 2 hours of administration and the administration, and the administration phase was 2 weeks.Administration after 3 hours the back blood pressure drops above to 20mmHg be effective.Institute's medicament, dosage, medication are seen the results of pharmacodynamic test table:
Figure BSA00000545503400262
4, antitumor drug pharmacodynamics test:
Select rat kind tumor model: watt gram carcinosarcoma (W256) type.Body weight 50-70g, 10 of every treated animals.If negative control group and positive controls.Negative control group injecting normal saline, positive controls adopt sells the paclitaxel medicine at present.1 administration every day, 15 days treatment times.Drug withdrawal was put to death animal after 24 hours, dissected and peeled off the tumor piece, claimed that tumor is heavy.Calculating the therapeutic evaluation formula is:
Tumor control rate %=(C-T)/CX100%
When suppression ratio greater than 30%, effectively.
The result of the test table:
Project Tumor control rate % Remarks
Sell paclitaxel injection 50mg/kg lumbar injection at present 70
Embodiment 11-16 ifosfamide 500mg/kg lumbar injection 75
Embodiment 1-5 paclitaxel and Alprostadil 50mg/kg lumbar injection 88
Embodiment 11-15 cytosine arabinoside 2mg/kg lumbar injection 83
Embodiment 16-20 hydroxy camptothecin 8m/the kg lumbar injection 78
Embodiment 16-20 doxorubicin 20mg/kg lumbar injection 81
Embodiment 16-20 etoposide 100mg/kg lumbar injection 82
Embodiment 6-10 mitoxantrone 20mg/kg lumbar injection 78
Embodiment 11-15 Ondansetron Hydrochloride 8mg/kg lumbar injection Emesis rate 95% End the tumor guiding drug and play vomiting
Embodiment 15-20 water soluble vitamins 100mg/kg lumbar injection Effective percentage 100% The tumour patient supplementary
5, hypoglycemic medicine pharmacodynamics test: medicine of the present invention stimulates insulin secretion, so select the normal health white mice for use, 15 every group.The experiment white mice is in fasting (can freely drink water) administration after 5 hours, and be administered once every day.Administration was got blood after 2 hours, measured the serum glucose value.Connect administration 7 days.Calculate blood glucose average rate of decrease (with blank group ratio).The blood glucose rate of descent is effective greater than 20%.Institute's medicament and dosage, route of administration are seen the result of the test table:
Figure BSA00000545503400271
Figure BSA00000545503400281
6, antiviral agents pharmacodynamics test:
Mice encephalitis model: mice 11-13g body weight, male and female are regardless of, 15 every group.HSV-1 type Sm44 strain, viral lumbar injection can cause encephalitis death, calculates LD 50HSV-1 virus abdominal cavity injecting virus dosage LD successively again 01/2,1/4,1/8 dosage is each 2 days, once a day.Calculate mortality rate, average life number of days, with medication therapy groups contrast disease die protective rate, prolong vital rates.Treatment group administration 15 days, every day 2 times.Institute's medicament, dosage, route of administration are seen the result of the test table:
7, antifungal agent pharmacodynamics test: select healthy mice, body weight 18-20g, male and female half and half.Random packet, 6 groups, after the infection immediately with 6 hours after the tail vein injection administration, 10 every group, make systemic infection mycosis model and use.Adopt the strain of cryptococcus encephalitis fungus to make infection strain.Measure earlier the bacterial strain that makes to 100% minimum lethal dose (100%MLD) of mice as infection dosage.After the infection immediately with 6 hours after the tail vein injection administration, face connect administration 7 days, the comparison of record animal dead rate % and blank group.
Result of the test is following:
Visible through above-mentioned results of pharmacodynamic test, liposome composite medicine medicine of the present invention all is superior to showing of prior art for preparing in safety, stability, curative effect comprehensively and sells corresponding medicine.

Claims (4)

1. liposome composite medicine such as Alprostadil is characterized in that, the each component feed molar number of the standard of suitability for industrialized production liposome composite medicine of the present invention is such as down:
Figure FSA00000545503300011
Said crude drug is strong fat-soluble strong or water solublity powerful feature, and prescription dosage is 1/3rd to 1/5th of the oral or injection preparation minimum gauge amount of formulation of existing secondary correspondence.Preferably: Alprostadil and 1: 30 compositions of indapamide mole ratio, or CEFUROXIME AXETIL and 2500: 1 compositions of Alprostadil mole ratio, or fluconazol; Or voriconazole, or sorbide nitrate, or ribavirin and 1: 1 compositions of cefadroxil mole ratio; Or paclitaxel and 333: 1 compositions of Alprostadil molal quantity, or clindamycin phosphate, or ganciclovir; Or noroxylin, or tanshinone IIA, or prostaglandin A 1, or meropenem, or pioglitazone, or rosiglitazone, or simvastatin; Or cytosine arabinoside, or hydroxy camptothecin, or sodium nitroprusside, or valaciclovir; Or doxorubicin, or etoposide, or adefovir ester, or ribavirin and 1000: 1 compositionss of Alprostadil weight ratio; Or ligustrazine microcosmic salt or Pazufloxacin Mesilate, or cefpiramide sodium, or mitoxantrone, or Ondansetron Hydrochloride.
The mean molecule quantity of said phospholipid raw material all defines with 800D and calculates, and the phospholipid raw material is the compositions of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine, and mole ratio is 1-5: 0.5 compositions.
The antioxidant of said phospholipid is reduced glutathion.
Said immobilized artificial membrane molecular state diluent is again an antioxidant, is dimercaprol.
Said liposome medicine carrying body dispersant is again an excipient, is xylitol.
Said surfactant is a sodium dehydrocholate.
The each component raw material of liposome composite medicine all should have national standard, and all is the national standard of pharmaceutical injection agent level.Both met national GMP standard, met the regulation of country's " medicine registration management way " again, in order to industrialization development.
The present invention also provides the normalized process for preparing of said group of plastid composition of medicine:
(1) in dissolving tank; The xylitol dosage is dissolved into 10% percentage by weight solution of xylitol in the injection phosphorus phthalate buffer; With this solution 121 ℃ of steam sterilizations 20 minutes, when solution temperature is 20-25 ℃, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D; Remove pyrogen and pyrogen molecule fragment in the solution, get the solution that ultrafiltration obtains; Again at room temperature; The solution that the five equilibrium ultrafiltration obtains; Be divided into A, B solution, A, B solution used the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8% respectively, with A, B solution respectively through the membrane filtration mistake in the following aperture of 0.05 μ m; Remove the precipitate of insoluble particle, high volence metal ion, metal ion, use 8% analytically pure hydrochloric acid solution adjust pH to be 5.0-8.0 respectively A, B solution again; If the crude drug that water solublity is strong is complete with an amount of water for injection dissolving; With the membrane ultrafiltration of molecular cut off 1000D, depyrogenation, gained ultrafiltration solution merges in the B solution and stirs; The following membrane filtration mistake through 0.05 μ m aperture is removed bacterium in the raw material medicine solution, insoluble particle again; The raw material medicinal liquid requires check pyrogen and qualified could the permission of insoluble particle to add in the B solution.If fat-soluble crude drug dissolving is then handled by following the 3rd step;
(2) with A solution in the spray dryer of preparation pharmaceutical injection agent level; By the spray drying well-established law; A solution is by mixing ejection with 100 grades of compressed airs of cleanliness factor (being come room temperature by compressor) in the spraying nozzle at equipment top, and 150 ℃ of-190 ℃ of 100 grades of pure airs of temperature that get into device bottom (are attracted by air-introduced machine; High temperature) gas-liquid counter current mixes, and is spray dried to 120-150 order left and right sides porous granule dry powder; Drying finishes, and it is subsequent use that dried material leaves this device bottom in;
(3) it is complete to add fat-soluble crude drug, phospholipid, phospholipid dispersant stirring and dissolving in the ethanol respectively; Process proportion at 1.0 to 1.2 solution; Through the membrane ultrafiltration of molecular cut off 1000D, the membrane filtration mistake through the following aperture of 0.05 μ m is removed pyrogen, antibacterial, insoluble particle again;
(4) with the composition dries granule of the A solution of (2) step preparation, be put in the boiling coating machine, by boiling coating and the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume with the preparation of (3) step divides three parts earlier; Device bottom change into introduce anhydrous, aseptic, do not have oil, do not have the room temperature purity nitrogen air-flow of the particle of the above particle diameter of 0.001 μ m, under 40 ℃ of-65 ℃ of temperature, the dry thing particle of xylose that (2) step the was made coating under the fluidized state that seethes with excitement: earlier with (1/3rd volumes) phospholipid alcoholic solution of first part; Being transported in the coating nozzle at equipment middle part with clean rank through compression by pump is that 100 grades of pure nitrogen gas mix; Be spray form and be sprayed onto the thick that boiling is highly flowed for 400mm-450mm material (xylitol) in the machine, at boiling material particle surface coating, the mixed equably and dispersion of the material simultaneous altitude under the boiling; And make solvent evaporates as quick as thought; Form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide is accomplished, airpillow-dry 15 minutes; Again with three parts of the B solution of first step preparation also five equilibrium; With 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, do not have oil, do not have in 100 grades of purity nitrogen air-flows of particle of the above particle diameter of 0.001 μ m, press the aforesaid operations coating, behind the coating; Airpillow-dry 20 minutes has carried out coating-drying process for the first time like this; Repeat above-mentioned coating-drying process, the solution that carries out second part, the 3rd part 1/3rd volumes of two kinds of solution of second, third time respectively carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.The outermost layer coatings is the dry thing layer of xylitol micropore, or the dry thing layer of micropore of the compositions of water-soluble crude drug, xylitol, for the third time behind the coating, and residual moisture content≤1.0% in the coating dried material that obtains, residual dimercaprol≤0.2%.Note,, do not contain crude drug in its alcoholic solution if water miscible crude drug then is crude drug and xylitol three coatings of dried particles to A solution in B solution;
(5) in material-compound tank, add the isopyknic water for injection of using with the first step of injection phosphorus acid salt solution, inflated with nitrogen maintains an equal level with jar external pressure in jar, under 100 rev/mins of mixing speeds, is heated to 60 ± 5 ℃; Transferring speed of agitator is 500-700 rev/min, and under the inflated with nitrogen, the dry thing of the coating that in 30 minutes to 60 minutes, made for (4) step joins in the material-compound tank in jar; After adding the dry thing of coating, in jar, under the inflated with nitrogen environment, keep 60 ± 5 ℃ of temperature, and under 100 rev/mins of stirrings, kept 60-120 minute; Under 100 rev/mins of stirrings, be cooled to 30-40 ℃ to a jar inner liquid medicine again; Under 100 rev/mins of stirrings, add the dissolving of antioxidant glutathion and sodium dehydrocholate respectively fully again, and adjustment medicinal liquid pH value 5.0-8.0;
(6) hold temperature in 30 ± 5 ℃ of scopes at guarantor's medicinal liquid, under the 0.1-0.2Mpa nitrogen pressure, cross the medicinal liquid that (5) step made, get filterable medicinal liquid, obtain the liposome medicinal liquid of particle diameter less than 150nm with 0.15 μ m membrane filtration; The dosage packing liposomal body liquid of pressing this medicine of pharmaceutics permission is in cillin bottle, and the false add plug, well-established law lyophilization in the freeze drying box of lyophilization unit; To medicine solid residue moisture be less than 2%, the dimercaprol residual quantity is less than 0.2%; Lid is rolled in the vacuum tamponade, and laggard storehouse is up to the standards; Process the lyophilized injection of the nanometer particle size of liposome medicine carrying body; This lyophilized injection also can be made into aseptic spray;
(7) under 100 grades of aseptic ranks; The lipid drug particles that (6) step was held back on the filterable filter membrane greater than 150nm wash 10% by in the operation sterilization of (1) step, freshly prepd 10% xylitol solution of depyrogenation; Measure the content of total phospholipids raw material in the medicinal liquid; And, reach in the control medicinal liquid total phospholipids content at 40-80mg/ml with the qualified freshly prepd 10% xylitol solution adjustment of sterilization depyrogenation medicine liquid volume; Join this medicinal liquid during another batching irritates, under nitrogen, 100 rev/mins of mixing speeds, 30-60 minute internal heating to 50 ± 5 ℃ keep this temperature range to stir 60-120 minute; Keep again under nitrogen, 100 rev/mins of rotating speeds, the cooling medicinal liquid installs to the medicinal liquid branch in the rustless steel pallet of 316L to 20-25 ℃, is put in the freeze drying box of another lyophilizing unit, the well-established law lyophilization, moisture is less than 2% to the medical solid; The dimercaprol residual quantity is less than 0.2%; Obtain the liposome medicament solid, under 100 grades of aseptic ranks, be crushed to the 80-100 order to the liposome medicament solid, press the dosage that pharmaceutics allows, well-established law is processed the aseptic enteric oral preparation of this medicine, asepticly fastens agent;
(8) all operations all should carry out in strict accordance with the aseptic requirement of injection in the national GMP standard.Oral formulations also must be undertaken by the aseptic requirement of injection.
2. according to liposome composite medicines such as the described Alprostadils of claim 1; It is characterized in that; Press the dosage that pharmaceutics allows; Process the lyophilized injection of the liposome composite medicines such as Alprostadil of the said scope of claim 1, or oral formulations or be mixed with spray or be mixed with suppository by well-established law again by well-established law again;
3. according to liposome composite medicines such as the described Alprostadils of claim 1, it is characterized in that its purposes is for being used for antiviral, antitumor, antianginal, blood pressure lowering;
4. the equipment for preparing liposome medicament; It is characterized in that the equipment that themes as the big suitability for industrialized production liposome medicament of dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze-drying is the combination of dissolving tank-ultrafiltration post-spray dryer-boiling coating machine-freezer dryer.
CN2011102121399A 2010-07-29 2011-07-28 Liposome combined medicament of alprostadil and like and large-scale industrial production technology and application thereof Pending CN102697726A (en)

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CN201310475983.XA Pending CN103919724A (en) 2010-07-29 2011-07-28 Baicalein liposome combination drug and large-scale industrialized production technology and purpose
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