CN104324000A - Etoposide liposome combined medicine, and large-scale production process and application thereof - Google Patents

Etoposide liposome combined medicine, and large-scale production process and application thereof Download PDF

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Publication number
CN104324000A
CN104324000A CN201310522901.2A CN201310522901A CN104324000A CN 104324000 A CN104324000 A CN 104324000A CN 201310522901 A CN201310522901 A CN 201310522901A CN 104324000 A CN104324000 A CN 104324000A
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solution
liposome
medicine
coating
etoposide
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蔡海德
王秀丽
刘会梅
张连印
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HUNAN KANGDU PHARMACEUTICAL CO Ltd
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HUNAN KANGDU PHARMACEUTICAL CO Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Abstract

The invention relates to an etoposide liposome combined medicine, and a large-scale production process and an application thereof. The invention discloses molar ratios of raw materials for the etoposide liposome combined medicine, and also provides a large-scale production method for the liposome combined medicine. According to the dosage permissible in the pharmacy, the etoposide liposome combined medicine can be made into lyophilized power injections, oral preparations, spray preparations or suppository preparations. The etoposide liposome combined medicine is used for resisting tumors.

Description

Etoposide liposome composite medicine and greatly industrialized producing technology and purposes
The application is for enjoying domestic priority application.Earlier application state is China, and the number of patent application of earlier application is 201010240184.0, and the applying date is on 07 29th, 2010, and name is called " dissolving ultrafiltration-spraying dry-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine ", the application is again divisional application, earlier application state is China, the number of patent application of earlier application is 201110212139.9, the applying date is on 07 28th, 2011, name is called " liposome composite medicine such as Alprostadil and large industrialized producing technology and purposes " thereof, the number of patent application that this patent enjoys the earlier application of domestic priority is 201010240184.0, the applying date is on 07 29th, 2010, name is called " dissolving ultrafiltration-spraying dry-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine ", on 07 12nd, 2013, dispatch sequence number is in " the first time notification of examiner's opinion " of 2013070900958420, auditor proposes divisional application.
Technical field
The present invention relates to a kind of large suitability for industrialized production liposome composite medicine preparation method, it is characterized in that, subject matter is with dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze-drying, both can suitability for industrialized production liposomal body composition injection greatly with unified formula, technique, equipment, again can suitability for industrialized production liposomal body composition oral preparation greatly.
Background technology
China's pharmaceutical technology, crude drug technology of preparing and international most advanced level gap are only within 5 years, and what have meets or exceeds international most advanced level, and preparation technique will fall behind international most advanced level 20 years.Now a large amount of is produce secondary ordinary preparation, and three generations's slow release, controlled release agent, especially four generation the targeting preparation such as liposome be only in the laboratory research stage at present.Reason has:
1, liposome medicament technology injection and oral formulations formula, technique, equipment disunity are prepared in existing production, scientific research, have both wasted resource, the energy, and investment is large, of low quality again, contaminated environment.
2, the method for liposome medicament suitability for industrialized production may be made in prior art to have: high pressure homogenization, supercritical ultrasonics technology, organic solvent seasoning, spray drying method, fluidized bed coating, single phase soln freeze-drying.High pressure homogenization and supercritical ultrasonics technology size tunable, but high energy is broken, has destruction to crude drug; Rear four kinds of methods to particle diameter uncontrollable and particle size distribution do not concentrate, organic solvent residual, the quality problems such as have leakage, precipitation, cohesion, phospholipid corrupt;
3, existing method for preparing lipidosome makes the envelop rate of lipidosome drug carrier not reach 100%, and each batch of fluctuation, change are large; Slip is large, loses liposome medicament meaning;
4, production process is turned from side to side many, and during energy charge, equipment investment is large, prescription, technique shakiness by, immature, cause that the quality of the pharmaceutical preparations is uncontrollable, unstable, poor reproducibility;
5, sterilizing, depyrogenation method are improper, and omnidistance aseptic, apyrogeneity operation is difficult to ensure, lacks height aseptic concept to liposome medicament, 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 national drug quality standard mostly, and have patent also do not criticize New Drug Certificate and produce certification, registration difficulty is very large, chronic;
8, depart from Chinese truth, obtain liposome new drug production certification from developing to, spend nearly 10 years, cost more than 2,000 ten thousand yuan, better drug discovery patent, exhausted most enterprise dare not be invested and developed.Visible, medical reform and national system for basic pharmaceutical period is carried out in country, the large product of sales volume is selected to rise to the Liposomal formulation of forth generation from entering the secondary preparation of national essential drugs, carry out preparation technique innovation, eliminate its side effect and untoward reaction, such medicine sales volume is large, and investment recovery time is short.Reach safety, effective, high-quality, this basic principle economic.
Summary of the invention
The present invention seeks to the defect overcoming above-mentioned prior art.Theme of the present invention is: with dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze-drying, both can suitability for industrialized production liposomal body composition injection greatly with unified formula, technique, equipment, again can suitability for industrialized production liposomal body composition oral preparation greatly.Specification formula 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.Formed secondary pharmaceutical preparation innovation rise to four generation targeting preparation.
The present invention is achieved by the following technical solutions:
The each component feed molar number of the specification of suitability for industrialized production liposome composite medicine of the present invention is than as follows:
Described crude drug is strong fat-soluble strong or water solublity powerful feature, and formula dosage is 1/1 to five/3rd of the oral or injection preparation minimum gauge amount of formulation of existing secondary correspondence.Preferred: the compositions of Alprostadil and indapamide mole ratio 1:30, or the compositions of CEFUROXIME AXETIL and Alprostadil mole ratio 2500:1, or fluconazol, or voriconazole, or sorbide nitrate, or the compositions of ribavirin and cefadroxil mole ratio 1:1, or the compositions of paclitaxel and Alprostadil molal quantity 333:1, 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 Alprostadil weight ratio 1000:1 compositions, or ligustrazine microcosmic salt or Pazufloxacin Mesilate, or cefpiramide sodium, or mitoxantrone, or Ondansetron Hydrochloride.
The mean molecule quantity of described lecithin materials all defines and calculates with 800D, and lecithin materials is the compositions of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine, and mole ratio is the compositions of 1-5:0.5.
The antioxidant of described phospholipid is reduced glutathion.
Described immobilized artificial membrane molecular state diluent, or claim phospholipid dispersions, or claim immobilized artificial membrane dispersant, being again antioxidant, is dimercaprol.
Described liposome medicine carrying body dispersant, being again excipient, is xylitol.
Described surfactant is sodium dehydrocholate.
The each component raw material of liposome composite medicine all should have national standard, and is all the national standard of pharmaceutical injection agent level.Both meet national GMP specification, meet again the regulation of country's " drug registration management method ", in order to industrialization development.
The present invention also provides the normalized process for preparing of described liposome composite medicine:
1, in dissolving tank, xylitol dosage is dissolved in injection phosphorus phthalate buffer the weight percent solution of 10% of xylitol, by this solution 121 DEG C of steam sterilizations 20 minutes, when solution temperature is 20-25 DEG C, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D, except the pyrogen in solution and pyrogen molecule fragment, get the solution that ultrafiltration obtains; Again at room temperature, the solution that decile ultrafiltration obtains, be divided into A, B solution, A, B solution are used respectively the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in less than 0.05 μm aperture, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with the analytically pure hydrochloric acid solution adjust pH of 8% respectively by A, B solution.If the crude drug that water solublity is strong dissolves completely with appropriate water for injection, with the membrane ultrafiltration of molecular cut off 1000D, depyrogenation, gained ultrafiltration solution is merged in B solution and stirs, again through 0.05 μm of following membrane filtration mistake in aperture, bacterium, insoluble particle in removing raw material medicine solution.Raw material medicinal liquid requires that inspection pyrogen and qualified could the permission of insoluble particle add in B solution.If fat-soluble crude drug dissolves then by the 3rd step process below.
2, by solution A in the spray dryer preparing pharmaceutical injection agent level, by spraying dry well-established law, solution A (is come by compressor with cleanliness factor 100 grades of compressed airs by the spraying nozzle at equipment top, room temperature) mixing ejection, the temperature entered with device bottom 150 DEG C of-190 DEG C of 100 grades of pure airs (are attracted by air-introduced machine, high temperature) gas-liquid counter current mixing, be spray dried to 120-150 order left and right porous granule dry powder.Dry complete, it is for subsequent use that dried material leaves this device bottom in.
3, stirring and dissolving in fat-soluble crude drug, phospholipid, phospholipid dispersions to ethanol is added respectively complete, make proportion 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, then through less than 0.05 μm aperture membrane filtration mistake, except pyrogen removal, antibacterial, insoluble particle.
The composition dries granule of the solution A 4, the 2nd step prepared, is put in boiling seed-coating machine, by boiling coating and the operation of airpillow-dry well-established law, first divides three parts by phospholipid alcoholic solution equal-volume prepared by the 3rd step.Introducing is changed into anhydrous in device bottom, aseptic, without oil, without the room temperature purity nitrogen air-flow of the particle of more than 0.001 μm particle diameter, at 40 DEG C of-65 DEG C of temperature, coating under boiling fluidized state is carried out to the dry thing particle of the xylose that the 2nd step is obtained: first by (1/3rd volumes) phospholipid alcoholic solution of first part, by being that 100 grades of pure nitrogen gas mix with compressed clean rank in the coating nozzle in the middle part of transport pump to equipment, the thick that in machine, boiling is highly flowed for 400mm-450mm material (xylitol) is sprayed onto in spray form, at boiling material particle surface coating, material simultaneous altitude under boiling is mixed and dispersion equably, and make solvent volatilize as quick as thought, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, the B solution first step prepared again is decile three parts also, by 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, without oil, in 100 grades of purity nitrogen air-flows without the particle of more than 0.001 μm particle diameter, by aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out first time coating-drying process like this, repeat above-mentioned coating-drying process, the solution carrying out 1/3rd volumes of second part of second, third time two kinds of solution, the 3rd part respectively carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.Outermost layer coatings is the dry nitride layer of xylitol micropore, or water-soluble crude drug, xylitol the dry nitride layer of micropore of compositions, after third time coating, residual moisture content≤1.0% in the coating dried material obtained, residual dimercaprol≤0.2%.Note, if water miscible crude drug, be then crude drug and xylitol in B solution to dried particles three coatings of solution A, not containing crude drug in its alcoholic solution.
5, in material-compound tank, add the isopyknic water for injection of injection phosphorus acid salt solution with the first step, in tank, inflated with nitrogen and tank external pressure maintain an equal level, and under 100 revs/min of mixing speeds, are heated to 60 ± 5 DEG C; Tune speed of agitator is 500-700 rev/min, in tank under inflated with nitrogen, in 30 minutes to 60 minutes, dry for coating obtained for the 4th step thing is joined in material-compound tank; After adding the dry thing of coating, in tank under inflated with nitrogen environment, keep temperature 60 ± 5 DEG C, and keep 60-120 minute under stirring at 100 revs/min; Under stirring at 100 revs/min again, tank inner liquid medicine is cooled to 30-40 DEG C; Under stirring at 100 revs/min again, add antioxidant glutathion and sodium dehydrocholate respectively and dissolve completely, and adjust medicinal liquid pH value 5.0-8.0.
6, hold temperature within the scope of 30 ± 5 DEG C at guarantor's medicinal liquid, under 0.1-0.2Mpa nitrogen pressure, cross the obtained medicinal liquid of the 5th step by 0.15 μm of membrane filtration, get the medicinal liquid of filtration, obtain the liposome medicinal liquid that particle diameter is less than 150nm.Allow the dosage subpackage liposome medicinal liquid of this medicine in cillin bottle by pharmaceutics, and partly jump a queue, well-established law lyophilization in the freeze drying box of lyophilization unit.To medicine solid residue moisture for being less than 2%, dimercaprol residual quantity is for being less than 0.2%.Vacuum tamponade, rolls lid, and be up to the standards laggard storehouse.Make 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 sterilization grade, on the filter membrane that 6th step is filtered the Lipid pharmaceutical granule being greater than 150nm that retains wash 10% by the 1st step operation sterilizing, freshly prepd 10% xylitol solution of depyrogenation, measure the content of total phospholipids raw material in medicinal liquid, and with the qualified freshly prepd 10% xylitol solution adjustment medicine liquid volume of sterilizing depyrogenation, reach and to control in medicinal liquid total phospholipids content at 40-80mg/ml; This medicinal liquid is joined in another batching filling, and under rushing nitrogen, 100 revs/min of mixing speeds, are heated to 50 ± 5 DEG C in 30-60 minute, keep this temperature range to stir 60-120 minute; Under keeping rushing nitrogen again, 100 revs/min of rotating speeds, cooling medicinal liquid is to 20-25 DEG C, and medicinal liquid is dispensed in the rustless steel pallet of 316L, and be put in the freeze drying box of another lyophilizing unit, well-established law lyophilization, to medical solid, moisture is less than 2%.Dimercaprol residual quantity is for being less than 0.2%.Obtain liposome medicament solid, liposome medicament solid under 100 grades of sterilization grade, be crushed to 80-100 orders, the dosage allowed by pharmaceutics, well-established law makes the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
8, all operations all should carry out in strict accordance with injection sterility requirements in national GMP specification.Oral formulations also must be undertaken by injection sterility requirements.
Liposome medicament of the present invention, aseptic freeze-dried injection in use, when dissolving by transfusion aquation in cillin bottle, phospholipid dispersions disperses liposome medicine carrying body rapidly, and under xylitol liquid surface tension and Action of Surfactant, form the liposome medicine carrying uniform particle dispersion of particle diameter 50nm-150nm scope single chamber nanometer particle size; Oral formulations forms 150-1000nm particle at enteral.Envelop rate is all 100%.Liposome medicine carrying body is dispersed in 6 hours internal leakage rates less than 5% in transfusion, does not precipitate, does not condense, not stratified, is uniformly dispersed.After drug oral of the present invention, in gastrointestinal fluid, dispersion forms single chamber and multicell Coliposomes medicine, improves the therapeutic index of medicine.
Advantage of the present invention has:
1, both can suitability for industrialized production liposomal body composition injection greatly with unified formula, technique, equipment, again can suitability for industrialized production liposomal body composition oral preparation greatly.
2, with the develop of secondary preparation and the innovative combination of secondary preparation process prepare four generation targeting preparation, make mysterious liposome medicament from laboratory implementation industrialization steady production.Specification formula, the normalized process for preparing of liposome composite medicine are opened up, and be injection, oral formulations, other route of administration preparation have unified core formulation and preparation method, produce in cheap apparatus, greatly save Factory Building, equipment, manpower, time, the energy, also can realize zero emission.
3, the present invention focuses on theory ground-breaking and brings innovative technology to break through: with safety, effectively, high-quality, this basic principle economic, to invention medicine from selecting materials, to preparation process, be all high request ground to using final liposome medicament to be distributed in transfusion omnidistance aseptic, pyrogen, particle diameter, particle size distribution, envelop rate, slip, Decayed rate, the rate of settling to medicine, cohesion rate, effect duration etc., perfect meet this basic principle, pharmaceutical industry of the present invention is melted send out listing risk little.
4, the medicine core technology in the present invention has: lecithin materials molal quantity input amount breaks through prior art consumption, it is 5 times of prior art consumption, it is 10 times of crude drug, and crude drug is the medicine selecting fat-soluble or water solublity to be better than dispersant xylitol, phospholipid is greater than the envelop rate to xylitol widely to the envelop rate of medicine, and envelop rate reaches 100%; Lecithin materials consumption is large simultaneously, and there is a large amount of blank liposome, blank liposome is by macrophage phagocytic in vivo, and drug-loaded liposome is engulfed less, and curative effect is higher; Surfactant is dissolved in liposomal phospholipids rete, liposome bilayers is risen " shutoff ", reinforcement effect, this is because Liposomal surfactant agent is sodium salt, when pH value such as dissolving normal saline and glucose etc. is less than in 6 transfusions, its sodium salt of part becomes water-fast acid molecule, and enter in phospholipid bilayer, cholesterol is replaced also to play " shutoff ", reinforce liposome particles effect, make slip very little, surfactant also has the precipitation of lipotropism plastid in transfusion, cohesion, also has and strengthens liposomal dispersion uniformly liposome transfusion effect; Owing to adding immobilized artificial membrane dispersant dimercaprol, when coating is dry, immobilized artificial membrane is made to be that the micropore solid dispersion of molecular state replaces that high pressure impingement is broken, the broken immobilized artificial membrane particle of ultrasound waves, thousands of times less of the lecithin materials particle of high pressure impingement fragmentation, when coating, xylitol replaces the dimercaprol position of volatilization, composition phospholipid and xylitol molecules state microporous solids dispersion, make xylitol become the dispersant of liposome; This research finds, xylitol also has protection liposome medicine carrying body when lyophilization not by the protective effect that little ice slag destroys with mannitol sample, but mannitol has stimulation when intravenous drip to blood vessel; Dimercaprol is antioxidation when coating, and protection glutathion, phospholipid, crude drug are not oxidized, make glutathion play antioxidation and anti-peroxidation group use in vivo, and the liver protecting is not by drugs damage; This research of phospholipid material finds, this saturated phospholipid of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine compositions make that liposome is stable, slip is low, phospholipid to human body without antigen and harmless to liver; The lyophilization again of liposome dispersed system made by lipidosome freeze-dried injection of the present invention, when aquation again, keep liposome physics and chemical property constant.
5, because the particle diameter of above-mentioned effect medicine of the present invention in transfusion, particle size distribution are constant, envelop rate 100%, slip≤5%, Decayed rate are 0%, sedimentation rate is 0%, cohesion rate is 0%, eliminate 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 excellent can be practical four generation preparation.
6, the liposome medicament prepared of the present invention, in immobilized artificial membrane, phospholipid becomes solid solution to be scattered in immobilized artificial membrane with molecularity to inhale and release in agent and surfactant, and thousands of times less of supercritical ultrasonics technology, the broken phospholipid particles of high-pressure uniform matter; When coating-drying, the volatilization of solvent and dimercaprol makes phospholipid rete form countless small aperture layer, it is much bigger that this forms network structure specific surface area than freeze-drying, because hydrone distillation volatilization distance thousands of times longer than coatings distance in solid, makes network structure dissolve condensation in freeze-drying process; Again because phospholipid rete and xylose alcohol layer are immobilized artificial membrane dispersant layers, rapid, the high degree of dispersion phospholipid when aquation.These three kinds of advantages, the liposome particles particle diameter formed than prior art is more stable, more form nanometer size range to favorable reproducibility, and particle diameter is normal distribution.
7, composition of medicine of the present invention due to choosing phospholipid be natural phospholipid, human body and microbial cell film component, better targeting drug release function is had to pathogenic bacteria, virocyte, tumor cell and vascular wall damage place, therapeutic index is high, so crude drug consumption is only 1/1 to five/3rd of secondary medicine, add the encapsulating of phospholipid, the untoward reaction of crude drug almost without.The consumption of crude drug reduces, and strengthens phospholipid consumption, guarantees that envelop rate reaches 100%, and have " 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 with liposome particles size during surfactant co-controlling proliposome aquation, they are caused by the surface tension effects forming certain limit in aqueous.Xylitol can supply energy to diabetes, hepatopath, is desirable immobilized artificial membrane dispersant and excipient.
9, the immobilized artificial membrane diluent of composition of medicine of the present invention; by being not only dissolved in ethanol but also water-soluble; volatilize when spraying dry; form the micropore phospholipid rete that immobilized artificial membrane becomes molecular state solid dispersion system; when aquation in immobilized artificial membrane phospholipid be with molecular state degree of crushing and and surface dispersant phospholipid is distributed in water; form uniform nanoparticle liposome medicine carrying body, dimercaprol is wherein again the antioxidant of excellent liposome, protects phospholipid and medicine when coating.
10, the Action of Surfactant first of composition of medicine of the present invention when phospholipid aquation, phospholipid is distributed in water, second in the transfusion entering pH value 4.0-6.0, it is molecular structure organic acid by sodium salt acidify again, enter again in the two point lipid layer of liposome, 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: one is added antioxidant, and protection immobilized artificial membrane and crude drug are not oxidized; Two is in phospholipid dispersions coatings outside immobilized artificial membrane coatings, and bag protects phospholipid rete; Three are oral formulations is also by injection selection, sterilizing and sterile working, and eliminate antibacterial and decompose the corruption of phospholipid, this is the place of all existing lipidosome oral preparations and even injection technology significant error; Four be liposomal dispersion in transfusion in, there is metal ion in the dimercaprol complexation transfusion of 0.2%, make the metal ion brought in transfusion can not destroy phospholipid and liposome medicine carrying body, at vitamin C-glutathion-dimercaprol combination antioxidant, do not leak under Liposomal surfactant agent, dispersant combined effect, do not precipitate, not stratified, do not condense, be not oxidized, not corrupt, thus make liposome carry real mistake of about body to have actual use value difficulty.Liposome medicine carrying body is dispersed in transfusion, and due under the effect of the defect of liposome own and transfusion, making liposome composite medicine produce qualitative change, is also the significant error part that the present invention makes up prior art.
12, liposome medicament of the present invention is in preparation process, phospholipid liquid and the phospholipid dispersions liquid membrane filtration all below 0.05 μm of aperture is crossed (usual injection preparation is all cross through 0.22 μm of membrane filtration), make indissolubility particle diameter be down to 1/4th of permissible value, after making liposome aquation, particle diameter 50nm to 150nm particle is liposome particles entirely.Can the particle diameter of Accurate Measurement liposome medicine carrying body and particle size distribution.This is also the place that the present invention makes up prior art significant error.
Detailed description of the invention:
Embodiment 1
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine specification is as follows:
The specification preparation process of the present embodiment and method:
1, in dissolving tank, xylitol dosage is dissolved in injection phosphorus phthalate buffer the weight percent solution of 10% of xylitol, by this solution 121 DEG C of steam sterilizations 20 minutes, when solution temperature is 20-25 DEG C, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D except the pyrogen in solution and pyrogen molecule fragment, get the solution that ultrafiltration obtains; Again at room temperature, the solution that decile ultrafiltration obtains is A, B solution, A, B solution are used respectively the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in less than 0.05 μm aperture, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with the analytically pure hydrochloric acid solution adjust pH of 8% respectively by A, B solution.Material solution require inspection pyrogen and insoluble particle qualified.
2, by solution A in pharmaceutical injection agent level spray-type fluidized bed dryer, by spraying dry well-established law, solution A (is come by compressor with cleanliness factor 100 grades of compressed airs by the spraying nozzle at equipment top, room temperature) mixing ejection, the temperature entered with device bottom 150 DEG C of-190 DEG C of 100 grades of pure airs (are attracted by air-introduced machine, high temperature) gas-liquid counter current mixing, be spray dried to 120-150 order left and right porous granule dry powder.Dry complete, it is for subsequent use that dried material leaves this device bottom in.
3, stirring and dissolving in fat-soluble crude drug, phospholipid, phospholipid dispersions to ethanol is added respectively complete, if crude drug dissolves undesirable, a small amount of dichloromethane can be added in ethanol, to crude drug dissolubility ideal, do not add as far as possible and add methylene chloride less as far as possible, make proportion 1.0 to 1.2 solution, through the politef material membrane ultrafiltration of molecular cut off 1000D, filter, except pyrogen removal, antibacterial, insoluble particle through less than 0.05 μm aperture titanium film again.
The composition dries granule of the solution A 4, the 2nd step prepared, is put in spraying boiling coating-boiling drier, by boiling coating, the operation of airpillow-dry well-established law, first divides three parts by phospholipid alcoholic solution equal-volume prepared by the 3rd step.Introducing is changed into anhydrous in device bottom, aseptic, without oil, without the room temperature purity nitrogen air-flow of the particle of more than 0.001 μm particle diameter, at 40 DEG C of-65 DEG C of temperature, coating under boiling fluidized state is carried out to the dry thing particle of the xylose that the 2nd step is obtained: first by (1/3rd volumes) phospholipid alcoholic solution of first part, by being that 100 grades of pure nitrogen gas mix with compressed clean rank in the coating nozzle in the middle part of transport pump to equipment, spray form is sprayed onto the thick that in machine, boiling is highly flowed for 400mm-450mm material (fructose and mannitol compositions), at boiling material particle surface coating, material simultaneous altitude under boiling is mixed and dispersion equably, and make solvent volatilize as quick as thought, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, the B solution first step prepared again is decile three parts also, by 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, without oil, in 100 grades of purity nitrogen air-flows without the particle of more than 0.001 μm particle diameter, by aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out first time coating-drying process like this, repeat above-mentioned coating-drying process, the solution carrying out 1/3rd volumes of second part of second, third time two kinds of solution, the 3rd part respectively carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.Outermost layer coatings is the dry nitride layer of xylitol micropore, or water-soluble crude drug, xylitol the dry nitride layer of micropore of compositions, after third time coating, residual moisture content≤1.0% in the coating dried material obtained, residual dichloromethane and ethanol are 0%, residual dimercaprol≤0.2%.
5, in material-compound tank, the isopyknic water for injection of injection phosphorus acid salt solution with the first step is added, in tank, inflated with nitrogen and tank external pressure maintain an equal level, under 100 revs/min of mixing speeds, be heated to 60 ± 5 DEG C, tune speed of agitator is 500-700 rev/min, in tank under inflated with nitrogen, in 30 minutes-60 minutes, dry for coating obtained for the 4th step thing is joined in material-compound tank, after adding the dry thing of coating, in tank under inflated with nitrogen environment, keep temperature 60 ± 5 DEG C, and keep 60-120 minute under stirring at 100 revs/min.Under stirring at 100 revs/min again, tank inner liquid medicine is cooled to 30-40 DEG C.Under stirring at 100 revs/min again, add antioxidant glutathion and sodium dehydrocholate respectively and dissolve completely, and adjust medicinal liquid pH value 5.0-8.0.
6, hold temperature within the scope of 30 ± 5 DEG C at guarantor's medicinal liquid, under 0.1-0.2Mpa nitrogen pressure, cross the obtained medicinal liquid of the 5th step by 0.15 μm of membrane filtration, get the medicinal liquid of filtration, obtain the liposome medicinal liquid that particle diameter is less than 150nm.Allow the dosage subpackage liposome medicinal liquid of this medicine in cillin bottle by pharmaceutics, and partly jump a queue, well-established law lyophilization in the freeze drying box of lyophilization unit.To medicine solid residue moisture for being less than 2%, dimercaprol residual quantity is less than 0.2%, and it is all 0% that ethanol and dichloromethane remain.Vacuum tamponade, rolls lid, and be up to the standards laggard storehouse.Make lyophilized injection.This lyophilized injection can be made into aseptic spray.
7, under 100 grades of sterilization grade, the Lipid pharmaceutical granule being greater than 150nm that the filter membrane 6th step filtered retained is washed in the xylitol solution qualified by the 1st step operation sterilizing depyrogenation of 10%, measure the content of total phospholipids raw material in medicinal liquid, and with the qualified 10% xylitol solution adjustment medicine liquid volume of sterilizing depyrogenation, reach and to control in medicinal liquid total phospholipids content at 40-80mg/ml.Medicinal liquid is joined in another batching filling, under rushing nitrogen, 100 revs/min of mixing speeds, 50 are heated in 30-60 minute ± DEG C, this temperature range is kept to stir 60-120 minute, under keeping rushing nitrogen again, 100 revs/min of rotating speeds, cooling medicinal liquid, to 20-25 DEG C, is dispensed into Pharmaceutical in the rustless steel pallet of 316L, is put in the freeze drying box of another lyophilizing unit, well-established law lyophilization, to medical solid, moisture entrapment amount is less than 2%, and dimercaprol residual quantity is little by 0.2%, and it is 0% that ethanol and dichloromethane remain.Obtain liposome medicament solid, liposome medicament solid under 100 grades of sterilization grade: be crushed to 80-100 orders, the dosage allowed by pharmaceutics, well-established law makes the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
8, all operations all should carry out in strict accordance with injection sterility requirements in national GMP specification.Oral formulations also must be undertaken by injection sterility requirements.
Embodiment 2
Crude drug is that each material component mole ratio of fat-soluble strong liposome composite medicine specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the 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 specification is as follows:
The specification preparation process of the present embodiment and method are with embodiment 1.
Fat-soluble crude drug described in above embodiment, or the compositions of CEFUROXIME AXETIL and Alprostadil mole ratio 2500:1, or fluconazol, or voriconazole, or sorbide nitrate, or the compositions of ribavirin and cefadroxil mole ratio 1:1, or the compositions of paclitaxel China fir alcohol and Alprostadil molal quantity 333:1, or clindamycin phosphate, or 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 Alprostadil weight ratio 1000:1 compositions, or mitoxantrone.
Embodiment 11
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method:
1, in dissolving tank, xylitol dosage is dissolved in injection phosphorus phthalate buffer the weight percent solution of 10% of xylitol, by this solution 121 DEG C of steam sterilizations 20 minutes, when solution temperature is 20-25 DEG C, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D except the pyrogen in solution and pyrogen molecule fragment, get the solution that ultrafiltration obtains; Again at room temperature, the solution that decile ultrafiltration obtains is A, B solution, A, B solution are used respectively the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in less than 0.05 μm aperture, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with the analytically pure hydrochloric acid solution adjust pH of 8% respectively by A, B solution.Dissolved completely by the appropriate water for injection of crude drug strong for water solublity, with the membrane ultrafiltration of molecular cut off 1000D, depyrogenation, is merged in B solution and stirs, then through 0.05 μm of following membrane filtration mistake in aperture, except bacterium in crude drug, except insoluble particle.Raw material medicinal liquid requires that inspection pyrogen and qualified could the permission of insoluble particle add in B solution.
2, solution A is being prepared in pharmaceutical injection agent level spray dryer, by spraying dry well-established law, solution A (is come by compressor with cleanliness factor 100 grades of compressed airs by the spraying nozzle at equipment top, room temperature) mixing ejection, the temperature entered with device bottom 150 DEG C of-190 DEG C of 100 grades of pure airs (are attracted by air-introduced machine, high temperature) gas-liquid counter current mixing, be spray dried to 120-150 order left and right porous granule dry powder.Dry complete, it is for subsequent use that dried material leaves this device bottom in.
3, to add in phospholipid, phospholipid dispersions to ethanol stirring and dissolving respectively complete, make proportion 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, then through less than 0.05 μm aperture membrane filtration mistake, except pyrogen removal, antibacterial, insoluble particle.
The composition dries granule of the solution A 4, the 2nd step prepared, is put in spraying boiling coating-boiling drier, by boiling coating, the operation of airpillow-dry well-established law, first divides three parts by phospholipid alcoholic solution equal-volume prepared by the 3rd step.Introducing is changed into anhydrous in device bottom, aseptic, without oil, without the room temperature purity nitrogen air-flow of the particle of more than 0.001 μm particle diameter, at 40 DEG C of-65 DEG C of temperature, coating under boiling fluidized state is carried out to the dry thing particle of the xylitol that the 2nd step is obtained: first by (1/3rd volumes) phospholipid alcoholic solution of first part, by being that 100 grades of pure nitrogen gas mix with compressed clean rank in the coating nozzle in the middle part of transport pump to equipment, spray form is sprayed onto the thick that in machine, boiling is highly flowed for 400mm-450mm material (fructose and mannitol compositions), at boiling material particle surface coating, material simultaneous altitude under boiling is mixed and dispersion equably, and make solvent volatilize as quick as thought, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, the B solution first step prepared again is decile three parts also, by 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, without oil, in 100 grades of purity nitrogen air-flows without the particle of more than 0.001 μm particle diameter, by aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out first time coating-drying process like this, repeat above-mentioned coating-drying process, the solution carrying out 1/3rd volumes of second part of second, third time two kinds of solution, the 3rd part respectively carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.Outermost layer coatings is the dry nitride layer of micropore of compositions of water-soluble crude drug, xylitol, and after third time coating, residual moisture content≤1.0% in the coating dried material obtained, residual dimercaprol≤0.2%, Residual ethanol is 0%.
5, in material-compound tank, the isopyknic water for injection of injection phosphorus acid salt solution with the first step is added, in tank, inflated with nitrogen and tank external pressure maintain an equal level, under 100 revs/min of mixing speeds, be heated to 60 ± 5 DEG C, tune speed of agitator is 500-700 rev/min, in tank under inflated with nitrogen, in 30 minutes-60 minutes, dry for coating obtained for the 4th step thing is joined in material-compound tank, after adding the dry thing of coating, in tank under inflated with nitrogen environment, keep temperature 60 ± 5 DEG C, and keep 60-120 minute under stirring at 100 revs/min.Under stirring at 100 revs/min again, tank inner liquid medicine is cooled to 30-40 DEG C.Under stirring at 100 revs/min again, add antioxidant reduced glutathion and sodium dehydrocholate respectively and dissolve completely, and adjust medicinal liquid pH value 5.0-8.0.
6, keeping fluid temperature within the scope of 30 ± 5 DEG C, under 0.1-0.2Mpa nitrogen pressure, crossing the obtained medicinal liquid of the 5th step by 0.15 μm of membrane filtration, getting the medicinal liquid of filtration, obtain the liposome medicinal liquid that particle diameter is less than 150nm.Allow the dosage subpackage liposome medicinal liquid of this medicine in cillin bottle by pharmaceutics, and partly jump a queue, well-established law lyophilization in the freeze drying box of lyophilization unit.To medicine solid residue moisture for being less than 2%, dimercaprol residual quantity is less than 0.2%, and Residual ethanol is 0%.Vacuum tamponade, rolls lid, and be up to the standards laggard storehouse.Make lyophilized injection.This lyophilized injection maybe can be made into aseptic spray.
7, under 100 grades of sterilization grade, the Lipid pharmaceutical granule being greater than 150nm that the filter membrane 6th step filtered retained is washed in the freshly prepd xylitol solution qualified by the 1st step operation sterilizing depyrogenation of 10%, measure the content of total phospholipids raw material in medicinal liquid, and with the qualified 10% xylitol solution adjustment medicine liquid volume of sterilizing depyrogenation, reach and to control in medicinal liquid total phospholipids content at 40-80mg/ml.Medicinal liquid is joined in another batching filling, under rushing nitrogen, 100 revs/min of mixing speeds, 50 are heated in 30-60 minute ± DEG C, keep this temperature range to stir 60-120 minute, then under keeping rushing nitrogen, 100 revs/min of rotating speeds, cooling medicinal liquid, to 20-25 DEG C, is dispensed into Pharmaceutical in the rustless steel pallet of 316L, is put in the freeze drying box of another lyophilization unit, well-established law lyophilization, to medical solid, moisture is less than 2%, and dimercaprol residual quantity is 0.2%, and Residual ethanol is 0%.Obtain liposome medicament solid, liposome medicament solid under 100 grades of sterilization grade, be crushed to 80-100 orders, the dosage allowed by pharmaceutics, well-established law makes the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
8, all operations all should carry out in strict accordance with injection sterility requirements in national GMP specification.Oral formulations also must be undertaken by injection sterility requirements.
Embodiment 12
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 13
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 14
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 15
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 16
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 17
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 18
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 19
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Embodiment 20
Crude drug is that each material component mole ratio of the liposome composite medicine specification that water solublity is strong is as follows:
The specification preparation process of the present embodiment and method are with embodiment 11.
Water miscible crude drug described in embodiment 11 to embodiment 20: preferably ganciclovir or cytosine arabinoside or sodium nitroprusside or valaciclovir or doxorubicin or etoposide or ligustrazine microcosmic salt or levofloxacin hydrochloride or a head born of the same parents amine sodium or Ondansetron Hydrochloride or meropenem.
Technological Economy and quality index contrast
Conclusion: the technology of the present invention prepares liposome medicine carrying body compared with existing homogeneous freeze-drying, fluidized bed coating law technology liposome medicine carrying body, the technology of the present invention economy and primary quality measure are all superior to homogeneous freeze-drying, and quality index is all better than fluidized bed coating.
Pharmacodynamics demonstration test:
1, medicament for anti-gastric ulcer pharmacodynamics demonstration test: laboratory animal selects Jiankang rat, male or female, body weight 200-250g, often organizes 8.Medicine and dosage is used to see result of the test table.Before experiment, Rat Fast 24 hours, freely drinks water, under etherization open abdominal cavity, the glass tubing of internal diameter 5mm, long 30mm is vertically positioned on body of stomach serosal surface, in tube chamber, adds glacial acetic acid 0.2ml, glacial acetic acid is dipped in out with cotton swab, suture operation otch after 1.5 minutes.Postoperative normal diet, within second day, set up blank group 1 group and positive controls 1 group at random, blank group saline administration, 0.5ml/ time, intraperitoneal injection, positive controls, with famotidine physiological saline solution, is got 0.5ml/ time, and liposome medicament administration group of the present invention establishes drug administration by injection, oral administration group.Liposome medicament drug administration by injection, uses physiological saline solution liposome medicament, gets 0.5ml/ time.Administration 15 days, administration every day 2 times, 12 hours once.Be divided into drug administration by injection and Kou take Give medicine.Every embodiment is made sample and is connected administration respectively 3 days.Administration, after 15 days, is dissected and is taken out stomach, and fix with formaldehyde, measures ulcer area mm 2, calculate each group of average ulcer area.
Results of pharmacodynamic test table:
Visible, said medicine of the present invention is higher than contrast positive drug curative effect.
2, anti-infectives pharmacodynamics test:
(1) animal is selected: the mice selecting the animalbioassay model prepared by Experimental Animal Center, body weight 18-22g, male and female half and half, random packet, every treated animal 50.
(2) infection bacteria species: model mice two groups that staphylococcus aureus causes the model mice of pneumonia, streptococcus pneumoniae causes pneumonia.
(3) infection dosage: 100% minimum lethal dose (100%MLD) being measured tested bacterial strain by Experimental Animal Center, as infection dosage.
(4) route of infection: bacterium stock solution 5% gastric Mucin is diluted to desired concn (Experimental Animal Center is determined), through tail vein injection.
(5) test method: mice is divided: model mice group two groups that A. staphylococcus aureus causes the model mice group of pneumonia, B. streptococcus pneumoniae causes pneumonia.Carry out not administration contrast, clindamycin phosphate for injection prepared by prior art contrast, drug control of the present invention.Every group model animal 50.Bolos intravenous administration or oral immediately after infection, was administered once every 6 hours again.Observe the reaction of animal thing, continuous 7 days, record dead mouse number.Medicine used and dosage, effect are shown in result of the test table:
3,1 myocardial ischemic antagonist pharmacodynamics demonstration test:
Select healthy mice, male or female, body weight 18-20g, often organize 10.Mouse cardiac muscle ischemia (preparing myocardial ischemia mouse model by Experimental Animal Center) is caused with isoproterenol.If blank and positive drug control group.Positive control medicine is defined as nitroglycerin, and every day is administered once, administration 10 days.The double staining of ischemia or infarcted myocardium is carried out, i.e. N-BT or TTC dyeing after 10 days; Under microscope, quantitative myocardial ischemia and infarct size, calculate the percent of every cell mean and positive control cell mean and the ratio with blank cell mean.Medicine used, dosage, administering mode are shown in results of pharmacodynamic test table:
3, the pharmacodynamics test of 2 hypotensors:
Select spontaneous hypertensive rat (SHR), often organize 10, Renal vascular stenotic type rat, often organize 10.First survey control period blood pressure and the rhythm of the heart, when administration after blood pressure stabilization, within 3 hours, measure blood pressure respectively after first 2 hours of administration and administration, the administration phase is 2 weeks.Administration after 3 hours after blood pressure drops be effective to more than 20mmHg.Medicine used, dosage, medication are shown in results of pharmacodynamic test table:
4, antitumor drug pharmacodynamics test:
Select rat kind tumor model: watt gram carcinosarcoma (W256) type.Body weight 50-70g, every treated animal 10.If negative control group and positive controls.Negative control group injecting normal saline, positive controls adopts and now sells paclitaxel medicine.1 administration every day, 15 days treatment times.Drug withdrawal put to death animal after 24 hours, dissected and peeled off tumor block, claimed tumor weight.Calculating therapeutic evaluation formula is:
Tumor control rate %=(C-T)/C X 100%
When suppression ratio is greater than 30%, effectively.Result of the test table:
Project Tumor control rate % Remarks
Now sell paclitaxel injection 50mg/kg lumbar injection 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/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% Only tumor medicine causes vomiting
Embodiment 15-20 water soluble vitamins 100mg/kg lumbar injection Effective percentage 100% Tumour patient supplementary
5, hypoglycemic medicine pharmacodynamics test: medicine of the present invention stimulates insulin secretion, so select normal health white mice, often organizes 15.Laboratory mouse is in fasting (can freely drink water) administration after 5 hours, and every day is administered once.Administration got blood after 2 hours, measured serum glucose values.Connect administration 7 days.Calculate blood glucose average rate of decrease (with blank group ratio).Blood glucose rate of descent is greater than 20% effective.Medicine used and dosage, route of administration are shown in result of the test table:
6, antiviral agents pharmacodynamics test:
Mice encephalitis model: mice 11-13g body weight, male and female regardless of, often organize 15.HSV-1 type Sm44 strain, viral lumbar injection, can cause encephalitis death, calculates LD 50.HSV-1 virus abdominal cavity injecting virus dosage LD successively again 01/2, each 2 days of 1/4,1/8 dosage, once a day.Calculate mortality rate, on average life number of days, contrast disease with medication therapy groups and to die protective rate, extending life rate.Treatment group administration 15 days, every day 2 times.Medicine used, dosage, route of administration are shown in 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 infection immediately with 6 hours after tail vein injection administration, often organize 10, be used as systemic infection mycosis model.The strain of cryptococcus encephalitis fungus is adopted to make infection strain.First measure 100% minimum lethal dose (100%MLD) of made bacterial strain to mice as infection dosage.After infection immediately with 6 hours after tail vein injection administration, face connects administration 7 days, and record mortality of animals % compares with blank group.
Result of the test is as follows:
Visible by above-mentioned results of pharmacodynamic test, liposome composite medicine medicine of the present invention sells corresponding medicine in safety, stability, curative effect showing of being better than prepared by prior art all comprehensively.

Claims (6)

1. an etoposide liposome composite medicine, is characterized in that, etoposide liposome composite medicine nanometer particle size lyophilized injection, or the aseptic enteric oral preparation of etoposide liposome composite medicine; The proportioning of the molal quantity of each component raw material of etoposide liposome composite medicine nanometer particle size lyophilized injection and etoposide liposome composite medicine aseptic enteric oral preparation is as follows:
The mean molecule quantity of lecithin materials all defines and calculates with 800D, and lecithin materials is the compositions of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine, and mole ratio is the compositions of 1-5:0.5;
The antioxidant of phospholipid is reduced glutathion;
Phospholipid dispersions, or claim immobilized artificial membrane dispersant, or claim immobilized artificial membrane molecular state diluent, being again antioxidant, is dimercaprol;
Liposome medicine carrying body dispersant is again excipient, is xylitol, xylitol is except the amount of above-mentioned molal quantity proportioning, as etoposide liposome composite medicine nanometer particle size lyophilized injection with outward, also to use as the aseptic enteric oral preparation of etoposide liposome composite medicine by following provisions recruitment: the xylitol solution of 10% is that phosphate buffer makes solvent, xylitol amount and phosphate solution amount all should be determined according to the liposome medicament amount being greater than 150nm particle diameter, newly increase, exceed 10% xylitol solution of the amount in above-mentioned formula, the Lipid pharmaceutical being greater than 150nm particle diameter is scattered in sterilizing, in the 10% freshly prepd xylitol solution that depyrogenation is qualified, measure the content being greater than the particle diameter liposome medicament total phospholipids raw material of 150nm in liposome medicament dispersion medicinal liquid, and adjust medicine liquid volume with qualified freshly prepd 10% xylitol solution of sterilizing depyrogenation, reach and to control in medicinal liquid total phospholipids content at 40-80mg/ml, refer to (7) step of preparation method,
Surfactant is sodium dehydrocholate;
The normalized process for preparing of etoposide liposome composite medicine:
(1) by etoposide liposome composite medicine nanometer particle size lyophilized injection xylitol dosage, the weight percent solution of 10% of xylitol is dissolved in injection phosphorus phthalate buffer, by this solution 121 DEG C of steam sterilizations 20 minutes, when solution temperature is 20-25 DEG C, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D, except the pyrogen in solution and pyrogen molecule fragment, get the solution that ultrafiltration obtains; Again at room temperature, the solution that decile ultrafiltration obtains, be divided into A, B solution, A, B solution are used respectively the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in less than 0.05 μm aperture, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with the analytically pure hydrochloric acid solution adjust pH of 8% respectively by A, B solution;
(2) by solution A in the spray dryer preparing pharmaceutical injection agent level, by spraying dry well-established law, solution A by the spraying nozzle at equipment top with cleanliness factor 100 grades of compressed airs, by compressor come, room temperature, mixing ejection, the temperature entered with device bottom 150 DEG C of-190 DEG C of 100 grades of pure airs, are attracted by air-introduced machine, high temperature, gas-liquid counter current mixes, and is spray dried to 120-150 order left and right porous granule dry powder; Dry complete, it is for subsequent use that dried material leaves this device bottom in;
(3) stirring and dissolving in fat-soluble crude drug etoposide, phospholipid, phospholipid dispersions dimercaprol to ethanol is added respectively complete, make proportion 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, again through less than 0.05 μm aperture membrane filtration mistake, except pyrogen removal, antibacterial, insoluble particle;
(4) the composition dries granule of the solution A (2) step prepared, is put in boiling seed-coating machine, by boiling coating and the operation of airpillow-dry well-established law, first divides three parts by phospholipid alcoholic solution equal-volume prepared by (3) step, introducing is changed into anhydrous in device bottom, aseptic, without oil, without the room temperature purity nitrogen air-flow of the particle of more than 0.001 μm particle diameter, at 40 DEG C of-65 DEG C of temperature, coating under boiling fluidized state is carried out to the dry thing particle of the xylose that (2) step is obtained: first by the phospholipid alcoholic solution of 1/3rd volumes of first part, by being that 100 grades of pure nitrogen gas mix with compressed clean rank in the coating nozzle in the middle part of transport pump to equipment, being sprayed onto boiling in machine in spray form is highly the thick of 400mm-450mm material xylitol stream, at boiling material particle surface coating, material simultaneous altitude under boiling is mixed and dispersion equably, and make solvent volatilize as quick as thought, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, the B solution first step prepared again is decile three parts also, by 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, without oil, in 100 grades of purity nitrogen air-flows without the particle of more than 0.001 μm particle diameter, by aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out first time coating-drying process like this, repeat above-mentioned coating-drying process, the solution carrying out 1/3rd volumes of second part of second, third time two kinds of solution, the 3rd part respectively, by aforesaid operations, carries out the alternately coating-drying process of phospholipid liquid and B solution, outermost layer coatings is the dry nitride layer of xylitol micropore, for the third time after coating, and residual moisture content≤1.0% in the coating dried material obtained, residual dimercaprol≤0.2%,
(5) in material-compound tank, add the isopyknic water for injection of injection phosphorus acid salt solution with the first step, in tank, inflated with nitrogen and tank external pressure maintain an equal level, and under 100 revs/min of mixing speeds, are heated to 60 ± 5 DEG C; Tune speed of agitator is 500-700 rev/min, in tank under inflated with nitrogen, in 30 minutes to 60 minutes, dry for coating obtained for the 4th step thing is joined in material-compound tank; After adding the dry thing of coating, in tank under inflated with nitrogen environment, keep temperature 60 ± 5 DEG C, and keep 60-120 minute under stirring at 100 revs/min; Under stirring at 100 revs/min again, tank inner liquid medicine is cooled to 30-40 DEG C; Under stirring at 100 revs/min again, add antioxidant glutathion and sodium dehydrocholate respectively and dissolve completely, and adjust medicinal liquid pH value 5.0-8.0;
(6) keeping fluid temperature within the scope of 30 ± 5 DEG C, under 0.1-0.2Mpa nitrogen pressure, crossing the obtained medicinal liquid of (5) step by 0.15 μm of membrane filtration, getting the medicinal liquid of filtration, obtain the liposome medicinal liquid that particle diameter is less than 150nm; Allow the dosage subpackage liposome medicinal liquid of this medicine in cillin bottle by pharmaceutics, and partly jump a queue, well-established law lyophilization in the freeze drying box of lyophilization unit; To medicine solid residue moisture for being less than 2%, dimercaprol residual quantity is for being less than 0.2%, and vacuum tamponade, rolls lid, and be up to the standards laggard storehouse; Make 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 sterilization grade, the Lipid pharmaceutical granule being greater than 150nm that the filter membrane (6) step filtered retained is washed by the 1st step operation, sterilizing, freshly prepd 10% xylitol solution of depyrogenation; The standby definition of this brand-new: the xylitol solution of 10% is that phosphate buffer makes solvent, xylitol amount and phosphate liquid measure all should be determined according to the liposome medicament amount being greater than 150nm particle diameter, it is 10% xylitol solution that newly increase, the amount exceeded in formula, measure the content of total phospholipids raw material in medicinal liquid, and with the qualified freshly prepd 10% xylitol solution adjustment medicine liquid volume of sterilizing depyrogenation, reach and to control in medicinal liquid total phospholipids content at 40-80mg/ml; This medicinal liquid is joined in another batching filling, and under rushing nitrogen, 100 revs/min of mixing speeds, are heated to 50 ± 5 DEG C in 30-60 minute, keep this temperature range to stir 60-120 minute; Under keeping rushing nitrogen again, 100 revs/min of rotating speeds, cooling medicinal liquid is to 20-25 DEG C, and medicinal liquid is dispensed in the rustless steel pallet of 316L, and be put in the freeze drying box of another lyophilizing unit, well-established law lyophilization, to medical solid, moisture is less than 2%; Dimercaprol residual quantity is for being less than 0.2%; Obtain liposome medicament solid, liposome medicament solid under 100 grades of sterilization grade, be crushed to 80-100 orders, the dosage allowed by pharmaceutics, well-established law makes the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
2., according to the normalized process for preparing of etoposide plastid composition of medicine according to claim 1, it is characterized in that, in manufacturing step: (1) step is dissolving ultrafiltration; (2) step is spraying dry; (3) step portion is molecular dispersion and ultrafiltration; (4) step is molecule dispersion coating; (5) step is that aquation pelletize adds antioxidant; (6) step is lyophilization lyophilized injection; (7) step is lyophilization donsole formulation; Be summarized as: the method for the preparation of industrialization liposome medicament of dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-cryodesiccated molecular dispersion method.
3. according to etoposide liposome composite medicine according to claim 1, it is characterized in that, the dosage allowed by pharmaceutics, makes the lyophilized injection of etoposide liposome composite medicine, or is mixed with spray by well-established law again.
4. according to etoposide liposome composite medicine according to claim 1, it is characterized in that, etoposide liposome composite medicine is the aseptic enteric oral preparation of the etoposide liposome composite medicine that pharmaceutics allows, or the aseptic suppository of etoposide liposome composite medicine.
5., according to etoposide liposome composite medicine according to claim 1, it is characterized in that, its purposes is for antitumor.
6., according to a kind of etoposide liposome composite medicine according to claim 1, it is characterized in that, its industrialization manufactures the combination that equipment used is dissolving tank-ultrafiltration post-spray dryer-boiling seed-coating machine-freezer dryer.
CN201310522901.2A 2010-07-29 2011-07-28 Etoposide liposome combined medicine, and large-scale production process and application thereof Pending CN104324000A (en)

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