CN103919727A - Fluconazole liposome combination drug and large-scale industrialized production technology and purpose - Google Patents

Fluconazole liposome combination drug and large-scale industrialized production technology and purpose Download PDF

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CN103919727A
CN103919727A CN201310478836.8A CN201310478836A CN103919727A CN 103919727 A CN103919727 A CN 103919727A CN 201310478836 A CN201310478836 A CN 201310478836A CN 103919727 A CN103919727 A CN 103919727A
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solution
medicine
liposome
coating
fluconazole
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蔡海德
王秀丽
刘会梅
张连印
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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 provides a fluconazole liposome combination drug and large-scale industrialized production and purpose thereof, and is characterized in that: the fluconazole liposome combination drug comprises raw materials in the mole number ratio as shown in the specification; the invention also provides a large-scale industrialized preparation method of the fluconazole liposome combination drug; the fluconazole liposome combination drug is prepared into a freeze-dried injection, or an oral preparation, or a spray agent, or a suppository according to pharmaceutically allowed dosage.

Description

Fluconazole liposome composition of medicine and large 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-spray drying-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 ", the number of patent application that this patent is enjoyed the earlier application of domestic priority is 201010240184.0, the applying date is on 07 29th, 2010, name is called " dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine ", on 07 12nd, 2013, in " notification of examiner's opinion for the first time " that dispatch sequence number is 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, with unified formula, technique, 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.Now a large amount of is to produce secondary ordinary preparation, and three generations's slow release, controlled release agent, especially four generation the targeting preparation such as liposome at present only in the laboratory research stage.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, in prior art, may make the method for liposome medicament suitability for industrialized production 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 particle diameter are controlled, but high energy fragmentation has destruction to crude drug; Rear four kinds of methods to particle diameter uncontrollable and particle size distribution do not concentrate, organic solvent residual, has the quality problems such as leakage, precipitation, cohesion, phospholipid corruption;
3, existing method for preparing lipidosome makes the envelop rate of lipidosome drug carrier can not reach 100%, each batch of fluctuation, change large; Slip is large, loses liposome medicament meaning;
4, production process is turned from side to side manyly, and when energy charge, equipment investment is large, prescription, technique unstable 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, liposome medicament is lacked to 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 national drug quality standard mostly, have patent not criticize New Drug Certificate yet and produce certification, and 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 is more than 2,000 ten thousand yuan, better medicine patent of invention, and absolutely large multiple enterprises dare not be invested and developed.Visible, carry out medical reform and national system for basic pharmaceutical period in country, from enter the secondary preparation of national essential drugs, select the large product of sales volume to rise to the Liposomal formulation in the 4th generation, carry out preparation technique innovation, eliminate its side effect and untoward reaction, medicine sales volume is large like this, and 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 defect 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 formula, technique, equipment both suitability for industrialized production liposomal body composition injection greatly, suitability for industrialized production liposomal body composition oral preparation greatly again.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.Form 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 1/3rd to 1/5th of the oral or injection preparation minimum gauge amount of formulation of existing secondary correspondence.Preferred: Alprostadil and the indapamide mole ratio compositions of 1: 30, or CEFUROXIME AXETIL and the Alprostadil mole ratio compositions of 2500: 1, or fluconazol, or voriconazole, or sorbide nitrate, or ribavirin and the cefadroxil mole ratio compositions of 1: 1, or paclitaxel and the Alprostadil molal quantity compositions of 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 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 described phospholipid raw material all defines with 800D and calculates, and 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 described phospholipid is reduced glutathion.
Described immobilized artificial membrane molecular state diluent, or claim phospholipid dispersant, or claim immobilized artificial membrane dispersant, be again antioxidant, be dimercaprol.
Described liposome medicine carrying body dispersant, is 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, met again the regulation of country's " medicine registration management way ", 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 to 10% percentage by weight solution of xylitol, by this solution 121 DEG C of steam sterilizations 20 minutes, in the time that solution temperature is 20-25 DEG C, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D, except pyrogen and pyrogen molecule fragment in solution, 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 to the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in the 0.05 following aperture of μ m, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with 8% analytically pure hydrochloric acid solution adjust pH 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 merges in B solution and stirs, through the 0.05 following membrane filtration mistake in μ m aperture, remove bacterium in raw material medicine solution, insoluble particle again.Raw material medicinal liquid requires inspection pyrogen and qualified could the permission of insoluble particle to add in B solution.If fat-soluble crude drug dissolves by the 3rd step processing below.
2, by A solution preparing in the spray dryer of pharmaceutical injection agent level, by the dry well-established law of spraying, A solution is by (being come by compressor with 100 grades of compressed airs of cleanliness factor in the spraying nozzle at equipment top, room temperature) mixing ejection, 150 DEG C of-190 DEG C of 100 grades of pure airs of temperature that enter with device bottom (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, add respectively fat-soluble crude drug, phospholipid, phospholipid dispersant complete to stirring and dissolving in ethanol, make proportion at 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, then through the 0.05 following aperture of μ m membrane filtration mistake, remove pyrogen, antibacterial, insoluble particle.
The composition dries granule of the A solution of 4, being prepared by the 2nd step, is put in boiling seed-coating machine, and by boiling coating and the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume of first being prepared by the 3rd step divides three parts.Change introducing in device bottom anhydrous, aseptic, without oil, the room temperature purity nitrogen air-flow of the particle of the above particle diameter of nothing 0.001 μ m, at 40 DEG C of-65 DEG C of temperature, the dry thing particle of xylose that the 2nd step the is made coating under fluidized state that seethes with excitement: first by (1/3rd volumes) phospholipid alcoholic solution of first part, being transported in the coating nozzle in the middle part of equipment by pump is that 100 grades of pure nitrogen gas mix with compressed clean rank, be spray form and be sprayed onto the thick that in machine, boiling is highly flowed for 400mm-450mm material (xylitol), at boiling material particle surface coating, material simultaneous altitude under boiling is mixed and dispersion equably, and make as quick as thought solvent evaporates, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, also three parts of deciles of the B solution of again being prepared by the first step, 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 of the particle of the above particle diameter of nothing 0.001 μ m, press aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out like this coating-drying process for the first time, repeat above-mentioned coating-drying process, the solution that carries out respectively 1/3rd volumes of second part, the 3rd part of two kinds of solution of second, third time carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.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 after coating, and residual moisture content≤1.0% in the coating dried material obtaining, residual dimercaprol≤0.2%.Note, if water miscible crude drug is crude drug and xylitol three coatings of dried particles to A solution in B solution, in its alcoholic solution, do not contain crude drug.
5, in material-compound tank, add the isopyknic water for injection of injection phosphorus acid salt solution of using 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, and in tank, under inflated with nitrogen, the dry thing of coating in 30 minutes to 60 minutes, the 4th step being made joins in material-compound tank; Add after the dry thing of coating, in tank, under inflated with nitrogen environment, keep 60 ± 5 DEG C of temperature, and keep 60-120 minute under 100 revs/min of stirrings; Under 100 revs/min of stirrings, tank inner liquid medicine is cooled to 30-40 DEG C again; Under 100 revs/min of stirrings, add respectively antioxidant glutathion and sodium dehydrocholate to dissolve completely, and adjust medicinal liquid pH value 5.0-8.0 again.
6, hold temperature within the scope of 30 ± 5 DEG C at guarantor's medicinal liquid, under 0.1-0.2Mpa nitrogen pressure, cross by 0.15 μ m membrane filtration the medicinal liquid that the 5th step makes, 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 laggard storehouse is up to the standards.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 aseptic ranks, on the filter membrane that the 6th step is filtered the lipid drug particles that is greater than 150nm held back 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 adjust medicine liquid volume with qualified freshly prepd 10% xylitol solution of sterilizing depyrogenation, reach and control in medicinal liquid total phospholipids content at 40-80mg/ml; This medicinal liquid is joined in another batching filling, rush under 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; Keep again rushing under nitrogen, 100 revs/min of rotating speeds, cooling medicinal liquid, to 20-25 DEG C, divides medicinal liquid in the rustless steel pallet that installs to 316L, is put in the freeze drying box of another lyophilizing unit, and well-established law lyophilization, is less than 2% to moisture in medical solid.Dimercaprol residual quantity is for being less than 0.2%.Obtain liposome medicament solid, liposome medicament solid, under 100 grades of aseptic ranks, is crushed to 80-100 order, the dosage allowing by pharmaceutics, well-established law is made 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 national GMP specification.Oral formulations also must be undertaken by the aseptic requirement of injection.
Liposome medicament of the present invention, aseptic freeze-dried injection in use, in the time dissolving by transfusion aquation in cillin bottle, phospholipid dispersant disperses liposome medicine carrying body rapidly, and under xylitol liquid surface tension and Action of Surfactant, form the liposome medicine carrying particle dispersed system 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 transfusion 6 hours internal leakage rates below 5%, does not precipitate, does not condense, not stratified, is uniformly dispersed.After drug oral of the present invention, in gastrointestinal fluid, disperse composition single chamber and multicell Coliposomes medicine, improve the therapeutic index of medicine.
Advantage of the present invention has:
1, with unified formula, technique, 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 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 that injection, oral formulations, other route of administration preparation have unified core formula and preparation method, 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, be all high request ground to invention medicine from the beginning of selecting materials, to preparation process, to using final liposome medicament to be distributed to transfusion omnidistance aseptic, pyrogen to medicine, particle diameter, particle size distribution, envelop rate, slip, corrupt rate, the rate of settling, 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: phospholipid feed molar is counted input amount and broken through prior art consumption, 5 times of prior art consumption, 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, phospholipid is greater than the envelop rate to xylitol widely to the envelop rate of medicine, and envelop rate reaches 100%; Phospholipid raw material consumption is large simultaneously, has a large amount of blank liposomes, and blank liposome, by macrophage phagocytic, is engulfed drug-loaded liposome less in vivo, and curative effect is higher; Surfactant is dissolved in liposome phospholipid rete, liposome bilayer is played to " shutoff ", reinforcement effect, this is because surface of liposome activating agent is sodium salt, when pH value such as dissolving normal saline and glucose is less than in 6 transfusions, its sodium salt of part becomes water-fast acid molecule, and enter in phospholipid bilayer, replace cholesterol also to play " shutoff ", reinforce liposome particles effect, make slip very little, surfactant also has precipitation, the cohesion of lipotropism plastid in transfusion, strengthens in addition liposome and is dispersed into uniform liposome transfusion effect; Owing to adding immobilized artificial membrane dispersant dimercaprol, in the time that coating is dry, the micropore solid dispersion that makes immobilized artificial membrane be molecular state replaces high pressure to clash into broken, the broken immobilized artificial membrane particle of ultrasound waves, clash into the broken little thousands of times of phospholipid raw material particle than high pressure, in the time of 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 with mannitol sample the protective effect that protection liposome medicine carrying body is not destroyed by little ice slag when the lyophilization, but mannitol has stimulation to blood vessel in the time of intravenous drip; Dimercaprol is antioxidation in the time of coating, and protection glutathion, phospholipid, crude drug are not oxidized, make glutathion play in vivo antioxidation and anti-peroxidation group use, and the liver protecting are not damaged by medicine; 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; Lipidosome freeze-dried injection of the present invention is to have made the lyophilization again of liposome dispersed system, in the time of 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%, 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 that prepared by the present invention, in immobilized artificial membrane, phospholipid is to become solid solution to be scattered in immobilized artificial membrane suction with molecularity to release in agent and surfactant, and than supercritical ultrasonics technology, the little thousands of times of the broken phospholipid particle of high-pressure uniform matter; In the time of coating-dry, the volatilization of solvent and dimercaprol makes phospholipid rete form countless micro hole layers, it is much bigger that this forms network structure specific surface area than freeze-drying, because in solid, hydrone distillation volatilization distance, than the long thousands of times of coatings distance, is dissolved network structure and is condensed in freeze-drying process; Again because phospholipid rete and xylitol layer are immobilized artificial membrane dispersant layers, in the time of aquation rapidly, high degree of dispersion phospholipid.These three kinds of advantages, the liposome particles particle diameter that forms than prior art is more stable, more favorable reproducibility form nanometer particle size scope, and particle diameter is normal distribution.
7, composition of medicine of the present invention is because the phospholipid of choosing is natural phospholipid, human body and microbial cell film component, there is to better targeting drug release function at pathogenic bacteria, virocyte, tumor cell and blood vessel wall destruction place, therapeutic index is high, so crude drug consumption is only 1/3rd to 1/5th of secondary medicine, add sealing of phospholipid, the untoward reaction of crude drug has not almost had.The consumption of crude drug reduces, and strengthens 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 during with surfactant co-controlling proliposome aquation, they are by forming in aqueous solution due to the surface tension effects of certain limit.Xylitol can be supplied with 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; volatilization in the time that spraying is dry; form the micropore phospholipid rete that immobilized artificial membrane becomes molecular state solid dispersion system; in the time of 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 good liposome, protects phospholipid and medicine in the time of coating.
10, the Action of Surfactant of composition of medicine of the present invention first is in the time of phospholipid aquation, phospholipid to be distributed in water, second entering in the transfusion of pH value 4.0-6.0, it is molecular structure organic acid by sodium salt acidify again, enter again in two points of fat layers 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: the one, add antioxidant, and protection immobilized artificial membrane and crude drug are not oxidized; The 2nd, in phospholipid dispersant coatings, in immobilized artificial membrane coatings outside, bag protects phospholipid rete; The 3rd, oral formulations is also by injection selection, sterilizing 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 transfusion at liposome, there is metal ion in 0.2% dimercaprol complexation transfusion, make the metal ion bringing in 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, be not oxidized, not corrupt, thereby make liposome carry that about body is real has crossed actual use value difficulty.Liposome medicine carrying body is dispersed in transfusion, under the effect due to the defect of liposome own and transfusion, makes 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 phospholipid dispersant liquid are all crossed (injection preparation is all to cross through 0.22 μ m membrane filtration conventionally) through the membrane filtration below 0.05 μ m aperture, make indissolubility particle diameter be down to 1/4th of permissible value, making particle diameter 50nm to 150nm particle after liposome aquation is liposome particles entirely.Particle diameter and particle size distribution that can Accurate Measurement liposome medicine carrying body.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:
Specification preparation process and the method for the present embodiment:
1, in dissolving tank, xylitol dosage is dissolved in injection phosphorus phthalate buffer to 10% percentage by weight solution of xylitol, by this solution 121 DEG C of steam sterilizations 20 minutes, in the time that solution temperature is 20-25 DEG C, except pyrogen and pyrogen molecule fragment in solution, get the solution that ultrafiltration obtains with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D; Again at room temperature, the solution that decile ultrafiltration obtains is A, B solution, A, B solution are used respectively to the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in the 0.05 following aperture of μ m, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with 8% analytically pure hydrochloric acid solution adjust pH respectively by A, B solution.Material solution requirement inspection pyrogen and insoluble particle are qualified.
2, by A solution in pharmaceutical injection agent level spray-type fluidized bed dryer, by the dry well-established law of spraying, A solution is by (being come by compressor with 100 grades of compressed airs of cleanliness factor in the spraying nozzle at equipment top, room temperature) mixing ejection, 150 DEG C of-190 DEG C of 100 grades of pure airs of temperature that enter with device bottom (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, add respectively fat-soluble crude drug, phospholipid, phospholipid dispersant complete to stirring and dissolving in ethanol, if it is undesirable that crude drug dissolves, can in ethanol, add a small amount of dichloromethane, till crude drug dissolubility ideal, do not add as far as possible and add methylene chloride less as far as possible, making proportion at 1.0 to 1.2 solution, through the politef material membrane ultrafiltration of molecular cut off 1000D, filter through the 0.05 following aperture of μ m titanium film again, remove pyrogen, antibacterial, insoluble particle.
The composition dries granule of the A solution of 4, being prepared by the 2nd step, is put in spraying boiling coating-boiling drier, and by boiling coating, the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume of first being prepared by the 3rd step divides three parts.Change introducing in device bottom anhydrous, aseptic, without oil, the room temperature purity nitrogen air-flow of the particle of the above particle diameter of nothing 0.001 μ m, at 40 DEG C of-65 DEG C of temperature, the dry thing particle of xylose that the 2nd step the is made coating under fluidized state that seethes with excitement: first by (1/3rd volumes) phospholipid alcoholic solution of first part, being transported in the coating nozzle in the middle part of equipment by pump is that 100 grades of pure nitrogen gas mix with compressed clean rank, 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 as quick as thought solvent evaporates, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, also three parts of deciles of the B solution of again being prepared by the first step, 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 of the particle of the above particle diameter of nothing 0.001 μ m, press aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out like this coating-drying process for the first time, repeat above-mentioned coating-drying process, the solution that carries out respectively 1/3rd volumes of second part, the 3rd part of two kinds of solution of second, third time carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.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 after coating, residual moisture content≤1.0% in the coating dried material obtaining, residual dichloromethane and ethanol are 0%, residual dimercaprol≤0.2%.
5, in material-compound tank, add the isopyknic water for injection of injection phosphorus acid salt solution of using with the first step, 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, the dry thing of coating in 30 minutes-60 minutes, the 4th step being made joins in material-compound tank, add after the dry thing of coating, in tank under inflated with nitrogen environment, keep 60 ± 5 DEG C of temperature, and keep 60-120 minute under 100 revs/min of stirrings.Under 100 revs/min of stirrings, tank inner liquid medicine is cooled to 30-40 DEG C again.Under 100 revs/min of stirrings, add respectively antioxidant glutathion and sodium dehydrocholate to dissolve completely, and adjust medicinal liquid pH value 5.0-8.0 again.
6, hold temperature within the scope of 30 ± 5 DEG C at guarantor's medicinal liquid, under 0.1-0.2Mpa nitrogen pressure, cross by 0.15 μ m membrane filtration the medicinal liquid that the 5th step makes, 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 ethanol and dichloromethane are residual is all 0%.Vacuum tamponade, rolls lid, and laggard storehouse is up to the standards.Make lyophilized injection.This lyophilized injection can be made into aseptic spray.
7, under 100 grades of aseptic ranks, on the filter membrane that the 6th step is filtered the lipid drug particles that is greater than 150nm held back wash 10% by the qualified xylitol solution of the 1st step operation sterilizing depyrogenation, measure the content of total phospholipids raw material in medicinal liquid, and adjust medicine liquid volume with 10% qualified xylitol solution of sterilizing depyrogenation, reach and control in medicinal liquid total phospholipids content at 40-80mg/ml.Medicinal liquid is joined in another batching filling, rush under nitrogen, 100 revs/min of mixing speeds, in 30-60 minute, be heated to 50 ± DEG C, keep this temperature range to stir 60-120 minute, keep again rushing under nitrogen, 100 revs/min of rotating speeds, cooling medicinal liquid, to 20-25 DEG C, divides Pharmaceutical in the rustless steel pallet that installs to 316L, is put in the freeze drying box of another lyophilizing unit, well-established law lyophilization, be less than 2% to moisture entrapment amount in medical solid, dimercaprol residual quantity is little by 0.2%, and ethanol and dichloromethane are residual is 0%.Obtain liposome medicament solid, liposome medicament solid under 100 grades of aseptic ranks: be crushed to 80-100 order, the dosage allowing by pharmaceutics, well-established law is made 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 national GMP specification.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 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 CEFUROXIME AXETIL and the Alprostadil mole ratio compositions of 2500: 1, or fluconazol, or voriconazole, or sorbide nitrate, or ribavirin and the cefadroxil mole ratio compositions of 1: 1, or paclitaxel China fir alcohol and the Alprostadil molal quantity compositions of 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 1000: 1 compositionss of Alprostadil weight ratio, 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:
Specification preparation process and the method for the present embodiment:
1, in dissolving tank, xylitol dosage is dissolved in injection phosphorus phthalate buffer to 10% percentage by weight solution of xylitol, by this solution 121 DEG C of steam sterilizations 20 minutes, in the time that solution temperature is 20-25 DEG C, except pyrogen and pyrogen molecule fragment in solution, get the solution that ultrafiltration obtains with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D; Again at room temperature, the solution that decile ultrafiltration obtains is A, B solution, A, B solution are used respectively to the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in the 0.05 following aperture of μ m, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with 8% analytically pure hydrochloric acid solution adjust pH respectively by A, B solution.Crude drug strong water solublity is dissolved completely with appropriate water for injection, and with the membrane ultrafiltration of molecular cut off 1000D, depyrogenation, merges in B solution and stirs, then through the 0.05 following membrane filtration mistake in μ m aperture, except bacterium in crude drug, except insoluble particle.Raw material medicinal liquid requires inspection pyrogen and qualified could the permission of insoluble particle to add in B solution.
2, by A solution preparing in pharmaceutical injection agent level spray dryer, by the dry well-established law of spraying, A solution is by (being come by compressor with 100 grades of compressed airs of cleanliness factor in the spraying nozzle at equipment top, room temperature) mixing ejection, 150 DEG C of-190 DEG C of 100 grades of pure airs of temperature that enter with device bottom (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, add respectively phospholipid, phospholipid dispersant complete to stirring and dissolving in ethanol, make proportion at 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, then through the 0.05 following aperture of μ m membrane filtration mistake, remove pyrogen, antibacterial, insoluble particle.
The composition dries granule of the A solution of 4, being prepared by the 2nd step, is put in spraying boiling coating-boiling drier, and by boiling coating, the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume of first being prepared by the 3rd step divides three parts.Change introducing in device bottom anhydrous, aseptic, without oil, the room temperature purity nitrogen air-flow of the particle of the above particle diameter of nothing 0.001 μ m, at 40 DEG C of-65 DEG C of temperature, the dry thing particle of xylitol that the 2nd step the is made coating under fluidized state that seethes with excitement: first by (1/3rd volumes) phospholipid alcoholic solution of first part, being transported in the coating nozzle in the middle part of equipment by pump is that 100 grades of pure nitrogen gas mix with compressed clean rank, 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 as quick as thought solvent evaporates, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, also three parts of deciles of the B solution of again being prepared by the first step, 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 of the particle of the above particle diameter of nothing 0.001 μ m, press aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out like this coating-drying process for the first time, repeat above-mentioned coating-drying process, the solution that carries out respectively 1/3rd volumes of second part, the 3rd part of two kinds of solution of second, third time carries out the alternately coating-drying process of phospholipid liquid and B solution by aforesaid operations.Outermost layer coatings is the dry thing layer of micropore of the compositions of water-soluble crude drug, xylitol, for the third time after coating, and residual moisture content≤1.0% in the coating dried material obtaining, residual dimercaprol≤0.2%, Residual ethanol is 0%.
5, in material-compound tank, add the isopyknic water for injection of injection phosphorus acid salt solution of using with the first step, 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, the dry thing of coating in 30 minutes-60 minutes, the 4th step being made joins in material-compound tank, add after the dry thing of coating, in tank under inflated with nitrogen environment, keep 60 ± 5 DEG C of temperature, and keep 60-120 minute under 100 revs/min of stirrings.Under 100 revs/min of stirrings, tank inner liquid medicine is cooled to 30-40 DEG C again.Under 100 revs/min of stirrings, add respectively antioxidant reduced glutathion and sodium dehydrocholate to dissolve completely, and adjust medicinal liquid pH value 5.0-8.0 again.
6, keeping fluid temperature within the scope of 30 ± 5 DEG C, under 0.1-0.2Mpa nitrogen pressure, cross by 0.15 μ m membrane filtration the medicinal liquid that the 5th step makes, 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 Residual ethanol is 0%.Vacuum tamponade, rolls lid, and laggard storehouse is up to the standards.Make lyophilized injection.This lyophilized injection maybe can be made into aseptic spray.
7, under 100 grades of aseptic ranks, on the filter membrane that the 6th step is filtered the lipid drug particles that is greater than 150nm held back wash 10% by the qualified freshly prepd xylitol solution of the 1st step operation sterilizing depyrogenation, measure the content of total phospholipids raw material in medicinal liquid, and adjust medicine liquid volume with 10% qualified xylitol solution of sterilizing depyrogenation, reach and control in medicinal liquid total phospholipids content at 40-80mg/ml.Medicinal liquid is joined in another batching filling, rush under nitrogen, 100 revs/min of mixing speeds, in 30-60 minute, be heated to 50 ± DEG C, keep this temperature range to stir 60-120 minute, keep again rushing under nitrogen, 100 revs/min of rotating speeds, cooling medicinal liquid, to 20-25 DEG C, divides Pharmaceutical in the rustless steel pallet that installs to 316L, is put in the freeze drying box of another lyophilization unit, well-established law lyophilization, be less than 2% to moisture in medical solid, dimercaprol residual quantity is 0.2%, and Residual ethanol is 0%.Obtain liposome medicament solid, liposome medicament solid, under 100 grades of aseptic ranks, is crushed to 80-100 order, the dosage allowing by pharmaceutics, well-established law is made 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 national GMP specification.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 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 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 is prepared liposome medicine carrying body compared with existing homogeneous freeze-drying, fluidized bed coating law technology liposome medicine carrying processed body, the technology of the present invention economy and main quality index 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 is selected Jiankang rat, male or female, body weight 200-250g, 8 every group.Use medicine and dosage to see result of the test table.Before experiment, rat fasting 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, add glacial acetic acid 0.2ml, after 1.5 minutes, dip in out glacial acetic acid with cotton swab, suture operation otch.Postoperative normal diet, within second day, set up at random 1 group of 1 group of blank group and positive controls, the normal saline administration of blank group, 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 is established 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 are once.Be divided into drug administration by injection and oral administration.Every embodiment makes sample and connects respectively administration 3 days.After administration 15 days, dissect and take out stomach, and fix with formaldehyde, measure 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: select the mice of the animalbioassay model of being prepared by Experimental Animal Center, 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: measured 100% minimum lethal dose (100%MLD) of trial bacterial strain by Experimental Animal Center, as infection dosage.
(4) route of infection: bacterium stock solution is diluted to desired concn (Experimental Animal Center is determined) with 5% gastric Mucin, through tail vein injection.
(5) test method: mice is divided: A. staphylococcus aureus causes the model mice group of pneumonia, two groups of model mice group that B. streptococcus pneumoniae causes pneumonia.Carry out clindamycin phosphate for injection contrast, medicine of the present invention contrast prepared by not administration contrast, prior art.50 of every group model animals.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, 10 every group.Cause mouse cardiac muscle ischemia (preparing myocardial ischemia mouse model by Experimental Animal Center) with isoproterenol.If blank and positive drug matched group.Positive control medicine is defined as nitroglycerin, and be administered once every day, administration 10 days.After 10 days, carry out the double staining of ischemia or infarcted myocardium, i.e. N-BT or TTC dyeing; Quantitatively myocardial ischemia and infarct size under microscope, calculate every cell mean and positive control cell mean and the percent with the ratio of 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), 10 every group, kidney angiostenosis type rat, 10 every group.First survey control period blood pressure and the rhythm of the heart, when administration after blood pressure stabilization, after first 2 hours of administration and administration, within 3 hours, measure respectively blood pressure, the administration phase is 2 weeks.Administration after 3 hours after blood pressure drops be above effective to 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, 10 of every treated animals.If negative control group and positive controls.Negative control group injecting normal saline, positive controls adopts now sells paclitaxel medicine.1 administration every day, 15 days treatment times.Drug withdrawal was put to death animal after 24 hours, dissected and peeled off tumor piece, claimed tumor weight.Calculating therapeutic evaluation formula is:
Tumor control rate %=(C-T)/CX100%
When suppression ratio is greater than 30%, effectively.
Result of the test table:
5, hypoglycemic medicine pharmacodynamics test: medicine of the present invention stimulates insulin secretion, so select normal health white mice, 15 every group.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 serum glucose value.Connect administration 7 days.Calculate blood glucose average rate of decrease (with blank group ratio).It is 20% effective that blood glucose rate of descent is greater than.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, 15 every group.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, average life number of days, contrast disease die protective rate, extending life rate with medication therapy groups.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, 10 every group, be used as systemic infection mycosis model.Adopt the strain of cryptococcus encephalitis fungus to make infection strain.First measure made bacterial strain to 100% minimum lethal dose (100%MLD) of mice as infection dosage.After infection immediately with 6 hours after tail vein injection administration, face connects administration 7 days, records mortality of animals % and the comparison of blank group.
Result of the test is as follows:
Visible by above-mentioned results of pharmacodynamic test, corresponding medicine is sold in showing that liposome composite medicine medicine of the present invention is all better than prepared by prior art in safety, stability, curative effect comprehensively.

Claims (5)

1. a fluconazole liposome composition of medicine, is characterized in that, fluconazole liposome composition of medicine nanometer particle size lyophilized injection, or the aseptic enteric oral preparation of fluconazole liposome composition of medicine; The proportioning of the molal quantity of each component raw material of fluconazole liposome composition of medicine nanometer particle size lyophilized injection and the aseptic enteric oral preparation of fluconazole liposome composition of medicine is as follows:
The mean molecule quantity of phospholipid raw material all defines with 800D and calculates, and 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 phospholipid is reduced glutathion;
Phospholipid dispersant, or claim immobilized artificial membrane dispersant, or claim immobilized artificial membrane molecular state diluent, be again antioxidant, be dimercaprol;
Liposome medicine carrying body dispersant, is again excipient, is xylitol, xylitol is except the amount of above-mentioned molal quantity proportioning, outside using as fluconazole liposome composition of medicine nanometer particle size lyophilized injection, also to use as the aseptic enteric oral preparation of fluconazole liposome composition of medicine by following provisions recruitment: 10% xylitol solution is that phosphate buffer is made solvent, xylitol amount and phosphate solution amount all should be determined according to being greater than the liposome medicament amount of 150nm particle diameter, newly increase, exceed 10% xylitol solution of the amount in above-mentioned formula, the lipid medicine that is greater than 150nm particle diameter is scattered in to sterilizing, in the qualified 10% freshly prepd xylitol solution of depyrogenation, measure the content that is greater than the particle diameter liposome medicament total phospholipids raw material of 150nm in liposome medicament dispersion medicinal liquid, and with sterilizing depyrogenation qualified freshly prepd 10% xylitol solution adjust medicine liquid volume, reach and 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 fluconazole liposome composition of medicine:
(1) by fluconazole liposome composition of medicine nanometer particle size lyophilized injection xylitol dosage, in injection phosphorus phthalate buffer, be dissolved into 10% percentage by weight solution of xylitol, by this solution 121 DEG C of steam sterilizations 20 minutes, in the time that solution temperature is 20-25 DEG C, with the ultrafiltration post ultrafiltration of the ultrafilter membrane of molecular cut off 1000D, except pyrogen and pyrogen molecule fragment in solution, 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 to the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8%, by A, B solution respectively through the membrane filtration mistake in the 0.05 following aperture of μ m, remove the precipitate of insoluble particle, high volence metal ion, metal ion, then be 5.0-8.0 with 8% analytically pure hydrochloric acid solution adjust pH respectively by A, B solution;
(2) by A solution preparing in the spray dryer of pharmaceutical injection agent level, by the dry well-established law of spraying, A solution by the spraying nozzle at equipment top with 100 grades of compressed airs of cleanliness factor, by compressor come, room temperature, mix ejection, 150 DEG C of-190 DEG C of 100 grades of pure airs of temperature with device bottom enters, are attracted high temperature by air-introduced machine, 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) add respectively fat-soluble crude drug fluconazol, phospholipid, phospholipid dispersant dimercaprol complete to stirring and dissolving in ethanol, make proportion at 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, through the 0.05 following aperture of μ m membrane filtration mistake, remove pyrogen, antibacterial, insoluble particle again;
(4) the composition dries granule of the A solution of being prepared by (2) step, is put in boiling seed-coating machine, and by boiling coating and the operation of airpillow-dry well-established law, the phospholipid alcoholic solution equal-volume of first being prepared by (3) step divides three parts, change introducing in device bottom anhydrous, aseptic, without oil, the room temperature purity nitrogen air-flow of the particle of the above particle diameter of nothing 0.001 μ m, at 40 DEG C of-65 DEG C of temperature, the dry thing particle of xylose that (2) step the is made coating under fluidized state that seethes with excitement: first by the phospholipid alcoholic solution of 1/3rd volumes of first part, being transported in the coating nozzle in the middle part of equipment by pump is that 100 grades of pure nitrogen gas mix with compressed clean rank, be spray form and be sprayed onto the thick that in machine, boiling is highly flowed for 400mm-450mm material xylitol, at boiling material particle surface coating, material simultaneous altitude under boiling is mixed and dispersion equably, and make as quick as thought solvent evaporates, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide completes, airpillow-dry 15 minutes, also three parts of deciles of the B solution of again being prepared by the first step, 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 of the particle of the above particle diameter of nothing 0.001 μ m, press aforesaid operations coating, after coating, airpillow-dry 20 minutes, carry out like this coating-drying process for the first time, repeat above-mentioned coating-drying process, carry out respectively the solution of 1/3rd volumes of second part, the 3rd part of two kinds of solution of second, third time by aforesaid operations, carry out the alternately coating-drying process of phospholipid liquid and B solution, outermost layer coatings is the dry thing layer of xylitol micropore, for the third time after coating, and residual moisture content≤1.0% in the coating dried material obtaining, residual dimercaprol≤0.2%,
(5) in material-compound tank, add the isopyknic water for injection of injection phosphorus acid salt solution of using 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, and in tank, under inflated with nitrogen, the dry thing of coating in 30 minutes to 60 minutes, the 4th step being made joins in material-compound tank; Add after the dry thing of coating, in tank, under inflated with nitrogen environment, keep 60 ± 5 DEG C of temperature, and keep 60-120 minute under 100 revs/min of stirrings; Under 100 revs/min of stirrings, tank inner liquid medicine is cooled to 30-40 DEG C again; Under 100 revs/min of stirrings, add respectively antioxidant glutathion and sodium dehydrocholate to dissolve completely, and adjust medicinal liquid pH value 5.0-8.0 again;
(6) keeping fluid temperature within the scope of 30 ± 5 DEG C, under 0.1-0.2Mpa nitrogen pressure, cross by 0.15 μ m membrane filtration the medicinal liquid that (5) step makes, 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%, and vacuum tamponade, rolls lid, and laggard storehouse is up to the standards; 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 aseptic ranks, the lipid drug particles that is greater than 150nm of holding back on the filter membrane that (6) step is filtered is washed by the 1st step operation, sterilizing, freshly prepd 10% xylitol solution of depyrogenation; The standby definition of this new system: 10% xylitol solution is that phosphate buffer is made solvent, xylitol amount and phosphate liquid measure all should be determined according to being greater than the liposome medicament amount of 150nm particle diameter, it is 10% xylitol solution newly increasing, exceed the amount in formula, measure the content of total phospholipids raw material in medicinal liquid, and adjust medicine liquid volume with qualified freshly prepd 10% xylitol solution of sterilizing depyrogenation, reach and control in medicinal liquid total phospholipids content at 40-80mg/ml; This medicinal liquid is joined in another batching filling, rush under 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; Keep again rushing under nitrogen, 100 revs/min of rotating speeds, cooling medicinal liquid, to 20-25 DEG C, divides medicinal liquid in the rustless steel pallet that installs to 316L, is put in the freeze drying box of another lyophilizing unit, and well-established law lyophilization, is less than 2% to moisture in medical solid; Dimercaprol residual quantity is for being less than 0.2%; Obtain liposome medicament solid, liposome medicament solid, under 100 grades of aseptic ranks, is crushed to 80-100 order, the dosage allowing by pharmaceutics, well-established law is made the aseptic enteric oral preparation of this medicine, asepticly fastens agent.
2. according to the normalized process for preparing of fluconazol plastid composition of medicine claimed in claim 1, it is characterized in that, in manufacturing step: (1) step is dissolving ultrafiltration; (2) step is that spraying is 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 processed; (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 fluconazole liposome composition of medicine claimed in claim 1, it is characterized in that, the dosage allowing by pharmaceutics, makes the lyophilized injection of fluconazole liposome composition of medicine, or is mixed with spray by well-established law again.
4. according to fluconazole liposome composition of medicine claimed in claim 1, it is characterized in that, fluconazole liposome composition of medicine, is the aseptic enteric oral preparation of the fluconazole liposome composition of medicine of pharmaceutics permission, or the aseptic suppository of fluconazole liposome composition of medicine.
5. according to a kind of fluconazole liposome composition of medicine claimed in claim 1, it is characterized in that, the combination that equipment used is dissolving tank-ultrafiltration post-spray dryer-boiling seed-coating machine-freezer dryer is manufactured in its industrialization.
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CN2011101523652A Pending CN102258472A (en) 2010-07-29 2011-06-09 Combined medicament formulation of cefuroxime sodium liposome, preparation method and applications thereof
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Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2021180184A1 (en) * 2020-03-12 2021-09-16 石药集团中奇制药技术（石家庄）有限公司 Use of mitoxantrone hydrochloride liposomes
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030235610A1 (en) * 2002-06-21 2003-12-25 Piedmont Pharmaceuticals, Llc Liposomes containing biologically active compounds
CN1483400A (en) * 2002-09-17 2004-03-24 西安力邦医药科技有限责任公司 automatic liposome preparation apparatus and method for prepaving liplsome by same
CN101273971A (en) * 2008-05-09 2008-10-01 绍兴文理学院 Ethosomes preparation of antimycotics pharmaceutical and method for preparing the same
CN101703470A (en) * 2009-11-17 2010-05-12 海南美兰史克制药有限公司 Solid preparation of fluconazole liposome and new application thereof

Family Cites Families (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE18353T1 (en) * 1981-07-02 1986-03-15 Hoffmann La Roche PROCESS FOR PREPARING LIPOSOME SOLUTIONS.
GB2135268A (en) * 1983-02-15 1984-08-30 Squibb & Sons Inc Method of preparing liposomes and products produced thereby
US4744989A (en) * 1984-02-08 1988-05-17 E. R. Squibb & Sons, Inc. Method of preparing liposomes and products produced thereby
US5880141A (en) * 1995-06-07 1999-03-09 Sugen, Inc. Benzylidene-Z-indoline compounds for the treatment of disease
TW367324B (en) * 1995-08-16 1999-08-21 Ono Pharmaceutical Co Prostaglandin derivatives
US5718917A (en) * 1995-12-15 1998-02-17 Harvard Scientific Corporation PGE-1 containing lyophilized liposomes for use in the treatment of erectile dysfunction
JP2001511780A (en) * 1997-02-04 2001-08-14 アボツト・ラボラトリーズ Analgesic parenteral liposome formulation
RU2111744C1 (en) * 1997-03-20 1998-05-27 Всероссийский научно-исследовательский институт ветеринарной вирусологии и микробиологии Preparation abactan for treatment and prophylaxis of infectious sicknesses in animals
US6106858A (en) * 1997-09-08 2000-08-22 Skyepharma, Inc. Modulation of drug loading in multivescular liposomes
IT1298575B1 (en) * 1998-02-06 2000-01-12 Vectorpharma Int PHARMACEUTICAL COMPOSITIONS IN THE FORM OF NANOPARTICLES INCLUDING LIPID SUBSTANCES AND ANTIPHILIC SUBSTANCES AND RELATED PROCESS OF
PT1194145E (en) * 1999-06-22 2003-06-30 Boehringer Ingelheim Int STABILITY SOLUTION OF XYLOMETAZOLIN AND OXIMETAZOLIN
KR100669507B1 (en) * 2000-08-01 2007-01-16 보령제약 주식회사 Process for the preparation of cefuroxime
CN1469735A (en) * 2000-10-16 2004-01-21 ����˹��ҩ�﹫˾ Liposomal formulation of mitoxantrone
CN1127986C (en) * 2001-06-21 2003-11-19 中国人民解放军第二军医大学 Process for preparing lipoid as precursor of medicine carrier
CN1449759A (en) * 2002-04-10 2003-10-22 南阳普康集团化学制药厂 Prostaglandin E1 liposome frozen dry powder injection and production technology thereof
US20030215493A1 (en) * 2002-04-30 2003-11-20 Patel Pravin M. Composition and method for dermatological treatment
WO2003099362A1 (en) * 2002-05-20 2003-12-04 Research Development Foundation Aerosol drug inhibition of lung metastases
CN1411803A (en) * 2002-08-29 2003-04-23 四川大学 Method for preparing precursor liposome and its device
US6702850B1 (en) * 2002-09-30 2004-03-09 Mediplex Corporation Korea Multi-coated drug-eluting stent for antithrombosis and antirestenosis
SE0203065D0 (en) * 2002-10-16 2002-10-16 Diabact Ab Gastric acid secretion inhibiting composition
US20040092735A1 (en) * 2002-11-08 2004-05-13 Orchid Chemicals & Pharmaceuticals Limited Process for the preparation of cefuroxime sodium
US7691905B2 (en) * 2002-12-24 2010-04-06 New York University Inhibition of melanogenesis and melanoma metastasis with p-aminobenzoic acid (PABA)
CN1215839C (en) * 2003-07-18 2005-08-24 中国药科大学 Nano granules of solid lipid of tanshinone and its preparation method
CN1623538A (en) * 2003-12-02 2005-06-08 刘力 Tanshinone II A sulfonic acid or tanshinone II A sodium sulfonate freeze-dried powder injection and its preparation method
EP1706148A2 (en) * 2004-01-14 2006-10-04 Gilead Sciences, Inc. Lipid-based dispersions useful for drug delivery
CN1669554A (en) * 2004-03-17 2005-09-21 昆明希捷医药研发有限公司 Liposome vitality conazole preparation
CN1563007A (en) * 2004-04-07 2005-01-12 复旦大学 9-(2-fatty ester ethoxy methyl) guanine, liposome, and preparation emthod
ES2388064T3 (en) * 2004-04-22 2012-10-08 Celator Pharmaceuticals, Inc. Liposomal formulations of anthracycline agents and cytidine analogues
ATE450251T1 (en) * 2004-05-17 2009-12-15 Tekmira Pharmaceuticals Corp LIPOSOMAL FORMULATIONS CONTAINING DIHYDROSPHINGOMYELIN AND METHODS OF USE THEREOF
CN1242740C (en) * 2004-08-05 2006-02-22 常州太平洋药物研究所有限公司 Mitoxantrone or mitoxantrone hydrochloride liposome injection and its preparing process
CN1745750A (en) * 2004-09-11 2006-03-15 胡才忠 Lansoprazole liposome and its preparation
JP4228230B2 (en) * 2004-11-08 2009-02-25 独立行政法人産業技術総合研究所 Method for producing liposome suspension and use using liposome
CN1660119A (en) * 2004-12-22 2005-08-31 王剑 Liposome combination of precursor of vitamine D3 and preparation method
DE102005002469B3 (en) * 2005-01-18 2006-05-11 Abnoba Heilmittel Gmbh Encapsulation of substances in liposome comprises applying two different monolayers on porous carrier membrane; applying different fluid volumes on monolayers; bringing compressible membrane and lacing the dismantled area to liposome
CN100364533C (en) * 2005-04-19 2008-01-30 北京正大绿洲医药科技有限公司 Pyrolidone hydrochloride drip pill and its preparation method
CN1686125A (en) * 2005-05-08 2005-10-26 北京正大绿洲医药科技有限公司 Rogelinone drip pill and its preparation method
CN1751751A (en) * 2005-09-07 2006-03-29 华北制药集团有限责任公司 Immediate dispensing infusion
CN1977826A (en) * 2005-11-23 2007-06-13 兰贝克赛实验室有限公司 Method for increasing prodrug bioavailability using solid lipid nano granule
CN100506962C (en) * 2005-12-09 2009-07-01 郭涛 Garlic oil refining process and the Preparation process of its emulsion and solid nanometer liposome particle
US20070231390A1 (en) * 2006-03-29 2007-10-04 Andrx Labs, Llc Formulations including hygroscopic compounds
CN100459978C (en) * 2006-04-28 2009-02-11 广东药学院 Rosiglitazone slow-release tablet and its preparation method
AR061070A1 (en) * 2006-05-23 2008-07-30 Takeda Pharmaceutical ORAL PREPARATION UNDERSTANDING PIOGLITAZONA
CN1951386A (en) * 2006-06-05 2007-04-25 张宏宇 Medicinal combinations composed by meropenem with three kinds of sputum removing medicament respectively
CN101091698A (en) * 2006-06-22 2007-12-26 刘祥华 New type antineoplastic medicine, and preparation method
CN101095659A (en) * 2006-06-28 2008-01-02 蔡海德 Liposome combined medicine and method for preparing the same
CN101108188A (en) * 2006-07-17 2008-01-23 广州瑞济生物技术有限公司 Novel long circulation alprostadil liposome drug feeding system for injection and method of preparing the same
CN1887271A (en) * 2006-08-02 2007-01-03 刘祥华 Azithromycin liposome composition medicine and its prepn process
CN1907266A (en) * 2006-08-22 2007-02-07 刘祥华 Potassium dehydroandrographolide succinate/potassium dehydroandrographolide succinate liposome composition and production method thereof
CN1915222B (en) * 2006-09-18 2010-08-04 蔡海德 Composition of liposome, and preparation method
US7976743B2 (en) * 2006-10-16 2011-07-12 Northwestern University Gas-containing liposomes
CN100490807C (en) * 2006-10-23 2009-05-27 石药集团欧意药业有限公司 Cephalofruxin ester liposome, its preparation and medicinal composition containing it
CN100586421C (en) * 2006-11-09 2010-02-03 刘祥华 Ligustrazine microcosmic salt liposome medicine and preparing method
CN100586430C (en) * 2006-11-09 2010-02-03 刘祥华 Paclitaxel/multialkene paclitaxel liposome composite medicine and preparation method thereof
CN1973826A (en) * 2006-12-18 2007-06-06 沈阳药科大学 Injection containing lipoid microsphere of etoposide and its prepn process
CN101209243B (en) * 2006-12-29 2010-12-08 石药集团中奇制药技术（石家庄）有限公司 Liposome medicament and preparation thereof
DE602008003522D1 (en) * 2007-02-01 2010-12-30 Takeda Pharmaceutical SOLID PREPARATION WITH ALOGLIPTIN AND PIOGLITAZONE
CN101657098A (en) * 2007-02-16 2010-02-24 切拉托尔制药公司 The fixed drug ratios that is used for the treatment of hematopoiesis cancer and proliferative disorders
CN101019869B (en) * 2007-03-09 2010-10-13 蔡海德 Medicine composition of alprostadil and Chuanhuning/Yanhuning liposome and its preparation
GB0710277D0 (en) * 2007-05-30 2007-07-11 Univ Birmingham Use of antivirals in the treatment of medical disorders
CN101322690A (en) * 2007-06-12 2008-12-17 广州瑞济生物技术有限公司 Stable medicament lipid complexes
CA2595485A1 (en) * 2007-08-01 2009-02-01 Bc Cancer Agency Liposomal compositions for parenteral delivery of statins
CN101156853A (en) * 2007-09-27 2008-04-09 刘全胜 Hydrochloric acid glitazone dispersion piece and its preparation method
CN101152178B (en) * 2007-10-11 2010-10-06 蔡海德 Sophoridine nano liposome medicament and preparation of the same
CN101152182A (en) * 2007-10-17 2008-04-02 沈阳药科大学 Drug administration preparations of ligustrazine for nasal mucosa and method for preparing the same
CN101439034A (en) * 2007-11-22 2009-05-27 沈阳沃森药物研究所 Tanshinone IIA lipid complexes and micelle composition thereof for injection
WO2009075391A1 (en) * 2007-12-13 2009-06-18 Kyushu University, National University Corporation Drug-containing nanoparticles
KR100970911B1 (en) * 2007-12-13 2010-07-20 재단법인서울대학교산학협력재단 External preparation comprising triazole derivative antifungal agent and preparation method thereof
CN101524448B (en) * 2008-03-04 2012-04-18 华东理工大学 Analgesic and anti-inflammatory Chinese medicinal composition as well as preparation method and application of preparation thereof
CN101507708B (en) * 2008-03-28 2011-01-19 中国人民解放军济南军区第四○一医院 Preparation method of liposome
EP2143422A1 (en) * 2008-07-11 2010-01-13 S.I.F.I - Società Industria Farmaceutica Italiana - S.P.A. Ophthalmic compositions containing gemifloxacin for the treatment of ocular infections
CN101366698A (en) * 2008-09-28 2009-02-18 中国药科大学 Biogastrone acid prosome liposome with long circulation function and preparation method thereof
TR201102640T1 (en) * 2008-12-01 2011-08-22 Glade Organics Private Limited Synergistic combinations of aztreonam with meropenem and ertapenem.
CN101474155B (en) * 2009-01-24 2011-03-16 重庆医科大学 Lung-targeted medicine carrying precursor liposome for injection and method of use thereof
CN101491499B (en) * 2009-02-19 2010-10-13 陶灵刚 Composite liposome for injection containing 12 vitamins and preparation method thereof
CN101530393B (en) * 2009-04-07 2010-10-13 王明 Clindamycin phosphate lipidosome freeze-dried preparation
CN101658493B (en) * 2009-09-09 2012-08-15 苏州纳康生物科技有限公司 Azithromycin nanostructured lipid carrier and preparation method thereof
CN101721379B (en) * 2009-11-19 2011-02-02 海南美兰史克制药有限公司 Cefuroxime sodium suspension powder injection
CN101703469B (en) * 2009-11-24 2011-10-19 东北农业大学 Preparation method and products of danofloxacin mesylate liposome
CN101766571B (en) * 2010-02-05 2011-09-14 王明 Cefpiramide, sodium benzoate, sodium bicarbonate pharmaceutical composite lipidosome injection
CN101912363A (en) * 2010-07-29 2010-12-15 蔡海德 Dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine
CN101912364B (en) * 2010-08-09 2015-07-15 刘会梅 Ginkgolide B liposome medicinal composition
CN102091035A (en) * 2010-08-20 2011-06-15 邓学峰 Pefloxacin mesilate liposome medicine composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030235610A1 (en) * 2002-06-21 2003-12-25 Piedmont Pharmaceuticals, Llc Liposomes containing biologically active compounds
CN1483400A (en) * 2002-09-17 2004-03-24 西安力邦医药科技有限责任公司 automatic liposome preparation apparatus and method for prepaving liplsome by same
CN101273971A (en) * 2008-05-09 2008-10-01 绍兴文理学院 Ethosomes preparation of antimycotics pharmaceutical and method for preparing the same
CN101703470A (en) * 2009-11-17 2010-05-12 海南美兰史克制药有限公司 Solid preparation of fluconazole liposome and new application thereof

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