CN102258472A - Combined medicament formulation of cefuroxime sodium liposome, preparation method and applications thereof - Google Patents
Combined medicament formulation of cefuroxime sodium liposome, preparation method and applications thereof Download PDFInfo
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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
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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
- A61K31/33—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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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 a combined medicament of cefuroxime sodium liposome. The combined medicament is characterized in that all components and the mole ratio of the combined medicament of the cefuroxime sodium liposome are disclosed; and the invention also provides a large-industrialization preparation method of the combined medicament of the cefuroxime sodium liposome. The invention is characterized in that according to the dosage allowed pharmaceutically, a freeze-drying injection, or an oral preparation, or a spraying agent or a suppository of the combined medicament of the cefuroxime sodium liposome is prepared; and the combined medicament of the cefuroxime sodium liposome is characterized by being used for infection resistance.
Description
The application is for enjoying the domestic priority application.Formerly applicant country is a China, is 201010240184.0 at the application number of first to file, and the applying date is on 07 29th, 2010, and name is called " dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine ".
Technical field
The present invention relates to a kind of big suitability for industrialized production liposome composite medicine prescription and preparation method, it is characterized in that, subject matter is with dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze-drying, with unified prescription, technology, equipment both suitability for industrialized production liposomal body composition injection greatly, suitability for industrialized production liposomal body composition oral preparation greatly again.
Background technology
China's pharmaceutical technology, crude drug technology of preparing and international most advanced level gap be only in 5 years, and what have meets or exceeds international most advanced level, and preparation technique will fall behind international most advanced level 20 years.Now a large amount of is produces secondary ordinary preparation, and three generations's slow release, controlled release agent, especially four generation targeting preparation such as liposome only be in the laboratory research stage at present.Reason has:
1, existingly produce, scientific research prepares liposome medicament technology injection and oral formulations prescription, technology, equipment disunity, both wasted resource, the energy, investment is greatly, and is of low quality again, contaminated environment.
2, the method for liposome medicament suitability for industrialized production is had: high pressure homogenization method, supercritical ultrasonics technology, organic solvent seasoning, spray drying method, fluidized bed coating, single phase soln freeze-drying.High pressure homogenization method and supercritical ultrasonics technology particle diameter are controlled, but the high energy fragmentation has destruction to crude drug; The four kinds of methods in back to particle diameter uncontrollable and particle size distribution do not concentrate, organic solvent residual has quality problems such as leakage, precipitation, cohesion, phospholipid corruption;
3, existing method for preparing lipidosome makes the envelop rate of lipidosome drug carrier can not reach 100%, and each batch fluctuation, variation are greatly; Slip is big, loses the liposome medicament meaning;
4, production process is turned from side to side manyly, and during energy charge, equipment investment is big, prescription, technology unstable by, immature, cause that the quality of the pharmaceutical preparations is uncontrollable, unstable, poor reproducibility;
5, sterilization, depyrogenation method are improper, and omnidistance aseptic, apyrogeneity operation is difficult to ensure, liposome medicament is lacked the height aseptic concept, cause liposome medicament corrupt under antibacterial corrodes, envelop rate falls progressively, and slip increases progressively, effect duration is extremely short, almost loses medical value;
6, injection indissolubility population and particle diameter exceed standard;
7, crude drug, phospholipid and adjuvant, solvent selection do not have the national drug quality standard mostly, have patent not criticize New Drug Certificate and production certification yet, and the registration difficulty is very big, chronic;
8, break away from Chinese truth, obtain liposome new drug production certification, spend nearly 10 years from developing to, expensive more than 2,000 ten thousand yuan, good again medicine patent of invention, exhausted big multiple enterprises dare not be invested and developed.As seen, carry out medical reform and national system for basic pharmaceutical period in country, from enter the secondary preparation of national essential drugs, select the big product of sales volume to rise to the Liposomal formulation in the 4th generation, carry out the preparation technique innovation, eliminate its side effect and untoward reaction, the medicine sales volume is big like this, and the investment recovery time is short.Reach safety, effectively, high-quality, economic this basic principle.
Summary of the invention
The present invention seeks to overcome the defective of above-mentioned prior art.Theme of the present invention is: with dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze-drying, with unified prescription, technology, equipment both suitability for industrialized production liposomal body composition injection greatly, suitability for industrialized production liposomal body composition oral preparation greatly again.The standard prescription and the normalized process for preparing of 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:
Each pharmacodynamic raw materials mole ratio of the standard of suitability for industrialized production liposome composite medicine of the present invention is as follows:
1, crude drug 0.05-0.20
2, phospholipid raw material 0.50-4.00
3, antioxidant 0.01-0.06
4, immobilized artificial membrane molecular state diluent 1.00-6.00
5, liposome medicine carrying body dispersant and excipient 2.00-8.00
6, surfactant 0.01-0.05
7, ethanol
〉=75% concentration (volume ratio, ethanol: water 〉=75% evaporates into to the greatest extent when dry) is an amount of
8, injection phosphorus phthalate buffer
0.01-0.05M concentration pH value 5.0-8.0 (evaporating into to the greatest extent during drying) is an amount of
9, water for injection (evaporating into to the greatest extent during drying) and injection phosphorus hydrochlorate equal-volume
Described crude drug is the water solublity powerful feature, and prescription dosage is 1/3rd to 1/5th of the oral or injection preparation minimum gauge amount of formulation of existing secondary correspondence.Preferably: Cefuroxime Sodium.
The mean molecule quantity of described phospholipid raw material all defines with 800D and calculates, and the phospholipid raw material is the compositions of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine, and mole ratio is 1-5: 0.5 compositions.
The antioxidant of described phospholipid is reduced glutathion.
Described immobilized artificial membrane molecular state diluent is again an antioxidant, is dimercaprol.
Described liposome medicine carrying body dispersant is again an excipient, is xylitol.
Described surfactant is a sodium dehydrocholate.
Each pharmacodynamic raw materials of liposome composite medicine all should have national standard, and all is the national standard of pharmaceutical injection agent level.Both met national GMP standard, met the regulation of country's " medicine registration management way " again, in order to industrialization development.
The present invention also provides the normalized process for preparing of described group of plastid composition of medicine:
(1) the xylitol dosage is dissolved into 10% percentage by weight solution of xylitol in the injection phosphorus phthalate buffer, with this solution 121 ℃ of steam sterilizations 20 minutes, when solution temperature is 20-25 ℃, ultrafiltration post ultrafiltration with the ultrafilter membrane of molecular cut off 1000D, remove pyrogen and pyrogen molecule fragment in the solution, get the solution that ultrafiltration obtains; Again at room temperature, the solution that the five equilibrium ultrafiltration obtains, be divided into A, B solution, A, B solution are used the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8% respectively, with A, B solution respectively through the membrane filtration mistake in the following aperture of 0.05 μ m, removing the precipitate of insoluble particle, high volence metal ion, metal ion, is 5.0-8.0 with 8% analytically pure hydrochloric acid solution adjust pH respectively with A, B solution again; The crude drug Cefuroxime Sodium that water solublity is strong is complete with an amount of water for injection dissolving, with the membrane ultrafiltration of molecular cut off 1000D, depyrogenation, gained ultrafiltration solution merges in the B solution and stirs, through the following membrane filtration mistake in 0.05 μ m aperture, remove bacterium in the raw material medicine solution, insoluble particle again; Raw material medicinal liquid requirement check pyrogen and insoluble particle are qualified could to be allowed to add in the B solution;
(2) with A solution in the spray dryer of preparation pharmaceutical injection agent level, by the spray drying well-established law, A solution is by (being come by compressor with 100 grades of compressed airs of cleanliness factor in the spraying nozzle at equipment top, room temperature) mixes ejection, 150 ℃ of-190 ℃ 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 mixes, and is spray dried to 120-150 order left and right sides porous granule dry powder; Drying finishes, and it is standby that dried material leaves this device bottom in;
(3) it is complete to add fat-soluble phospholipid, phospholipid dispersant stirring and dissolving in the ethanol respectively, make proportion at 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, through the following aperture of 0.05 μ m membrane filtration mistake, remove pyrogen, antibacterial, insoluble particle again;
(4) the composition dries granule of the A solution that (2) step was prepared is put in the boiling coating machine, and by boiling coating and the operation of airpillow-dry well-established law, elder generation divides three parts with the phospholipid alcoholic solution equal-volume of (3) step preparation; It is anhydrous to change introducing in device bottom, aseptic, there is not oil, the room temperature purity nitrogen air-flow that does not have the particle of the above particle diameter of 0.001 μ m, under 40 ℃ of-65 ℃ of temperature, to the dry thing particle of the 2nd xylose that makes of the step coating under the fluidized state that seethes with excitement: earlier with (1/3rd volumes) phospholipid alcoholic solution of first part, being transported in the coating nozzle at equipment middle part with compressed clean rank by pump is that 100 grades of pure nitrogen gas mix, be spray form and be sprayed onto the thick that boiling is highly flowed for 400mm-450mm material (xylitol) in the machine, at boiling material particle surface coating, the mixed equably and dispersion of material simultaneous altitude under the boiling, and make solvent evaporates as quick as thought, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide is finished, airpillow-dry 15 minutes, again with three parts of the B solution of first step preparation also five equilibrium, with 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, there is not oil, do not have in 100 grades of purity nitrogen air-flows of particle of the above particle diameter of 0.001 μ m, press the aforesaid operations coating, behind the coating, airpillow-dry 20 minutes has carried out coating-drying process for the first time like this; Repeat above-mentioned coating-drying process, carry out the solution of second part, the 3rd part 1/3rd volumes of two kinds of solution of second, third time respectively and press aforesaid operations, carry out the alternately coating-drying process of phospholipid liquid and B solution, the outermost layer coatings is the dry thing layer of micropore of the compositions of water-soluble crude drug, xylitol, for the third time behind the coating, residual moisture content≤1.0% in the coating dried material that obtains, residual dimercaprol≤0.2%; Notice that water miscible crude drug then is crude drug and xylitol three coatings of dried particles to A solution in B solution;
(5) add the isopyknic water for injection of using with the first step of injection phosphorus acid salt solution in material-compound tank, inflated with nitrogen maintains an equal level with jar external pressure in jar, under 100 rev/mins of mixing speeds, is heated to 60 ± 5 ℃; Transferring speed of agitator is 500-700 rev/min, and under the inflated with nitrogen, the dry thing of the coating that in 30 minutes to 60 minutes the 4th step was made joins in the material-compound tank in jar; After adding the dry thing of coating, in jar, under the inflated with nitrogen environment, keep 60 ± 5 ℃ of temperature, and under 100 rev/mins of stirrings, kept 60-120 minute; Under 100 rev/mins of stirrings, a jar inner liquid medicine is cooled to 30-40 ℃ again; Under 100 rev/mins of stirrings, add the dissolving of antioxidant glutathion and sodium dehydrocholate respectively fully again, and adjust medicinal liquid pH value 5.0-8.0;
(6) hold temperature in 30 ± 5 ℃ of scopes at guarantor's medicinal liquid, under the 0.1-0.2Mpa nitrogen pressure, cross the medicinal liquid that the 5th step made with 0.15 μ m membrane filtration, get filterable medicinal liquid, obtain the liposome medicinal liquid of particle diameter less than 150nm, the dosage packing liposome medicinal liquid that allows this medicine by pharmaceutics is in cillin bottle, and the false add plug, well-established law lyophilization in the freeze drying box of lyophilization unit; To medicine solid residue moisture be less than 2%, the dimercaprol residual quantity is less than 0.2%; Lid is rolled in the vacuum tamponade, and laggard storehouse is up to the standards; 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 the 6th step was held back on the filterable filter membrane greater than 150nm wash 10% by the operation of the 1st step, sterilization, depyrogenation prepares newly that (this new preparation definition: 10% xylitol solution is that phosphate buffer is made solvent, another name for amount and phosphate liquid measure all should be according to deciding greater than the liposome medicament amount of 150nm particle diameter, increase newly, surpass the amount in the prescription) 10% xylitol solution in, measure the content of total phospholipids raw material in the medicinal liquid, and adjust medicine liquid volume with qualified freshly prepd 10% xylitol solution of sterilization depyrogenation, reach in the control medicinal liquid total phospholipids content at 40-80mg/ml; This medicinal liquid is joined during another batching irritates, under nitrogen, 100 rev/mins of mixing speeds, 30-60 minute internal heating to 50 ± 5 ℃ keep this temperature range to stir 60-120 minute; Keep again under nitrogen, 100 rev/mins of rotating speeds, the cooling medicinal liquid installs to the medicinal liquid branch in the rustless steel pallet of 316L to 20-25 ℃, is put in the freeze drying box of another lyophilizing unit, the well-established law lyophilization, moisture is less than 2% to the medical solid; The dimercaprol residual quantity is less than 0.2%; Obtain the liposome medicament solid, the liposome medicament solid under 100 grades of aseptic ranks, is crushed to the 80-100 order, press the dosage that pharmaceutics allows, 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 the national GMP standard, and oral formulations also must be undertaken by the aseptic requirement of injection.
Liposome medicament of the present invention, aseptic freeze-dried injection in use, when using the dissolving of transfusion aquation in the cillin bottle, the phospholipid dispersant disperses liposome medicine carrying body rapidly, and under xylitol liquid surface tension and Action of Surfactant, 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 diameter particle at enteral, envelop rate is all 100%, liposome medicine carrying body is dispersed in the transfusion 6 hours internal leakage rates below 5%, do not precipitate, do not condense, not stratified, be uniformly dispersed, in gastrointestinal fluid, disperse to form single chamber and multicell mixing liposome medicament behind the drug oral of the present invention, improve the therapeutic index of medicine.
Advantage of the present invention has:
1, dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine, with unified prescription, technology, equipment both suitability for industrialized production liposomal body composition injection greatly, suitability for industrialized production liposomal body composition oral preparation greatly again.
2, with the innovative combination of innovation of the equipment of secondary preparation and secondary preparation process prepare four generation targeting preparation, make mysterious liposome medicament from laboratory implementation industrialization steady production.Standard prescription, the normalized process for preparing of liposome composite medicine have been opened up, and be that injection, oral formulations, other route of administration preparation have unified core prescription and 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, the invention medicine all is high request ground from the beginning of selecting materials, to preparation process, to using final liposome medicament to be distributed to the transfusion omnidistance aseptic, pyrogen to medicine, particle diameter, particle size distribution, envelop rate, slip, corrupt rate, the rate of settling, cohesion rate, effect duration or the like, perfect meets this basic principle, make the medicine industrialization development of the present invention risk of going on the market little.
4, the medicine core technology among the present invention has: the phospholipid feed molar is counted input amount and is broken through the prior art consumption, be 5 times of prior art consumption, be 10 times of crude drug, and crude drug is to select fat-soluble or water solublity to be better than the medicine of dispersant xylitol, widely greater than the envelop rate to xylitol, envelop rate reaches 100% to phospholipid to the envelop rate of medicine; Phospholipid raw material consumption is big simultaneously, has a large amount of blank liposomes, and blank liposome is lacked drug-loaded liposome and engulfed by macrophage phagocytic in vivo, and curative effect is higher; Surfactant is dissolved in the liposome phospholipid rete, the liposome bilayer is played " shutoff ", reinforcement effect, this is because the surface of liposome activating agent is a sodium salt, in pH value such as dissolving normal saline and glucose are infused less than 6, its sodium salt of part becomes water-fast acid molecule, and enter in the phospholipid bilayer, replace cholesterol also to play " shutoff ", reinforce the liposome particles effect, make slip very little, surfactant also has precipitation, the cohesion of lipotropism plastid in transfusion, strengthens liposome in addition and is dispersed into uniform liposome transfusion effect; Owing to add immobilized artificial membrane dispersant dimercaprol, when coating is dry, make immobilized artificial membrane be the micropore solid dispersion of molecular state, than the broken little thousands of times of phospholipid raw material particle of high pressure bump, xylitol replaces evaporable dimercaprol position when coating, form phospholipid and xylitol molecules attitude microporous solids dispersion, make xylitol become the dispersant of liposome; Originally discover, xylitol also with the mannitol sample have protection liposome medicine carrying body when the lyophilization not by the destructive protective effect of little ice slag, but mannitol has stimulation to blood vessel when intravenous drip; Dimercaprol is antioxidation when coating, and protection glutathion, phospholipid, crude drug are not oxidized, make glutathion play antioxidation and anti-peroxidation group usefulness in vivo, and the liver protecting are not damaged by medicine; Phospholipid material originally discovers, this saturated phospholipid of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine compositions make that liposome is stable, slip is low, and phospholipid does not have antigen and harmless to liver to human body; Lipidosome freeze-dried injection of the present invention is to have made the lyophilization again of liposome dispersed system, when aquation again, keeps liposome physics and chemical property constant.
5, because particle diameter, the particle size distribution of above-mentioned effect medicine of the present invention in transfusion is constant, envelop rate 100%, slip≤5%, corrupt rate are 0%, sedimentation rate is 0%, the cohesion rate is 0%, eliminated the accumulating of liposome medicament refrigerator, content and envelop rate falls progressively, slip is risen progressively, effect duration is shorter than four big world property difficult problems of crude drug.Become satisfactorily good can be practical four generation preparation.
6, the liposome medicament of the present invention's preparation, phospholipid is to become solid solution to be scattered in the immobilized artificial membrane suction with molecularity to release in agent and the surfactant in the immobilized artificial membrane, and than supercritical ultrasonics technology, the little thousands of times of the broken phospholipid particle of high-pressure uniform matter; The volatilization of solvent and dimercaprol makes the phospholipid rete form countless micro hole layers in spray coating-drying, it is much bigger that this forms the network structure specific surface area than freeze-drying, because in the freeze-drying process in the solid hydrone distillation volatilization distance network structure is dissolved condenses than the long thousands of times of coatings distance; Again because phospholipid rete and xylitol layer are the immobilized artificial membrane dispersant layers, when aquation rapidly, high degree of dispersion phospholipid.These three kinds of advantages, more stable than the liposome particles particle diameter that prior art forms, more favorable reproducibility ground forms the 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, be human body and microbial cell film component, pathogenic bacteria, virocyte, tumor cell and blood vessel wall destruction place there is better targeting drug release function, the therapeutic index height, so the crude drug consumption only is 1/3rd to 1/5th of a secondary medicine, add sealing of phospholipid, the untoward reaction of crude drug has not almost had.The consumption of crude drug reduces, and strengthens the phospholipid consumption, guarantees that envelop rate reaches 100%, and has " shutoff " to reinforce the surfactant of liposome effect, so slip is zero.
8, the immobilized artificial membrane dispersant of composition of medicine of the present invention is again the proppant of immobilized artificial membrane coating.Be again the material of liposome particles size when controlling the proliposome aquation jointly with surfactant, they are by due to the surface tension effects that forms certain limit in aqueous solution.Xylitol can be ideal immobilized artificial membrane dispersant and excipient to diabetes, hepatopath's energize.
9, the immobilized artificial membrane diluent of composition of medicine of the present invention; by not only being dissolved in ethanol but also water-soluble; when spray drying, volatilize; form the micropore phospholipid rete that immobilized artificial membrane becomes the molecular state solid dispersion system; when aquation in the immobilized artificial membrane phospholipid be with the molecular state degree of crushing and and surface dispersant phospholipid is distributed in the water; form uniform nanoparticle liposome medicine carrying body, dimercaprol wherein is again the antioxidant of good liposome, protection phospholipid and medicine when coating.
10, the Action of Surfactant of composition of medicine of the present invention first is when the phospholipid aquation phospholipid to be distributed in the water, second in the transfusion that enters pH value 4.0-6.0, it is the molecular structure organic acid by the sodium salt acidify again, enter again in the two branch of the liposome fat layer, play liposome " shutoff " reinforcement effect, the 3rd plays Action of Surfactant at surface of liposome.
11, the present invention can make liposome medicament effect duration reach 1 year, adopts four effective measures: the one, added antioxidant, protection immobilized artificial membrane and not oxidation of crude drug; The 2nd, in immobilized artificial membrane coatings outside, bag protects the phospholipid rete in phospholipid dispersant coatings; The 3rd, oral formulations also is by injection selection, sterilization and sterile working, eliminates antibacterial the corruption of phospholipid is decomposed, and this is the place of all existing liposome oral formulations and even injection technology significant error; The 4th, be scattered in the transfusion at liposome, metal ion in 0.2% the dimercaprol complexation transfusion is arranged, make the metal ion that brings in the transfusion can not destroy phospholipid and liposome medicine carrying body, at vitamin C-glutathion-dimercaprol combination antioxidant, under surface of liposome activating agent, dispersant combined effect, do not leak, do not precipitate, not stratified, do not condense, not oxidation, not corrupt, thereby make liposome carry that about body is real has crossed actual use value difficulty.Liposome medicine carrying body is dispersed in the transfusion, owing under the effect of defective of liposome own and transfusion, make liposome composite medicine produce qualitative change, also is the significant error part that the present invention remedies prior art.
12, liposome medicament of the present invention is in preparation process, phospholipid liquid and phospholipid dispersant liquid are all crossed (the injection preparation all is to cross through 0.22 μ m membrane filtration usually) through the membrane filtration below the 0.05 μ m aperture, make the indissolubility particle diameter reduce to 1/4th of permissible value, make that particle diameter 50nm to 150nm particle is liposome particles entirely after the liposome aquation.Can accurately measure the particle diameter and the particle size distribution of liposome medicine carrying body.This also is the place that the present invention remedies the prior art significant error.
The specific embodiment:
Embodiment 1
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is a Cefuroxime Sodium 0.05
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 0.50
3, antioxidant is reduced glutathion 0.01
4, immobilized artificial membrane molecular state diluent is a dimercaprol 1.00
5, liposome medicine carrying body dispersant and excipient are xylitol 2.00
6, surfactant is a sodium dehydrocholate 0.01
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (dry time evaporate into to the greatest extent) and injection phosphorus phthalate buffer equal-volume preparation method are as previously mentioned.
Embodiment 2
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is a Cefuroxime Sodium 0.20
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 4.00
3, antioxidant is reduced glutathion 0.06
4, immobilized artificial membrane molecular state diluent is a dimercaprol 6.00
5, liposome medicine carrying body dispersant and excipient are xylitol 8.00
6, surfactant is a sodium dehydrocholate 0.05
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is described with the front with injection phosphorus phthalate buffer equal-volume preparation process and method.
Embodiment 3
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is a Cefuroxime Sodium 0.12
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 2.50
3, antioxidant is reduced glutathion 0.04
4, immobilized artificial membrane molecular state diluent is a dimercaprol 5.00
5, liposome medicine carrying body dispersant and excipient are xylitol 6.00
6, surfactant is a sodium dehydrocholate 0.03
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is described with the front with injection phosphorus phthalate buffer equal-volume preparation process and method.
Embodiment 4
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is a Cefuroxime Sodium 0.05
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 4.00
3, antioxidant is reduced glutathion 0.01
4, immobilized artificial membrane molecular state diluent is a dimercaprol 6.00
5, liposome medicine carrying body dispersant and excipient are xylitol 2.00
6, surfactant is a sodium dehydrocholate 0.05
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is described with the front with injection phosphorus phthalate buffer equal-volume preparation process and method.
Embodiment 5
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is a Cefuroxime Sodium 0.20
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 0.50
3, antioxidant is reduced glutathion 0.06
4, immobilized artificial membrane molecular state diluent is a dimercaprol 1.00
5, liposome medicine carrying body dispersant and excipient are xylitol 8.00
6, surfactant is a sodium dehydrocholate 0.01
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
Evaporate into to the greatest extent when 9, water for injection is dry) described with injection phosphorus phthalate buffer equal-volume preparation process and method with the front.
Embodiment 6
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is an oxacillin sodium 0.05
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 0.50
3, antioxidant is reduced glutathion 0.01
4, immobilized artificial membrane molecular state diluent is a dimercaprol 1.00
5, liposome medicine carrying body dispersant and excipient are xylitol 2.00
6, surfactant is a sodium dehydrocholate 0.01
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is described with the front with injection phosphorus phthalate buffer equal-volume preparation process and method.
Embodiment 7
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is an oxacillin sodium 0.20
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 4.00
3, antioxidant is reduced glutathion 0.01
4, immobilized artificial membrane molecular state diluent is a dimercaprol 6.00
5, liposome medicine carrying body dispersant and excipient are xylitol 8.00
6, surfactant is a sodium dehydrocholate 0.05
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is described with the front with injection phosphorus phthalate buffer equal-volume preparation process and method.
Embodiment 8
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is an oxacillin sodium 0.16
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 3.53
3, antioxidant is reduced glutathion 0.05
4, immobilized artificial membrane molecular state diluent is a dimercaprol 4.00
5, liposome medicine carrying body dispersant and excipient are xylitol 7.00
6, surfactant is a sodium dehydrocholate 0.05
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is ditto described with the standard preparation process and the method for injection phosphorus phthalate buffer equal-volume present embodiment.
Embodiment 9
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is an oxacillin sodium 0.05
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 4.00
3, antioxidant is reduced glutathion 0.01
4, immobilized artificial membrane molecular state diluent is a dimercaprol 6.00
5, liposome medicine carrying body dispersant and excipient are xylitol 2.00
6, surfactant is a sodium dehydrocholate 0.05
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is described with the front with injection phosphorus phthalate buffer equal-volume preparation process and method.
Embodiment 10
Crude drug is that each pharmacodynamic raw materials mole ratio of the strong liposome composite medicine standard of water solublity is as follows:
1, crude drug is an oxacillin sodium 0.20
2, the phospholipid raw material is soybean lecithin and polyene phosphatidylcholine
1: 0.1 compositions of molal quantity 0.50
3, antioxidant is reduced glutathion 0.06
4, immobilized artificial membrane molecular state diluent is a dimercaprol 1.00
5, liposome medicine carrying body dispersant and excipient are xylitol 8.00
6, surfactant is a sodium dehydrocholate 0.01
7, ethanol 80% (v/v) (evaporating into to the greatest extent during drying) is an amount of
8, injection phosphorus phthalate buffer 0.05M pH value 5.0-8.0 is an amount of
9, water for injection (evaporating into to the greatest extent during drying) is described with the front with injection phosphorus phthalate buffer equal-volume preparation process and method.
Technological Economy and quality index contrast
The inventive method is spared matter freeze-drying fluidized bed coating
But 1 preparation type is oral, injection injection, oral liposome
Liposome medicine carrying body liposome medicine carrying body medicine carrying body
2,100kg/ criticizes fat
1,600 ten thousand yuan 2,600 ten thousand yuan 1,200 ten thousand yuan of plastid equipment investments
3,24 hours man-hours/batches 48 hours/batches 8 hours/batches
4, aseptic rate 100% 90% limited bacterium colonies
5, pyrogen≤50EU/ml≤100EU/ml≤300EU/100mg
6, envelop rate 100% 80%-90% 80%-90%
7, slip≤5%≤20%≤20%
8, particle diameter nm≤150≤200≤2000
9, produce impurity 3%-5% 10%-20% 5%-10%
Conclusion: the technology of the present invention prepares liposome medicine carrying body and existing even matter freeze-drying, fluidized bed coating law technology system liposome medicine carrying bulk phase ratio, the technology of the present invention economy and main quality index all are superior to even matter freeze-drying, and quality index all is better than fluidized bed coating.
Learn demonstration test:
The anti-infectives pharmacodynamics test:
(1) animal is selected: select the mice by the infection animal experimental model of Experimental Animal Center preparation, body weight 18-22g, male and female half and half, random packet, 50 of every treated animals.
(2) infection bacteria species: staphylococcus aureus causes the model mice of pneumonia, two groups of model mice that streptococcus pneumoniae causes pneumonia.
(3) infection dosage: measure 100% minimum lethal dose (100%MLD) of the bacterial strain that tries by Experimental Animal Center, as 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: with the mice branch: the A. staphylococcus aureus causes the model mice group of pneumonia, two groups of model mice group that the B. streptococcus pneumoniae causes pneumonia.Carry out the clindamycin phosphate for injection contrast of not administration contrast, prior art for preparing, medicine of the present invention contrast.50 of every group model animals.Quiet immediately notes administration or oral was administered once every 6 hours again after the infection.Observe the reaction of animal thing, continuous 7 days, record dead mouse number.Used medicine and dosage, effect are seen the result of the test table:
By above-mentioned results of pharmacodynamic test as seen, liposome composite medicine medicine of the present invention all is better than showing of prior art for preparing in safety, stability, curative effect comprehensively and sells corresponding medicine.
Claims (3)
1. the Cefuroxime Sodium liposome composite medicine is characterized in that, each pharmacodynamic raw materials mole ratio of Cefuroxime Sodium liposome composite medicine of the present invention is as follows:
Described crude drug is the water solublity powerful feature, and prescription dosage is 1/3rd to 1/5th of the oral or injection preparation minimum gauge amount of formulation of existing secondary correspondence; Preferably: Cefuroxime Sodium;
The mean molecule quantity of described phospholipid raw material all defines with 800D and calculates, and the phospholipid raw material is the compositions of hydrogenated soy phosphatidyl choline and polyene phosphatidylcholine, and mole ratio is 1-5: 0.5 compositions;
The antioxidant of described phospholipid is reduced glutathion;
Described immobilized artificial membrane molecular state diluent is again an antioxidant, is dimercaprol;
Described liposome medicine carrying body dispersant is again an excipient, is xylitol;
Described surfactant is a sodium dehydrocholate;
Each pharmacodynamic raw materials of liposome composite medicine all should have national standard, and all is the national standard of pharmaceutical injection agent level; Both met national GMP standard, met the regulation of country's " medicine registration management way " again, in order to industrialization development;
The present invention also provides the normalized process for preparing of described group of plastid composition of medicine:
(1) the xylitol dosage is dissolved into 10% percentage by weight solution of xylitol in the injection phosphorus phthalate buffer, with this solution 121 ℃ of steam sterilizations 20 minutes, when solution temperature is 20-25 ℃, ultrafiltration post ultrafiltration with the ultrafilter membrane of molecular cut off 1000D, remove pyrogen and pyrogen molecule fragment in the solution, get the solution that ultrafiltration obtains; Again at room temperature, the solution that the five equilibrium ultrafiltration obtains, be divided into A, B solution, A, B solution are used the analytical pure sodium hydroxide solution adjust pH 8.5 of 5%-8% respectively, with A, B solution respectively through the membrane filtration mistake in the following aperture of 0.05 μ m, removing the precipitate of insoluble particle, high volence metal ion, metal ion, is 5.0-8.0 with 8% analytically pure hydrochloric acid solution adjust pH respectively with A, B solution again; The crude drug Cefuroxime Sodium that water solublity is strong is complete with an amount of water for injection dissolving, with the membrane ultrafiltration of molecular cut off 1000D, depyrogenation, gained ultrafiltration solution merges in the B solution and stirs, through the following membrane filtration mistake in 0.05 μ m aperture, remove bacterium in the raw material medicine solution, insoluble particle again; Raw material medicinal liquid requirement check pyrogen and insoluble particle are qualified could to be allowed to add in the B solution;
(2) with A solution in the spray dryer of preparation pharmaceutical injection agent level, by the spray drying well-established law, A solution is by (being come by compressor with 100 grades of compressed airs of cleanliness factor in the spraying nozzle at equipment top, room temperature) mixes ejection, 150 ℃ of-190 ℃ 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 mixes, and is spray dried to 120-150 order left and right sides porous granule dry powder; Drying finishes, and it is standby that dried material leaves this device bottom in;
(3) it is complete to add fat-soluble phospholipid, phospholipid dispersant stirring and dissolving in the ethanol respectively, make proportion at 1.0 to 1.2 solution, through the membrane ultrafiltration of molecular cut off 1000D, through the following aperture of 0.05 μ m membrane filtration mistake, remove pyrogen, antibacterial, insoluble particle again;
(4) the composition dries granule of the A solution that (2) step was prepared is put in the boiling coating machine, and by boiling coating and the operation of airpillow-dry well-established law, elder generation divides three parts with the phospholipid alcoholic solution equal-volume of (3) step preparation; It is anhydrous to change introducing in device bottom, aseptic, there is not oil, the room temperature purity nitrogen air-flow that does not have the particle of the above particle diameter of 0.001 μ m, under 40 ℃ of-65 ℃ of temperature, to the dry thing particle of (2) xylose that makes of the step coating under the fluidized state that seethes with excitement: earlier with (1/3rd volumes) phospholipid alcoholic solution of first part, being transported in the coating nozzle at equipment middle part with compressed clean rank by pump is that 100 grades of pure nitrogen gas mix, be spray form and be sprayed onto the thick that boiling is highly flowed for 400mm-450mm material (xylitol) in the machine, at boiling material particle surface coating, the mixed equably and dispersion of material simultaneous altitude under the boiling, and make solvent evaporates as quick as thought, form porosu solid coating thin layer, the alcoholic solution feed liquid coating of first three/monophosphatide is finished, airpillow-dry 15 minutes, again with three parts of the B solution of first step preparation also five equilibrium, with 1/3rd solution of the volume of first part of B solution anhydrous, aseptic, there is not oil, do not have in 100 grades of purity nitrogen air-flows of particle of the above particle diameter of 0.001 μ m, press the aforesaid operations coating, behind the coating, airpillow-dry 20 minutes has carried out coating-drying process for the first time like this; Repeat above-mentioned coating-drying process, carry out the solution of second part, the 3rd part 1/3rd volumes of two kinds of solution of second, third time respectively and press aforesaid operations, carry out the alternately coating-drying process of phospholipid liquid and B solution, the outermost layer coatings is the dry thing layer of micropore of the compositions of water-soluble crude drug, xylitol, for the third time behind the coating, residual moisture content≤1.0% in the coating dried material that obtains, residual dimercaprol≤0.2%; Notice that water miscible crude drug then is crude drug and xylitol three coatings of dried particles to A solution in B solution;
(5) add the isopyknic water for injection of using with the first step of injection phosphorus acid salt solution in material-compound tank, inflated with nitrogen maintains an equal level with jar external pressure in jar, under 100 rev/mins of mixing speeds, is heated to 60 ± 5 ℃; Transferring speed of agitator is 500-700 rev/min, and under the inflated with nitrogen, the dry thing of the coating that in 30 minutes to 60 minutes (4) step was made joins in the material-compound tank in jar; After adding the dry thing of coating, in jar, under the inflated with nitrogen environment, keep 60 ± 5 ℃ of temperature, and under 100 rev/mins of stirrings, kept 60-120 minute; Under 100 rev/mins of stirrings, a jar inner liquid medicine is cooled to 30-40 ℃ again; Under 100 rev/mins of stirrings, add the dissolving of antioxidant glutathion and sodium dehydrocholate respectively fully again, and adjust medicinal liquid pH value 5.0-8.0;
(6) hold temperature in 30 ± 5 ℃ of scopes at guarantor's medicinal liquid, under the 0.1-0.2Mpa nitrogen pressure, cross the medicinal liquid that (5) step made with 0.15 μ m membrane filtration, get filterable medicinal liquid, obtain the liposome medicinal liquid of particle diameter less than 150nm, the dosage packing liposome medicinal liquid that allows this medicine by pharmaceutics is in cillin bottle, and the false add plug, well-established law lyophilization in the freeze drying box of lyophilization unit; To medicine solid residue moisture be less than 2%, the dimercaprol residual quantity is less than 0.2%; Lid is rolled in the vacuum tamponade, and laggard storehouse is up to the standards; 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 (6) step was held back on the filterable filter membrane greater than 150nm wash 10% by the operation of the 1st step, sterilization, depyrogenation prepares newly that (this new preparation definition: 10% xylitol solution is that phosphate buffer is made solvent, another name for amount and phosphate liquid measure all should be according to deciding greater than the liposome medicament amount of 150nm particle diameter, increase newly, surpass the amount in the prescription) 10% xylitol solution in, measure the content of total phospholipids raw material in the medicinal liquid, and adjust medicine liquid volume with qualified freshly prepd 10% xylitol solution of sterilization depyrogenation, reach in the control medicinal liquid total phospholipids content at 40-80mg/ml; This medicinal liquid is joined during another batching irritates, under nitrogen, 100 rev/mins of mixing speeds, 30-60 minute internal heating to 50 ± 5 ℃ keep this temperature range to stir 60-120 minute; Keep again under nitrogen, 100 rev/mins of rotating speeds, the cooling medicinal liquid installs to the medicinal liquid branch in the rustless steel pallet of 316L to 20-25 ℃, is put in the freeze drying box of another lyophilizing unit, the well-established law lyophilization, moisture is less than 2% to the medical solid; The dimercaprol residual quantity is less than 0.2%; Obtain the liposome medicament solid, the liposome medicament solid under 100 grades of aseptic ranks, is crushed to the 80-100 order, press the dosage that pharmaceutics allows, 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 the national GMP standard, and oral formulations also must be undertaken by the aseptic requirement of injection;
2. agent; Liposome composite medicine according to the described Cefuroxime Sodium of claim 1, it is characterized in that, press the dosage that pharmaceutics allows, make the lyophilized injection of Cefuroxime Sodium liposome composite medicine, or oral formulations, or be mixed with suppository or be mixed with spraying by well-established law again by well-established law again;
3. according to the liposome composite medicine of the described Cefuroxime Sodium of claim 1, it is characterized in that the purposes of Cefuroxime Sodium liposome composite medicine is to be used for infection.
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| CN2011101523652A CN102258472A (en) | 2010-07-29 | 2011-06-09 | Combined medicament formulation of cefuroxime sodium liposome, preparation method and applications thereof |
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| CN201010240184.0 | 2010-07-29 | ||
| CN2010102401840A CN101912363A (en) | 2010-07-29 | 2010-07-29 | Dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine |
| CN2011101523652A CN102258472A (en) | 2010-07-29 | 2011-06-09 | Combined medicament formulation of cefuroxime sodium liposome, preparation method and applications thereof |
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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 |
| CN2011101524867A Pending CN102218029A (en) | 2010-07-29 | 2011-06-09 | Formula, preparation method and use of pefloxacin mesylate liposome combined medicament |
| CN2011101525018A Pending CN102218031A (en) | 2010-07-29 | 2011-06-09 | Formula, preparation method and use of lactose-azithromycin liposome combined medicine |
| CN2011101525249A Pending CN102218032A (en) | 2010-07-29 | 2011-06-09 | Formula, preparation method and application of lansoprazole liposome composite medicament |
| CN2011101525130A Pending CN102228435A (en) | 2010-07-29 | 2011-06-09 | Water-soluble vitamin liposome pharmaceutical composition formula and preparation method and application thereof |
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| CN2011101525499A Pending CN102218035A (en) | 2010-07-29 | 2011-06-09 | Formula of combined medicament of esomeprazole sodium liposomes, method for preparing same and application thereof |
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| CN2011101541294A Pending CN102218037A (en) | 2010-07-29 | 2011-06-10 | Ifosfamide liposome combination medicament, and formula, preparation method and purpose thereof |
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| CN201310475696.9A Pending CN103919723A (en) | 2010-07-29 | 2011-07-28 | Adefovir dipivoxil liposome combination drug and large-scale industrialized production technology and purpose |
| CN201310522901.2A Pending CN104324000A (en) | 2010-07-29 | 2011-07-28 | Etoposide liposome combined medicine, and large-scale production process and application thereof |
| CN201310521905.9A Pending CN104323996A (en) | 2010-07-29 | 2011-07-28 | Ligustrazine phosphate lipidosome combined drug, and large-scale production process and application thereof |
| CN201310524477.5A Pending CN104324001A (en) | 2010-07-29 | 2011-07-28 | Mitoxantrone lipidosome combined drug, and large-scale production technology and application thereof |
| CN201310524536.9A Pending CN104324002A (en) | 2010-07-29 | 2011-07-28 | Rosiglitazone lipidosome combined drug, and large-scale production technology and application thereof |
| CN201310475640.3A Pending CN103919721A (en) | 2010-07-29 | 2011-07-28 | Hydroxycamptothecin liposome combination drug and large-scale industrialized production technology and purpose |
| CN201310475983.XA Pending CN103919724A (en) | 2010-07-29 | 2011-07-28 | Baicalein liposome combination drug and large-scale industrialized production technology and purpose |
| CN201310522276.1A Pending CN104323998A (en) | 2010-07-29 | 2011-07-28 | Ganciclovir lipidosome combined drug, and large-scale production process and application thereof |
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| CN201310520781.2A Pending CN104323993A (en) | 2010-07-29 | 2011-07-28 | Ondansetron hydrochloride lipidosome combined drug, and large-scale production technology and application thereof |
| CN201310520821.3A Pending CN104352438A (en) | 2010-07-29 | 2011-07-28 | Tanshinone II A liposome combination drug, as well as large-scale industrial production process and application thereof |
| CN201310524596.0A Pending CN104324003A (en) | 2010-07-29 | 2011-07-28 | Cytarabine lipidosome combined drug, and large-scale production process and application thereof |
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