CN101670112A - Stable albumins lipid medicine carrying system and preparation method thereof - Google Patents
Stable albumins lipid medicine carrying system and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a stable albumins lipid medicine carrying system and a preparation method thereof. The method is to combine the albumins with the lipid cysts by using ultrasonic, high-pressure homogenization or micro-streaming technology, and thus can significantly improve the stability of the lipid cysts and the encapsulation efficiency of medicaments in the lipid cysts.
Description
Technical field
A kind of stable albumin lipid drug-loading system and preparation method thereof, by ultrasound wave, high pressure homogenize or Micro Fluid technology with albumin bound on the lipid cyst, can significantly improve the stability of lipid cyst and improve the envelop rate of medicine in the lipid cyst.
Background technology
The lipid cyst is to utilize phospholipid bilayer to be embedded in cholesterol formed vesicle packaging medicine molecule and the preparation that forms, and phospholipid is the main chemical compositions that constitutes the lipid cyst, and wherein the most representative is lecithin.Mainly from egg yolk and Semen sojae atricolor, preparation cost is low for lecithin, and stable in properties belongs to neutral phospholipid.Phosphatidylcholine is the main component that forms many cell membrane, it also is the primary raw material of preparation lipid cyst, cholesterol also is another important composition composition of lipid cyst, it is the important component of many natural biological films, itself does not form membrane structure, but can insert in the immobilized artificial membrane with the mol ratio of 1: 1 even 2: 1.Add cholesterol and can change the phase transition temperature of adipose membrane, thereby influence the permeability and the flowability of film.Therefore cholesterol has the effect of stable phospholipid bimolecular film.
Press the structure and the particle size classification of lipid cyst, can be divided into: single chamber lipid cyst, multicell lipid cyst and heterogeneous lipid cyst can be divided into neutral lipid cyst, elecrtonegativity lipid cyst, electropositive lipid cyst by lipid cyst electric charge.
Pharmaceutical pack is wrapped in the lipid cyst, can be reduced in the tissue diffusion and slowly in blood, discharge medicine, thus prolong drug action time, and the lipid cyst can optionally be distributed in some tissue and organ, increase medicine to lymphoid directionality, improve the treatment concentration of medicine at target site.Especially to cancer therapy drug, can make it optionally to kill and wound cancerous cell or anticancer, to the obviously reduction or the harmless effect of toxicity of normal structure, cell.Lipid capsule cellular surface character is changed,, can improve the selectivity of medicine, thereby also reduce toxicity, reduced untoward reaction the target area as size, surface charge, tissue specificity antibody etc.
The conventional preparation method of lipid cyst
The lipid cyst of preparation fat-soluble medicine generally adopts methods such as film dispersion method, injection method, precursor lipid cyst method, ultrasonic dispersion, and industrial method commonly used is: film dispersion method.
The lipid cyst of preparation water soluble drug, but require medicine that reasonable stability is arranged, these class methods comprise methods such as reverse phase evaporation, PH gradient method, multi-emulsion method, fusion method, freeze-thaw method, freeze-drying, surfactant facture, calcium fusion method, centrifuging particularly, and industrial method commonly used is: the PH gradient method.
The problem that exists during the lipid cyst is used mainly is lower for some water soluble drug envelop rate, and medicine is seepage from the lipid cyst easily.
Owing on the cell membrane albumin receptor GP60 is arranged, after Gp60 and albumin bound, activate after birth cave sample indent, carry out cell traffic, be rich in cysteine acidic secretion albumen by tumor cell secretion, be present between multiple malignant tumor tissue in the matter, with patient's prognosis direct relation is arranged, it and GP60 homology, can and albumin bound, utilize the characteristic of itself and albumin bound, make the surface be inlaid with albuminous lipid cyst relative rich collection in mesenchyma stroma of tumors, discharge medicine in tumor cell by film fusion and transhipment, the medicine local concentration in the tumor cell is increased, thereby increase the curative effect of tumor cell.
By the preparation method and relevant research of literature search to albumin microsphere and liposome, and the lipid cyst is inlayed the also not discovery of research that albumin improves lipid cyst drug loading and envelop rate.
Retrieve domestic and international patent, find a kind of pharmaceutical composition (application number 200510053892.2) for the treatment of cancer, liposome by anti-tumor activity medicine, Polyethylene Glycol and albumin bound, the medicine of the method preparation that this patent is used be with chemical synthesis process with albumin bound on phospholipid, Polyethylene Glycol also is chemical method and phospholipids incorporate, the preparation technology of said composition is too complicated, and cost is very high, can't realize that suitability for industrialized production makes operable clinically preparation; Patent (application number 03108361.7) discloses a kind of paclitaxel albumin conjugates, discovers that the medicine combination rate for preparing with this patent is low, and pulverous paclitaxel is difficult to fully and albumin bound in preparation process.
Albumin lipid drug-loading system of the present invention has not only effectively been realized the enrichment of tumour medicine around tumor cell, it is low meaningfully can effectively to overcome lipid cyst envelop rate, the defective of easy seepage, see accompanying drawing 1,2,3,4, the technology that the present invention more meaningfully adopts can realize that suitability for industrialized production makes the product of clinical use, has very important realistic price.
Summary of the invention
The invention discloses a kind of stable albumin lipid drug-loading system and preparation method thereof, it is characterized in that albumin bound on the lipid cyst, can significantly improve the stability of lipid cyst and improve the envelop rate of medicine in the lipid cyst, wherein comprise in the albumin lipid drug-loading system and have active medicine, phospholipid, sterol and albumin, its preparation method is for being rolled in pharmaceutical pack in the lipid cyst of phospholipid and sterol formation earlier with the conventional method for preparing the lipid cyst, in system, add albumin solution again, make the injectable albuminous lipid drug-loading system that combines with press filtration method or high pressure homogenize method, also albumin and medicine can be added the phospholipid that dissolves in organic solvent simultaneously, form precursor lipid cyst in the sterol, make the injectable albuminous lipid drug-loading system that combines with press filtration method or high pressure homogenize method after the reuse buffer salt solution aquation.
The albumin lipid drug-loading system that the present invention is stable, wherein each constituent mass percentage ratio is as follows:
Preferably each constituent mass percentage ratio is as follows for active medicine 0.01-20%, phosphatidase 10 .1-60%, sterol 0.01-20%, albumin 0.01-90%:
Active medicine 0.01-10%, phosphatidase 13-60%, sterol 1-20%, albumin 0.1-90%
The albumin lipid drug-loading system that the present invention is stable, also comprise frozen-dried supporting agent, be selected from micromolecule aminoacid, polysaccharide or polyhydric alcohol, specifically comprise a kind of or combination in any in 20 kinds of natural amino acids, trehalose, sucrose, lactose, maltose, mannitol, the sorbitol, described consumption is 2%-50% by weight.
The albumin lipid drug-loading system that the present invention is stable also comprises the PH regulator, is selected from hydrochloric acid, phosphoric acid, citric acid or its alkali metal sodium salt, oxalic acid or its metal and receives salt, sodium hydroxide, potassium hydroxide, sodium carbonate, glacial acetic acid or its alkali metal salt.
The albumin lipid drug-loading system that the present invention is stable, can also further comprise stabilizing agent, be selected from micromolecule aminoacid or PEG200,400,600, a kind of or its any mixture in Tween 80, poloxamer (poloxamer), the NaTDC, described consumption is 0.2%-5% by weight, wherein aminoacid specifically is selected from 20 kinds of aminoacid commonly used, such as 20 kinds of a-amino acids:
Nonpolar amino acid: alanine, valine, leucine, isoleucine, proline, tryptophan, phenylalanine, methionine (8 kinds);
Polarity, neutral aminoacid: serine, glycine, threonine, cysteine, agedoite, glutamine, tyrosine (7 kinds);
Acidic amino acid: aspartic acid, glutamic acid (2 kinds);
Basic amino acid: arginine, lysine, histidine (3 kinds)
The albumin lipid drug-loading system that the present invention is stable can also comprise antioxidant, is selected from one or more the mixture in vitamin E, vitamin C, sulfites, ethylenediaminetetraacetic acid and derivant thereof, the cysteine hydrochloride.
The albumin lipid drug-loading system that the present invention is stable can also comprise osmotic pressure adjustment agent, is selected from a kind of or combination in any in glucose, sodium chloride, glycerol, the sorbitol, and described consumption is 0.2%-5% by weight.
The albumin lipid drug-loading system that the present invention is stable, organic solvent are selected from low boiling point solvents such as dichloromethane, chloroform, ethanol, ethyl acetate, ether, acetone.
The albumin lipid drug-loading system that the present invention is stable, phospholipid is selected from natural or synthetic phospholipid in each component, such as lecithin (soybean lecithin, Ovum Gallus domesticus Flavus lecithin, two lauroyl phospholipid, two myristoyl phospholipid, two palmityl phospholipid or distearyl phospholipid etc.), PHOSPHATIDYL ETHANOLAMINE (two lauroyl PHOSPHATIDYL ETHANOLAMINE, two myristoyl PHOSPHATIDYL ETHANOLAMINE, two palmityl PHOSPHATIDYL ETHANOLAMINE or DSPE etc.) Phosphatidylserine (two lauroyl Phosphatidylserine, two myristoyl Phosphatidylserine, two palmityl Phosphatidylserine or distearyl Phosphatidylserine etc.), phosphatidic acid, phosphatidyl glycerol (two lauroyl phosphatidyl glycerols, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two palmityl phosphatidyl glycerols or distearyl phosphatidyl glycerol etc.), phosphatidylinositols (two lauroyl phosphatidylinositols, two myristoyl phosphatidylinositols, two palmityl phosphatidylinositols or distearyl phosphatidylinositols etc.), LYSOLECITHIN SUNLECITHIN A, sphingomyelins, Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydroxylated lecithin, the mixture of one or more in the phospholipid of hydrogenated phospholipid and process PEG modified; Sterol is selected from cholesterol and derivant thereof, specifically comprises one or more the mixture in cholesterol, Polyethylene Glycol butanediol cholesterol ethers (preferred short chain polyalkylene glycol), Cholesteryl hemisuccinate, ergosterol, the lanosterol; Albumin is selected from animal albumin (such as ovalbumin, serum albumin, lactalbumin or muscle albumin) and phytalbumin, preferred animal serum albumin, human serum albumin and and the human serum albumin that produces by genetic engineering in a kind of.
The albumin lipid drug-loading system that the present invention is stable gets preparation method, and concrete preparation method has two kinds, and first kind may further comprise the steps:
The first step: the lipid capsule cell space system that such as a kind of elder generation in selection rotary evaporation method, PH gradient method, injection method, the second emulsifying method pharmaceutical pack is rolled in phospholipid and sterol formation according to the characteristics of medicine with the conventional method for preparing the lipid cyst, make the lipid cyst form relatively homogeneous granules by ultrasound wave, high pressure homogenize or Micro Fluid technology, size is at 100nm-1000nm;
Second step: at the lipid capsule cell space is to add albumin solution in the system, forms the injectable albuminous lipid drug-loading system that combines by ultrasound wave, high pressure homogenize or Micro Fluid technology, and size is filtered promptly canned at 20nm-1000nm;
The 3rd step: if the preparation freeze-dried preparation adds an amount of frozen-dried supporting agent in system, lyophilizing promptly;
Second kind of preparation method may further comprise the steps:
The first step: the characteristics according to medicine are dissolved in albumin and medicine adding in the phospholipid and sterol of organic solvent such as a kind of elder generation in selection rotary evaporation method, PH gradient method, injection method, the second emulsifying method with the conventional method for preparing the lipid cyst, reduction vaporization adds buffer salt solution after removing organic solvent, make the lipid cyst form relatively homogeneous granules by ultrasound wave, high pressure homogenize or Micro Fluid technology, size is filtered promptly canned at 20nm-1000nm;
Second step: if the preparation freeze-dried preparation adds an amount of frozen-dried supporting agent in system, lyophilizing promptly;
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
The application of the albumin lipid drug-loading system that the present invention is stable, be parenterai administration, wherein has active medicine, comprise antibiotic, antifungal drug, tumour medicine, cardiovascular medicament, polypeptide and pharmaceutical grade protein etc., preferred antitumor drug, comprise antitumor antibiotics, alkylating agent, various metabolic antagonists, the anticancer plants micromolecule antitumor drug that becomes to grade, also comprise polypeptide and protein antitumor drug, wherein small-molecule drug for example as: ametycin, (hydrochloric acid) bleomycin, peplomycin, Anastrozole, Epothilones and derivant thereof (comprise Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, Epothilone F (-)-Epothilone F. etc.), amifostine, capecitabine, hydroxy camptothecin, troxacitabine, irinotecan hydrochloride, topotecan hydrochloride, the special health of rupee, epirubicin hydrochloride, doxorubicin hydrochloride, valrubicin, pirarubicin, the THP-amycin, carboplatin, cisplatin, oxaliplatin, docetaxel, cyclophosphamide, vinorelbine tartrate, letrozole, irinotecan hydrochloride, ifosfamide, actinomycin D, floxuridine, methotrexate, cladribine, fludarabine phosphate, vincristine sulfate, doxifluridine, mitomycin, cytarabine hydrochloride, daunorubicin hydrochloride, actinomycin D.
Polypeptide and pharmaceutical grade protein comprise: insulin, interferon (α, β, γ), interleukin (2,7) etc.
The albumin lipid drug-loading system that the present invention is stable, wherein the mean diameter size is at 20nm-1000nm;
The albumin lipid drug-loading system that the present invention is stable, the PH scope of solution was after injection or lyophilizing were redissolved: 5-8.
Specific embodiment
1, paclitaxel/Docetaxel albumin lipid conjugate
Get paclitaxel/Docetaxel 100mg, Ovum Gallus domesticus Flavus lecithin 3g, cholesterol 1g, albumin 1.0g, add the stirring of 50ml chloroform and make paclitaxel/Docetaxel, Ovum Gallus domesticus Flavus lecithin, cholesterol dissolving, remove chloroform with the rotary evaporator distilling under reduced pressure, add sucrose 5 grams, PH6-7 citric acid buffer salt to cumulative volume is 100ml, and high-pressure uniform machine homogenizing to granularity is 50-200nm, and 0.22 filter membrane canning sealing promptly excessively.
If the preparation freeze-dried preparation, the technology lyophilizing is promptly routinely than the phenylalanine of 2-3% to add system weight in aforesaid liquid.
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
2, epothilone B albumin lipid conjugate
Get epothilone B 50mg, Ovum Gallus domesticus Flavus lecithin 1g, Polyethylene Glycol butanediol cholesterol ethers 0.5g, albumin 3.0g, add to stir in the 50ml dehydrated alcohol and make epothilone B, Ovum Gallus domesticus Flavus lecithin, cholesterol dissolving, remove ethanol with the rotary evaporator distilling under reduced pressure, add sucrose 5g, cysteine hydrochloride 0.02g, PH6-7 citric acid buffer salt to cumulative volume are 100ml, and high-pressure uniform machine homogenizing to granularity is 50-200nm, and 0.22 filter membrane canning sealing promptly excessively.
If the preparation freeze-dried preparation, as freeze drying protectant, lyophilizing promptly than the mannitol of 2-3% for the adding system weight in aforesaid liquid.
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
3, pirarubicin albumin lipid conjugate
Get pirarubicin 50mg, Ovum Gallus domesticus Flavus lecithin 2.5g, hydrolecithin 0.5g, Polyethylene Glycol butanediol cholesterol ethers 0.1g, tryptophan 0.2g, albumin 1.0g, add the stirring of 50ml chloroform/ethanol and make pirarubicin, Ovum Gallus domesticus Flavus lecithin, hydrolecithin, cholesterol dissolving, remove chloroform/ethanol with the rotary evaporator distilling under reduced pressure, add sucrose 3g, glucose 2g, PH4 citric acid buffer salt to cumulative volume is 50ml, and ultrasonic dissolution is used Na
2CO
3Regulator solution PH is 7.5,40 ℃ of insulations 30 minutes, is 50-200nm with press filtration method or high-pressure uniform machine homogenizing to granularity, and 0.22 filter membrane canning sealing promptly excessively.
If the preparation freeze-dried preparation adds the lyophilizing of 5% (percentage by weight) mannitol promptly in aforesaid liquid.
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
4, peplomycin albumin lipid conjugate
Get peplomycin 50mg, Ovum Gallus domesticus Flavus lecithin 0.6g, Cholesteryl hemisuccinate 0.2g, add to stir in the 30ml dehydrated alcohol and make peplomycin, Ovum Gallus domesticus Flavus lecithin, Cholesteryl hemisuccinate, remove ethanol with the rotary evaporator distilling under reduced pressure, add albumin 2.5g, sucrose 5g, PH6-7 citric acid buffer salt to cumulative volume is 100ml, and press filtration or high-pressure uniform machine homogenizing to granularity are 50-200nm, and 0.22 filter membrane canning sealing promptly excessively.
If the preparation freeze-dried preparation adds the lyophilizing of 5% (percentage by weight) mannitol promptly in aforesaid liquid.
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
5, hydroxy camptothecin albumin lipid conjugate
Get hydroxy camptothecin 50mg, Ovum Gallus domesticus Flavus lecithin 0.6g, cholesterol 0.2g, add to stir in the 30ml dehydrated alcohol and make dissolving, remove ethanol with the rotary evaporator distilling under reduced pressure, add albumin 2.0g, trehalose 5g, PH6-7 citric acid buffer salt to cumulative volume is 100ml, and high-pressure uniform machine homogenizing to granularity is 50-200nm, and 0.22 filter membrane canning sealing promptly excessively.
If the preparation freeze-dried preparation adds the lyophilizing of 3% (percentage by weight) sucrose promptly in aforesaid liquid.
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
6, irinotecan hydrochloride albumin lipid conjugate
Get irinotecan hydrochloride 50mg, phosphatidylinositols 0.5g, soybean lecithin 2.0g, hydrolecithin 0.5g, cholesterol 0.5g, add the stirring of 50ml chloroform and make dissolving, remove ethanol with the rotary evaporator distilling under reduced pressure, add albumin 1.5g trehalose 5g, PH4 citric acid buffer salt to cumulative volume is 50ml, and Na is used in the ultrasonic agitation dissolving
2CO
3Regulator solution PH is 7.5,40 ℃ of insulations 30 minutes, is 50-200nm with press filtration method or high-pressure uniform machine homogenizing to granularity, and 0.22 filter membrane canning sealing promptly excessively.
If the preparation freeze-dried preparation adds the lyophilizing of 3% (percentage by weight) sucrose promptly in aforesaid liquid.
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
7, interleukin albumin lipid conjugate
Get interleukin-10 .5g, albumin 1.5g, PHOSPHATIDYL ETHANOLAMINE 0.5g, soybean lecithin 1.0g, hydrolecithin 0.5g, cholesterol 0.5g, add the stirring of 50ml ethyl acetate and make dissolving, remove ethyl acetate with the rotary evaporator distilling under reduced pressure, add albumin 1.5g, trehalose 5g, Tween 80 0.1g, PH7-8 citric acid buffer salt to cumulative volume is 50ml, the ultrasonic agitation dissolving, with press filtration method or high-pressure uniform machine homogenizing to granularity is 50-200nm, and canning sealing promptly.
If the preparation freeze-dried preparation adds the lyophilizing of 3% (percentage by weight) mannitol promptly in aforesaid liquid.
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production for fear of the loss of interleukin, can be considered sterile production.
Claims (10)
1, a kind of stable albumin lipid drug-loading system and preparation method thereof, it is characterized in that albumin bound on the lipid cyst, can significantly improve the stability of lipid cyst and improve the envelop rate of medicine in the lipid cyst, wherein comprise in the albumin lipid drug-loading system and have active medicine, phospholipid, sterol and albumin, its preparation method is for being rolled in pharmaceutical pack in the lipid cyst of phospholipid and sterol formation earlier with the conventional method for preparing the lipid cyst, in system, add albumin solution again, make the injectable albuminous lipid drug-loading system that combines with press filtration method or high pressure homogenize method, also albumin and medicine can be added the phospholipid that dissolves in organic solvent simultaneously, form precursor lipid cyst in the sterol, make the injectable albuminous lipid drug-loading system that combines with press filtration method or high pressure homogenize method after the reuse buffer salt solution aquation.
2, according to albumin lipid drug-loading system stable in the claim 1, wherein each constituent mass percentage ratio is as follows:
Active medicine 0.01-20%, phosphatidase 10 .1-60%, sterol 0.01-20%, albumin 0.01-90%
3, according to albumin lipid drug-loading system stable in the claim 1, also comprise frozen-dried supporting agent, be selected from micromolecule aminoacid, polysaccharide or polyhydric alcohol, specifically comprise a kind of or combination in any in 20 kinds of natural amino acids, trehalose, sucrose, lactose, maltose, mannitol, the sorbitol, described consumption is 2%-50% by weight.
4, according to albumin lipid drug-loading system stable in the claim 1, also comprise the PH regulator, be selected from hydrochloric acid, phosphoric acid, citric acid or its alkali metal sodium salt, oxalic acid or its metal and receive salt, sodium hydroxide, potassium hydroxide, sodium carbonate, glacial acetic acid or its alkali metal salt.
5, according to albumin lipid drug-loading system stable in the claim 1, can also further comprise stabilizing agent, be selected from micromolecule aminoacid or PEG200,400,600, a kind of or its any mixture in Tween 80, poloxamer (poloxamer), the NaTDC, described consumption are 0.2%-5% by weight; Can also comprise osmotic pressure adjustment agent, be selected from a kind of or combination in any in glucose, sodium chloride, glycerol, the sorbitol, described consumption is 0.2%-5% by weight.
6, according to albumin lipid drug-loading system stable in the claim 1, can also comprise antioxidant, be selected from one or more the mixture in vitamin E, vitamin C, sulfites, ethylenediaminetetraacetic acid and derivant thereof, the cysteine hydrochloride.
7, according to albumin lipid drug-loading system stable in the claim 1, organic solvent is selected from low boiling point solvents such as dichloromethane, chloroform, ethanol, ethyl acetate, ether, acetone.
8, according to albumin lipid drug-loading system stable in the claim 1, phospholipid is selected from one or more the mixture in natural or the synthetic phospholipid in each component; Sterol is selected from cholesterol and derivant thereof, specifically comprises one or more the mixture in cholesterol, Polyethylene Glycol butanediol cholesterol ethers, Cholesteryl hemisuccinate, ergosterol, the lanosterol; Albumin be selected from animal serum albumin, human serum albumin and the human serum albumin that produces by genetic engineering in a kind of.
9, get preparation method according to albumin lipid drug-loading system stable in the claim 1, specifically comprise following two kinds of methods:
First kind of preparation method may further comprise the steps:
The first step: the lipid capsule cell space system that such as a kind of elder generation in selection rotary evaporation method, PH gradient method, injection method, the second emulsifying method pharmaceutical pack is rolled in phospholipid and sterol formation according to the characteristics of medicine with the conventional method for preparing the lipid cyst, make the lipid cyst form relatively homogeneous granules by ultrasound wave, high pressure homogenize or Micro Fluid technology, size is at 100nm-1000nm;
Second step: at the lipid capsule cell space is to add albumin solution in the system, forms the injectable albuminous lipid drug-loading system that combines by ultrasound wave, high pressure homogenize or Micro Fluid technology, and size is filtered promptly canned at 20nm-1000nm;
The 3rd step: if the preparation freeze-dried preparation adds an amount of frozen-dried supporting agent in system, lyophilizing promptly; Second kind of preparation method may further comprise the steps:
The first step: the characteristics according to medicine are dissolved in albumin and medicine adding in the phospholipid and sterol of organic solvent such as a kind of elder generation in selection rotary evaporation method, PH gradient method, injection method, the second emulsifying method with the conventional method for preparing the lipid cyst, reduction vaporization adds buffer salt solution after removing organic solvent, make the lipid cyst form relatively homogeneous granules by ultrasound wave, high pressure homogenize or Micro Fluid technology, size is filtered promptly canned at 20nm-1000nm;
Second step: if the preparation freeze-dried preparation adds an amount of frozen-dried supporting agent in system, lyophilizing promptly;
If preparing product, environment, thermal source, aseptic etc. need finishing according to the requirement of big production.
10, according to the application of albumin lipid drug-loading system stable in the claim 1, be parenterai administration, wherein have active medicine, preferred antitumor drug comprises the micromolecule antitumor drug, also comprises polypeptide and protein antitumor drug.
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| CN104622810A (en) * | 2015-02-15 | 2015-05-20 | 中国药科大学 | Stable type difficultly-soluble anti-tumor medicine liposome and preparation method thereof |
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| CN108030088B (en) * | 2017-10-26 | 2021-05-28 | 武汉轻工大学 | Preparation method of protein-modified phytosterol liposome powder |
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Application publication date: 20100317 |