CN1079385A - The preparation method of liposome of anticancer medicine - Google Patents

Abstract

The present invention is the preparation method of liposome of anticancer medicine, belongs to anti-cancer drug preparation technology.The present invention provides a class and is more suitable for leveling off to the preparation method of liposome of 100% (carcinoma entity direct injection) in targeting administration rate.Since this liposome interior, in, outer three layers all adopted the particular processing mode, the liposome that this law is made, be applicable to industrialized great production, simultaneously because this liposome has been taked means such as thickening, slow release, so during the direct administration of focus polarization good, unload leakage less, long action time.Compare the carcinoma entity to get pharmaceutical quantities accurate, controlled with the whole body administration, and local drug concentration height, curative effect height, instant effect, overall side effect are little.

Description

The preparation method of liposome of anticancer medicine

The invention belongs to anti-cancer drug preparation technology.

Cancer is worldwide generally acknowledged obstinate disease, existing tens of kinds more than of the cancer therapy drug that the approval of countries in the world government is used.Great majority all are whole body administration therapeutic methods such as oral, quiet notes, intracavity, intramuscular injection.This kind chemotherapy has the growth of inhibition and killing action to carcinoma really.But when carcinoma is suppressed or is partly killed, human normal tissue (hemopoietic system, detoxification system, genitourinary system etc.) also is subjected to wrecking greatly and injuring accordingly, cause at last human normal tissue never can resist the efficacy of a drug injury and be forced to drug withdrawal midway.Because carcinoma is organized and thoroughly do not killed, cause carcinoma recurrence in a period of time after the chemotherapy, transfer etc. to become certainty.Therefore people place on hope in the research of targeting good anticancer preparation liposome.The preparation method of existing liposome has membrane process, reverse evaporation, injection method, surfactant dilution method, squeezing and pressing method etc.But the liposome that conventional method is made (solution) all exists, and envelop rate is low, storage period is short, easily unload the problem that leakage waits, after freezing, the spray drying liposome dry product of gained also exist easy adhesion, moisture absorption, become sour rotten and redissolve with distilled water when using after the difficult problem such as press filtration homogenize of still needing.Simultaneously to say objectively liposome is not only carcinoma to be had bigger affinity, and is very high in abundances such as the abundant tissue of phagocyte such as liver, spleen, bone marrow, lungs yet.Therefore say that the targeting of liposome also is relative.Corresponding toxicities after the administration also is unavoidable.

Task of the present invention is to can be used under the prerequisite of whole body administration not discharging this liposome, provides a class and is more suitable in the liposome of the direct administration of carcinoma entity (targeting administration rate nearly 100%).

Liposome of anticancer medicine its preparation method of the present invention is: (mainly select for use those to have the Cytotoxic cancer therapy drug that can directly play a role in the carcinoma entity medicine; Can suppress the synthetic medicine of biological nucleic acid, it is close fixed etc. to dredge basic purine, hydroxyl urine, 5-fluorine urine as: 6-; The medicine that can change nucleic acid structure is as alkylating agent, Amboclorin, L-Sarcolysinum, cyclophosphamide, nitrous urine class, mitomycin, daunorubicin, procarbazine, amycin, bleomycin etc., can suppress mitotic medicine as vincaleucoblastine, vincristine etc. and cell cycle nonspecific agent (CCNSA) are as Thiotepa, nitrogen mustards etc.), its charged situation of complying with is divided into cationic medicine or anionic drug (does not have anionic drug in the above-mentioned medicine example, the close both sexes medicine that belongs to surely of 5-fluorine urine, but because of its facile hydrolysis in alkali liquor, so can only be with the characteristic of its cationic medicine, so the anionic example is omitted) two big classes, and add according to the classification of its medicine at aqueous phase and can make medicine dissolves (salify) in water acid buffer agent accordingly (as citric acid, succinic acid, acetic acid or oxalic acid etc.) or ealkaline buffer (as sodium carbonate, sodium bicarbonate, sodium phosphate, dibastic sodium phosphate etc.), oil phase (can be selected axunge for use, vegetable oil, the benzyl benzyl formate, ethyl oleate, chloroform etc.), the oil phase suspending agent (can be selected list for use, two, Aluminium Tristearate Micronized steriles etc.) matrix material (can be selected phosphatidylcholine for use, the lecithin phatidylcholine, the fabaceous lecithin phatidylcholine, the hydrogenated soybean lecithin phatidylcholine, two lauroyl lecithin phatidylcholines, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, two spermaceti phospholipid, the distearyl phosphatidyl glycerol, thioester, cholesterol, coprostenol, cholestane, Dihydrocholesterol, alpha-tocopherol etc.), the spray drying anticoagulant of high-viscosity polymer, entity injection slow releasing agent (can be selected sodium alginate for use, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone, amylopectin and glue class etc.) above-mentioned former, adjuvant is standby after giving processing, medicine is dissolved in the internal layer water buffer, transfers PH4 or 9 standby.Phospholipid with suspending agent and 1/3 amount, cholesterol is dissolved in oil phase (oils and fats respectively, the chloroform mixed liquor) in, under agitation add above-mentioned pastille buffer in the oil phase then, carry out emulsifying and form w/o type Emulsion, again this W/O breast is removed most of organic solvent with gentle method, form spissated W/O Emulsion, this is concentrated the newborn fluidity that contains total amount 2/3 phospholipid and cholesterol that adds under the state that stirs transfer in PH6.5～7.5 aqueous solutions, form the compound breast of W/O/W type, after the homogenize, this breast is carried out spray drying simultaneously with high viscosity copolymer solution, get final product the liposome microgranule of surperficial formation one layer of polymeric thin film.

But the present invention is based on the direct administration of carcinoma entity owing to be on the basis of not discharging the whole body administration.Therefore have following characteristics: 1. to get pharmaceutical quantities accurate, controlled for the carcinoma entity, and local drug concentration height, curative effect height, instant effect, overall side effect are little; 2. this liposome has been taked means such as thickening, slow release, thus polarization is good, medicine from focus unload leakage less, long action time; 3. since this liposome interior, in, outer three layers all adopted special mode to handle.So the liposome that this law is made is not only applicable to industrialized great production, and solved that liposome (solution) preservation term is lacked, easily unloaded Lou, envelop rate is low, freezing, easy adhesion, moisture absorption that spraying, dry back gained dry product exist, become sour and redissolve with distilled water when using after need use a difficult problem such as particular device press filtration homogenize.

Prescription of the present invention, process example are: the 50mg vincristine sulfate is dissolved in the 60ml citric acid solution, and it is standby to transfer PH4.5 to constitute water.Neutral Oleum Glycines gel, 12g distearoylphosphatidylcholine phatidylcholine and cholesterol (1: 09 mole ratio) that 30g is contained 2% aluminum monostearate are dissolved in respectively in the 120g chloroform and constitute oil phase.Above-mentioned water is added in the oil phase, use the homogenizer homogenize, get w/o type Emulsion, this breast is evaporated 55～70% chloroforms under the decompression state below 50 ℃, get spissated w/o type Emulsion, this breast is contained transferring in the 600ml aqueous solution of PH7 through sodium bicarbonate of 24g distearoylphosphatidylcholine phatidylcholine and cholesterol (1: 0.7 mole ratio) in adding under the condition of stirring, be emulsified into W/O/W type multiple emulsion, then with this compound breast and the 600ml aqueous solution that contains the 6g methylcellulose evenly after spray drying immediately, get final product the liposome microgranule (about 130 grams) of surperficial formation one deck methylcellulose thin film packing promptly.

Annotate: during use, the redissolution of liposome microgranule can utilize methylcellulose easily molten in cold water, and insoluble characteristic in the water of temperature more than 45 ℃ can get homodisperse liposome suspension.

Claims (6)

1, the preparation method of liposome of anticancer medicine, the preparation that it is characterized in that this liposome is (to dredge basic purine as 6-by the medicine that will can directly play a role in the cancer entity, hydroxyl urine, the 5-fluorine is urinated close fixed, Amboclorin, L-Sarcolysinum, cyclophosphamide, nitrous urine class, mitomycin, daunorubicin, amycin, bleomycin, procarbazine, vincaleucoblastine, vincristine, Thiotepa, nitrogen mustards etc.) be dissolved in (internal layer water) in the corresponding buffer according to its charged situation and transfer the phospholipid of PH (making it to become water soluble salt) axunge (or oleogel) and 1/3 amount, constitute oil phase in the cholesterol solution chloroform, above-mentioned water is joined in the middle of the oil phase, carry out emulsifying and form w/o type Emulsion, this Emulsion is removed most of organic solvent with gentle method form spissated breast, this W/O is concentrated breast to add the PH that contains total amount 2/3 phospholipid and cholesterol and approximates in 7 the aqueous solution under the state that stirs, form the compound breast of W/O/W type after the emulsifying, this compound breast and high viscosity copolymer solution are carried out simultaneously operation such as spray drying and finish.

2, method for preparing lipidosome as claimed in claim 1, the buffer agent of aqueous phase should be selected according to the charged situation of its medicine in it is characterized in that, when medicine when being cationic, then need select for use with the acid buffer agent (as citric acid, succinic acid, acetic acid, oxalic acid etc.) of its composition water soluble salt, when medicine is anionic, then select ealkaline buffer (as sodium carbonate, sodium bicarbonate, sodium phosphate, dibastic sodium phosphate etc.) for use.

3, the preparation method of liposome as claimed in claim 1, it is characterized in that the double-deck molecular material of liposome can select phosphatidylcholine, lecithin phatidylcholine, fabaceous lecithin phatidylcholine, hydrogenated soybean lecithin phatidylcholine, two lauroyl lecithin phatidylcholines, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, two spermaceti phospholipid, distearyl phosphatidyl glycerol, thioester, cholesterol, coprostenol, cholestane, Dihydrocholesterol, alpha-tocopherol etc. for use, its total consumption is equivalent to 0.5～15% of spray drying proliposome solution; Inside and outside layer lipid ratio is about 1: 2; Wherein the ratio of phospholipid and cholesterol should be between 1: 0.2～1: 1, and the cholesterol level of internal layer lipid layer should be bigger than skin.

4, the preparation method of liposome as claimed in claim 1, the oil reservoir that it is characterized in that the compound breast of W/O/W type after the spray drying is the axunge or the oleogel of remaining trace only, so formed special liposome bilayer, axunge between this double-deck son or oleogel can effectively stop unloading leakage of water soluble drug.Wherein oleogel is made of suspending agent such as list, two, Aluminium Tristearate Micronized sterile etc. and oil phase such as vegetable oil, benzyl benzyl formate, ethyl oleate etc.The ratio of axunge or oleogel and liposome material should be between 0-500%, and the consumption of suspending agent should be 0.5%～5% of an oil phase in the oleogel.

5, the preparation method of liposome as claimed in claim 1, it is characterized in that to select extra large bath acid sodium, methylcellulose, carboxymethyl cellulose, each alkane ketone of polyethylene pyrrole, amylopectin and glue class etc. for use with the high-viscosity polymer of liposome simultaneous spray drying, its consumption should be looked the kind of polymer, and the back cancer entity that redissolves is injected required slow release degree and decided.Its spray drying process can will carry out spray drying method behind high-viscosity polymer liquid and the liposome mix homogeneously; Also can carry out spray drying method by different spray gun ejections with the chamber by two kinds of liquid.

6, the preparation method of liposome as claimed in claim 1, the foreign minister's aqueous solution that it is characterized in that containing 2/3 lipid should transfer to 7 with PH before emulsifying W/O/W breast about (slightly get final product on the contrary), so that the part medicine that spills when making preparation W/O/W newborn can return the internal layer water when spray drying in internal layer water PH.