CN102485211A - Doxorubicin liposome and its preparation method - Google Patents
Doxorubicin liposome and its preparation method Download PDFInfo
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- CN102485211A CN102485211A CN2010105681769A CN201010568176A CN102485211A CN 102485211 A CN102485211 A CN 102485211A CN 2010105681769 A CN2010105681769 A CN 2010105681769A CN 201010568176 A CN201010568176 A CN 201010568176A CN 102485211 A CN102485211 A CN 102485211A
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Abstract
Belonging to the technical field of medicines, the invention discloses a doxorubicin liposome and its preparation method. The doxorubicin liposome is composed of doxorubicin, a phospholipid substance, cholesterol, and a PEG lipid derivative, etc. The doxorubicin liposome prepared by a pH gradient method in the invention has an encapsulation rate higher than 96%, ethanol content not greater than 10%, and almost constant related parameters. The preparation and its preparation method provided in the invention can control the ethanol content during liposome preparation, and ensures that the residual ethanol has no substantial influence on liposome property in the preparation process, thus providing reference for liposome preparation and ethanol content control in industrial production.
Description
Technical field:
The invention belongs to medical technical field, relate to Evacet and preparation method thereof, this method for preparing can make in the liposome preparation process ethanol content controlled, and guarantees that ethanol residual in the preparation process does not have the significance influence to liposome property.
Background technology:
Amycin (Doxorubicin) is a kind of common classical antibiotics broad-spectrum anti-cancer drug; Its mechanism of action mainly is through influencing the activity of type; Suppress the synthetic of RNA and DNA; Inhibitory action to RNA is the strongest, belongs to cell cycle nonspecific agent (CCNSA), and the tumor cell of various growth cycles is all had killing action.Amycin is a broad-spectrum anti-tumor medicine, is used to treat acute lymphoblastic leukemia, acute myeloblastic leukemia, He Jiejin and non Hodgkin lymphoma, breast carcinoma, pulmonary carcinoma, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, nephroblastoma, neuroblastoma, bladder tumor, thyroid tumor, chorionic epithelioma, carcinoma of prostate, carcinoma of testis, gastric cancer, hepatocarcinoma etc. clinically.Amycin can pass through blood-neural barrier (blood-nerve barrier) and damage ganglionic cell.Other main toxic reactions comprise, leukocyte and thrombocytopenia, alopecia, cardiac toxicity, nauseating, loss of appetite; Particularly blood vessel is outer can to cause tissue ulcer and necrosis when medicine overflows.All these problems all can prepare liposome and solve.
Generally speaking; Liposome is suspended in to assemble in the aqueous solution by phospholipid molecule and forms, and immobilized artificial membrane is the symmetric double molecular film, and intermolecular is weak interaction (hydrophobic interaction, Van der Waals force, hydrogen bond etc.); Arrange between phospholipid molecule closely; The hydrocarbon chain high-sequential, membrane fluidity is little, but often undergoes phase transition because of the variation of factors such as temperature, pH value and water content and be separated.When gel phase → liquid crystalline phase phase transformation takes place, membrane molecule strengthens at interval, and mobile and permeability significantly increases; Be separated mutually when gel phase → hexagonal takes place, form hole on the film or film takes place and merge the rapid seepage of contained medicine.When the preparation liposome; Usually adopt ethanol as the solvent lipin dissolving, ethanol can be induced the acyl chain disordering of the phospholipid that flows, and also forms a staggered gel phase; It changes the ionic radius of lipid film, intermolecular Van der Waals force, electrostatic force size, and the structure of film is had certain influence.
Remote, there are Van der Waals force and electrostatic repulsion forces between liposome; When two surface contacts were very near, there was Hydration Force in 1-3nm between liposome, a kind of intensive repulsive force, and surpassing Van der Waals force and electrostatic repulsion becomes mastery reaction.Hydration Force is the hydrophilic group effect of hydrone and phospholipid, can stop the gathering between liposome membrane.When high concentration ethanol existed, hydrone was just replaced by ethanol molecule, and it is adsorbed in the film surface, perhaps is distributed in the hydrophobic region of film.This replacement disappears the hydration layer of surface of liposome, causes the gathering of DPPC (dipalmitoyl phosphatidyl choline) liposome.
Can cause that based on ethanol side direction is separated; Cause lecithin/phosphatidyl ethanolamine liposome permeability of the membrane to increase; Too much ethanol is prone to cause the seepage of gathering, bilayer fusion and the medicine of liposome, thereby influences the envelop rate of liposome, particle diameter and stability etc.Therefore (DOXIL, Kai Lai) the ethanol residual quantity requires less than 0.01% existing Evacet in the commodity.
Summary of the invention:
The technical problem that the present invention will solve provides a kind of Evacet and preparation method thereof.
Low based on alcohol toxicity, the good aspect of liposome membrane material dissolubility is considered we prepare blank liposome with the improvement alcohol injection, adopt ion gradient to load technology preparation Evacet.Investigate of the influence of different ethanol contents to blank liposome, gradient liposome and drug-loaded liposome envelop rate, particle diameter and antitumor efficient; The ethanol residual quantity of finding final Liposomal formulation can be controlled in 10% (v/v) pleasantly surprisedly; Guarantee that ethanol residual in the preparation process does not have the significance influence to liposome property, greatly shortening the ethanol content control of simplifying in the commercial production provides reference.We set up the preparation technology that the improvement alcohol injection prepares Evacet thus, and concrete grammar is following: preparation aquation medium is in 45 ~ 75 ℃ of heat preservation for standby use; Less than 10% ethanol, comprise dehydrated alcohol, with formulation products final volume percentage ratio in 45 ~ 75 ℃ of lipin dissolving phases; With the aquation medium according to certain speed be added to lipid mutually in, dispersed with stirring reduces particle diameter, blank liposome; Get final product according to gradient medicine carrying method.
Its prescription and preparation technology are following:
Amycin 0.5%～40%
Phospholipid substance 10%～90%
Cholesterol 0%～44.5%
PEG lipid derivate 0%～40%
Take by weighing recipe quantity hydrogenated soya phosphatide, cholesterol, PEG lipid derivate; With an amount of dehydrated alcohol/dissolve with ethanol; Citric acid-the sodium citrate buffer that adds finite concentration pH=4.0; Dispersed with stirring is to the suspension that forms homogeneous, pop one's head in ultrasonic/or other method reduce filtering with microporous membrane behind particle diameter, promptly get blank liposome turbid liquor.To wherein adding certain amount of alkaline solution, promptly get the gradient liposome.The gradient liposome is mixed with doxorubicin hydrochloride solution, under uniform temperature, hatch certain hour, promptly get hydrochloric doxorubicin liposome.Wherein citric acid-sodium citrate buffer concentration is 100～500mM, and medicine fat mass ratio is 1:1～1:20, and the medicine carrying temperature is 45～75 ℃, and the medicine carrying time is 2～60min, and the outer aqueous pH values of liposome is 5.0～8.0; Ethanol content is less than 10% (V/V).As preferably, wherein citric acid-sodium citrate buffer concentration is 200～400mM, and medicine fat mass ratio is 1:4～1:8, and the medicine carrying temperature is 50～55 ℃, and the medicine carrying time is 10～20min, and the outer aqueous pH values of liposome is 6.5～7.5; Ethanol content is less than 10% (V/V).
Liposomal pharmaceutical prepn can be measured the envelop rate of medicine in liposome through routine techniques.The liposome encapsulation method for measuring has ultrafiltration, dialysis, column chromatography, microtrabeculae centrifuging etc., and all there is certain problem in these methods.We adopt ion exchange resin (fiber) to carry out entrapment efficiency determination, have weak point consuming time, simple to operate, cheap, reusable, do not need expensive advantages such as instrument and equipment.
Preparation provided by the invention and preparation method thereof can make in the liposome preparation process ethanol content rationally controlled, and guarantees that ethanol residual in the preparation process does not have the significance influence to liposome property.
The specific embodiment:
Below in conjunction with specific embodiment the present invention is described further.These embodiment just illustrate, and they should not be construed as limiting the invention.
Embodiment 1
The pH gradient method prepares hydrochloric doxorubicin liposome (DOX-L)
The preparation of blank liposome
Take by weighing lipid components, dissolve in 65 ℃ of stirring in water bath with an amount of dehydrated alcohol, wave except that ethanol, add citric acid-sodium citrate buffer of finite concentration pH=4.0,65 ℃ of stirring in water bath 20 min get the blank liposome first product.First product is popped one's head in behind ultrasonic 8 min (200 w * 2 min, 400 w * 6 min), and successively through the microporous filter membrane of 0.8,0.45,0.22 μ m, (finally the phospholipid mass concentration is 50 mgmL promptly get blank liposome turbid liquor
-1).
The preparation of gradient liposome and medicine carrying
Get above-mentioned blank liposome suspension 1.0 mL, add a certain amount of 500 mmolL
-1Sodium radio-phosphate,P-32 solution, promptly get the gradient liposome.Get a certain amount of gradient liposome and doxorubicin hydrochloride solution (5.0 mgmL
-1) mix, under uniform temperature, hatch certain hour, promptly get DOX-L.
The mensuration of DOX-L envelop rate
Adopt cation exchange resin processes to measure the DOX-L envelop rate, concrete operations are following: precision pipettes 0.1 mLDOX-L in 10.0 mL volumetric flasks, adds 1.6 mL distilled water, is that 90% aqueous isopropanol (contains 0.75 molL with volume fraction
-1HCl) breakdown of emulsion and standardize solution shake up, and 480 nm wavelength are measured absorbance A down
0(the total trap of medicine).Precision pipettes 0.1 mLDOX-L in addition, places cation exchange resin column top end surface central authorities, 2000 rmin
-1Centrifugal 4 min add 400 μ L distilled water, 2000 rmin in the capital end again
-1Centrifugal 4 min repeat 4 times, merge eluent.Eluent is transferred in the 10.0 mL measuring bottles, and using volume fraction is that 90% aqueous isopropanol (contains 0.75 molL
-1HCl) breakdown of emulsion and standardize solution shake up, and measure absorbance A
1(entrapped drug trap), the computational envelope rate.
Orthogonal design is optimized the preparation technology of DOX-L
On the basis of preliminary experiment, with citric acid-sodium citrate buffer concentration (A), medicine fat mass ratio (B), medicine carrying temperature (℃), medicine carrying time (D) and △ pH value (E) be main investigation factor, each factor is got 4 levels (table 1), selects for use
L 16(4
5) orthogonal array (table 2) experimentizes, and measures envelop rate, is that index is analyzed the result with corresponding envelop rate (EE).
Table 15 factors 4 water-glasses
Table 2 orthogonal test
L
16
(4
5
) table
Can know prescription 13, i.e. A by table 2
4B
1C
1D
2E
3The envelop rate of (citric acid-sodium citrate buffer concentration 400mM, medicine fat are than 1:8,50 ℃ of medicine carrying temperature, medicine carrying time 15min and △ pH value 3) is the highest, can reach 99.4%.
In addition, can be known by table 2 that five factors are B ﹥ A ﹥ C ﹥ E ﹥ D to the influence of envelop rate in proper order, optimum combination is A
3B
2C
2D
2E
3, since 2 and 3 two levels of B factor be medicine fat than 1:6 and 1:4 to envelop rate to influence difference less, take all factors into consideration envelop rate and drug loading respectively with A
3B
2C
2D
2E
3(citric acid-sodium citrate buffer concentration 300mM, medicine fat are 3 than 1:6,55 ℃ of medicine carrying temperature, medicine carrying time 15min, △ pH value) and A
3B
3C
2D
2E
3(citric acid-sodium citrate buffer concentration 300mM, medicine fat are 3 than 1:4 medicine carrying temperature 55 ℃ of medicine carrying time 15min, △ pH value) two combinations respectively prepare three batches of liposomees, and its envelop rate and particle diameter are measured, and the result sees table 3.
Table 3 Evacet envelop rate and particle diameter
| Prescription | EE% | MD/nm |
| A 3B 2C 2D 2E 3 | 99.5±1.6 | 114.6±1.7 |
| A 3B 3C 2D 2E 3 | 98.3±1.2 | 113.1±2.6 |
Can be known by table 3, under the constant situation of other prescription factors, adopt medicine fat than liposome encapsulation and the particle diameter there was no significant difference of 1:6 with the 1:4 preparation, take all factors into consideration envelop rate and drug loading, final to select optimum the prescription be A
3B
3C
2D
2E
3, promptly adopt 300 mmolL of pH=4.0
-1Citric acid-sodium citrate buffer as the aquation medium, use 500 mmolL
-1Sodium radio-phosphate,P-32 solution regulate outer water pH=7.0, with medicine fat than 1:4 (w/w), 55 ℃ of medicine carrying 15 min.
Consolidated statement 2 results and A
4B
1C
1D
2E
3(citric acid-sodium citrate buffer concentration 400mM, medicine fat compare 1:8
,50 ℃ of medicine carrying temperature, medicine carrying time 15min and △ pH value 3), A
3B
2C
2D
2E
3(citric acid-sodium citrate buffer concentration 300mM, medicine fat are 3 than 1:6,55 ℃ of medicine carrying temperature, medicine carrying time 15min, △ pH value) and A
3B
3C
2D
2E
3Each parameter in (citric acid-sodium citrate buffer concentration 300mM, medicine fat are 3 than 1:4 medicine carrying temperature 55 ℃ of medicine carrying time 15min, △ pH value); And the undulatory property of consideration practical operation; We confirm that final prescription is formed and process conditions are: citric acid-sodium citrate buffer concentration 200～400mM; Medicine fat is than 1:4～1:8,50～55 ℃ of medicine carrying temperature, medicine carrying time 12～18min and △ pH value 2.8～3.2.
The residual influence of embodiment 2 ethanol to liposome
Prescription is formed
DSPC (DSPC) 3g
Cholesterol (CH) 1g
Cetomacrogol 1000 Cholesteryl hemisuccinate (mPEG1000-CHEMS) 0.5g
Take by weighing recipe quantity DSPC, CH, mPEG1000-CHEMS, use the anhydrous alcohol solution film material of 2.5%, 5.0%, 10%, 15%, 20%, 25%, 30% and 40% (ethanol and aquation medium volume ratio) respectively, add 300 mmolL of pH=4.0
-1Citric acid-sodium citrate buffer, final phospholipid mass concentration is 50 mgmL
-1, 65 ℃ of stirring in water bath 20 min get the blank liposome first product.First product is popped one's head in behind ultrasonic 8 min (200 w * 2 min, 400 w * 6 min); Through the microporous filter membrane of 0.8,0.45,0.22 μ m, promptly get blank liposome turbid liquor successively, adopt laser granulometry to measure each liposome particle diameter; The result shows; When the ethanol residual quantity did not surpass 10% (v/v), significant change did not take place in the liposome particle diameter between 107.3 ~ 111.8 nm; When the ethanol residual quantity increased to 15% (v/v), the liposome particle diameter increased to 122.1 nm; The liposome particle diameter is reduced to 80 nm when amount of alcohol is 20 ~ 25% (v/v); When the ethanol residual quantity was 30% (v/v), particle diameter increased to 120 nm again; When the ethanol residual quantity was 40% (v/v), the ultrasonic back of popping one's head in formed the milky gelatinous precipitate.According to optimum prescription preparation drug-loaded liposome, measure envelop rate, when the result did not surpass 10% (v/v) when the ethanol residual quantity, liposome encapsulation was between 96.2 ~ 98.9%; When the residual amount of ethanol was 15% (v/v), envelop rate dropped to 88.5%, and along with the increase envelop rate of ethanol residual quantity descends gradually, when the ethanol residual quantity was 30% (v/v), envelop rate had only 16.1%.
Therefore, prepare the formulation and technology of Evacet for the pH gradient method, the ethanol content in the final preparation should be controlled to be smaller or equal to 10% (v/v).
The preparation of embodiment 3 Evacets
Preparation lipid mixture powder: HSPC, CHOL are mixed according to the mass ratio of (3:1:1) with PEG2000-DSPE; Obtain clear and bright solution with dissolve with ethanol; Obtain lipid powder (also can adopt each lipid components of tert-butyl alcohol dissolving, freeze-drying method obtains the lipid powder) after the spray drying.
The preparation blank liposome: with above-mentioned lipid powder with the 300mM ammonium sulfate 50-65 ℃ of aquation, shear to disperse, obtain the multilamelar liposome of particle diameter inequality.Add not commensurability dehydrated alcohol, with the granularity (approximately 80nm) of microjet equipment reduction liposome, preparation contains the liposome of different concentration ethanol.
Preparation gradient liposome: adopt the ammonium sulfate of the outer water of ion exchange resins/fibers weeding of grease plastid promptly to get.
Medicine carrying: according to the ratio of medicine fat, in blank gradient liposome, add doxorubicin hydrochloride solution (10mg/mL), hatch about 20min, get final product at 60-65 ℃ than 1:6 (mass ratio).Measure envelop rate and particle diameter, the result sees table 4.
Table 4 ethanol is to the influence of Evacet envelop rate and particle diameter
| Concentration of alcohol (v/v) | 0% | 5% | 10% | 15% | 20% | 25% |
| Envelop rate (%) | 98.3 | 98.6 | 96.6 | 93.8 | 61.2 | 28.6 |
| Particle diameter (nm) | 81.3 | 86.5 | 83.2 | 95.6 | 110.1 | 118.6 |
Can know by table, when ethanol more than or equal to 20% the time, particle diameter increases, envelop rate descends, ethanol is obvious to the influence of particle diameter.Adopt ammonium sulphate gradient to prepare Evacet, the ethanol content in the final preparation should be controlled to be smaller or equal to 15% (v/v).
Also can add materials such as isoosmotic adjusting agent, antioxidant in the liposomal pharmaceutical prepn of the present invention, sucrose, trehalose, xylitol, histidine, tocopherol, EDTA calcium sodium etc.
Embodiment 4 other prescriptions
Phosphatidase 11 0g
Cholesterol 0 ~ 4g
PEG lipid derivate 0 ~ 4g
This said phospholipid of writing out a prescription comprises that natural or synthetic phospholipid or derivatives thereofs such as phosphatidylcholine, phosphatidyl glycerol, phosphatidic acid, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, sphingomyelin, cuorin such as DSPC, DSPG, DSPE, DPPC, DPPG, DPPE, DOPC, DOPC, DOPE replace HSPC, also can obtain similar results.The PEG lipid derivate can be a phospholipid derivative, like PEG-DSPE (PEG molecular weight 200～20000), also can be other lipid derivates.
Research method according to the foregoing description 3 finds that ethanol was more than or equal to 20% o'clock, and liposome each item index significance all takes place changes.
Equally, adopt EDTA ammonium gradient, ion gradient (like ionophore A23187), sucrose octasulfate gradient etc.; The method that gradient is set up comprises " ion exchange ", " dialysis ", " ultrafiltration ", " molecular sieve separation " etc.; Also can ethanol be controlled in 15%, its particle diameter of prepared Evacet and envelop rate with do not add the ethanol preparation and compare no significance and change.
The test of embodiment 5 antitumor
Medicine: the Evacet of " embodiment 3 ", ethanol content is respectively 0%, 5%, 10%, 15%, 20%, 25% in the preparation.
The mices of 48 inoculation S180 tumors are divided into 8 groups at random, i.e. normal saline matched group (NS), amycin solution group, Evacet group, every group of 6 animals, the inoculation back was respectively at tail vein injection administration (6mg/kg) in the 4th, 7,10 day.Animal is normally raised after the administration, and weighing every day mice body weight is observed the growth conditions of mice simultaneously.Animal is put to death in inoculation back the 13rd day, completely peels off Subcutaneous tumor, calculates tumour inhibiting rate, and the result sees table 5.
The different ethanol content Evacets of table 5 press down the tumor result
| ? | The solution group | 0% ethanol | 5% ethanol | 10% ethanol | 15% ethanol | 20% ethanol | 25% ethanol |
| Tumour inhibiting rate (%) | 43.1 | 89.5 | 90.2 | 92.3 | 70.2 | 50.6 | 52.7 |
Can know that by table ethanol content was more than or equal to 15% o'clock, antitumous effect significantly reduces.
Though ethanol content is little to the particle diameter and the envelop rate influence of liposome at 15% o'clock, drug effect obviously reduces in the body, and therefore when the preparation Evacet, ethanol content should be controlled in 10%.
Embodiment 6 existence tests
Adopt the model of " embodiment 5 ", observe the mice with tumor life span.Experimental result shows that the blank control group mice is all death in 12-17 days after inoculation; Amycin solution group and 25% alcohol liposome group are all dead during after the inoculation 16-22 days; 15% all animals of ethanol group are all dead during after the inoculation 13-23 days, and 0%, 5%, 10% all animals of ethanol group are all dead during after the inoculation 30-40 days.
Although described some preferred embodiment of the present invention here, these embodiments should not be understood that to limit the scope of the present invention.In fact; Except this paper showed and described, after the disclosure of having read the application, in conjunction with the general knowledge of this area; Those of ordinary skill is with various other modifications of the present invention fully aware of, change and variation, and they all should be encompassed within protection scope of the present invention.
Claims (9)
1. an Evacet is characterized in that, its composition and percentage by weight are following:
Amycin 0.5%～40%
Phospholipid substance 10%～90%
Cholesterol 0%～44.5%
PEG lipid derivate 0%～40%.
2. Evacet as claimed in claim 1; It is characterized in that described bimolecular film material is natural or synthetic phospholipid or derivatives thereofs such as phosphatidylcholine, phosphatidyl glycerol, phosphatidic acid, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, sphingomyelin, cuorin, reaches above-mentioned substance through the hydrogenant material of common method; Main membrane material as constituting bimolecular film can only contain a kind of phospholipid, also can contain multiple phospholipid; Still can add other compositions in the prescription, comprise glycolipid matter, cholesterol, sitoesterol apoplexy due to endogenous wind any one or multiple.
3. Evacet as claimed in claim 2 is characterized in that, the preferred HSPC of phospholipid, HEPC, DSPC in the film material of wherein said Liposomal formulation; " other compositions " preferred cholesterol.
4. Evacet as claimed in claim 1; It is characterized in that; The adjuvant that wherein can add further modified liposome surface character; The optional DSPE of modifying from Polyethylene Glycol (PEG-DSPE), polyethyleneglycol modified distearyl phosphatidyl glycerol (PEG-DSPG), polyethyleneglycol modified cholesterol (PEG-CHOL), DSPE that polyvidone is modified (the distearyl phosphatidyl glycerol modified of PVP-DSPE), polyvidone (PVP-DSPG) or its combination, more preferably Polyethylene Glycol-distearyl acyl group PHOSPHATIDYL ETHANOLAMINE (PEG-DSPE) derivant.
5. Evacet as claimed in claim 4 is characterized in that the molecular weight of PEG is generally 200-20000 dalton among the PEG-DSPE, preferred 1000-7000 dalton, more preferably 2000-5000 dalton; Its consumption is generally 0.0-20mol% with respect to the ratio of membrane lipid, preferred 0.5-10%.
6. Evacet as claimed in claim 1; It is characterized in that; Adopt pH gradient method, citric acid gradient method, ammonium sulphate gradient, sucrose octasulfate gradient method, EDTA ammonium gradient method, metal ion gradients method that medicine is loaded into liposome, the control ethanol content is 0-15% (V/V).
7. Evacet as claimed in claim 6 is characterized in that, ethanol content is less than 10% (V/V).
8. the method for preparing of Evacet as claimed in claim 6 is characterized in that, prepares Evacet through the pH gradient method; Its technology is: take by weighing recipe quantity hydrogenated soya phosphatide, cholesterol, PEG lipid derivate, use an amount of ethanol, comprise dehydrated alcohol; In 55～65 ℃ of stirring in water bath dissolvings, add citric acid-sodium citrate buffer of finite concentration pH=4.0,55～65 ℃ of stirring in water bath are to the suspension that forms homogeneous; The ultrasonic back filtering with microporous membrane of popping one's head in; Promptly get blank liposome turbid liquor,, promptly get the gradient liposome to wherein adding certain amount of alkaline solution.
9. the gradient liposome is mixed with doxorubicin hydrochloride solution, under uniform temperature, hatch certain hour, promptly get hydrochloric doxorubicin liposome; Wherein citric acid-sodium citrate buffer concentration is 100～500mM, and medicine fat mass ratio is 1:1～1:20, and the medicine carrying temperature is 45～75 ℃, and the medicine carrying time is 2～60min, and the outer aqueous pH values of liposome is 5.0～8.0; Ethanol content is less than 10% (V/V), and as preferably, wherein citric acid-sodium citrate buffer concentration is 200～400mM; Medicine fat mass ratio is 1:4～1:8; The medicine carrying temperature is 50～55 ℃, and the medicine carrying time is 10～20min, and the outer aqueous pH values of liposome is 6.5～7.5; Ethanol content is less than 10% (V/V).
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| CN114126589A (en) * | 2019-06-20 | 2022-03-01 | 茵农梅迪卡控股股份有限公司 | Liposomal doxorubicin preparation, method for producing a liposomal doxorubicin preparation and use of a liposomal doxorubicin preparation as a medicament |
| CN111714457A (en) * | 2020-06-22 | 2020-09-29 | 苏州大学 | Carbonate polymer vesicle carrying small-molecule drugs, and preparation method and application thereof |
| CN114831940A (en) * | 2022-05-11 | 2022-08-02 | 南通大学 | Medicine carrying system for carrying anti-cancer medicine and preparation method and application thereof |
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