CN103630508B - Method for measuring encapsulation efficiency of doxorubicin hydrochloride liposomal - Google Patents
Method for measuring encapsulation efficiency of doxorubicin hydrochloride liposomal Download PDFInfo
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Abstract
The invention belongs to the field of chemical medicine detection and in particular relates to a method for measuring the encapsulation efficiency of doxorubicin hydrochloride liposomal. The doxorubicin hydrochloride liposomal is a nano small ball formed by wrapping doxorubicin hydrochloride with a phospholipid double-layer film, and the uncovered doxorubicin hydrochloride is free outside the ball. When alkaline liquid is added to a system, the free doxorubicin hydrochloride and alkaline react; the absorption wavelength of the free doxorubicin hydrochloride is long, and the doxorubicin hydrochloride in the film and the alkaline do not reacts due to isolation from the film, and an original absorption wavelength is kept. The encapsulation efficiency of the liposomal is calculated due to the change of the wavelengths through an ultraviolet-visible light photometer. The method has the characteristics of short measurement time, convenience, accuracy, small error and high reproducibility and is suitable for control on the industrial production process.
Description
Technical field
The invention belongs to chemicals detection field, particularly a kind of assay method about Doxil envelop rate.
Background technology
Envelop rate is the important index of liposome and nanoparticle quality control one, and reflect the degree of medicine loaded body encapsulating, the concentration of medicine and carrier, the condition in preparation process is the principal element affecting its envelop rate.Envelop rate comprises the mensuration of percentage envelop rate and parcel volume, general document paper examines percentage envelop rate (Encapsulation percentage, EN%).Its expression formula is EN%=(1-Cf/Ct) × 100%.In formula, Cf is the amount of free drug; Ct is the total amount of nanoparticle or Liposomal suspensions Chinese traditional medicine.For Accurate Determining envelop rate, nanoparticle or liposome being separated with free drug is crucial step.Due to liposome or much larger than wrapped drug particle of nanoparticle, can utilize they vary in size be separated the medicine that removing do not wrap up, these methods have gel filtration column chromatography, dialysis etc.; If wrapped medicine is protein or DNA etc., or not wrapped medicine may form larger agglomerated thing, then them can be utilized from nanoparticle or liposome buoyancy, density different and adopt the method such as centrifugal to be separated.Common envelop rate detection method is as follows:
1. column chromatography
Gel Permeation Chromatography because of its effectively and be used widely in laboratory fast.It can be used for being separated remove non-packaging medicine also can to the liposome in suspension or nanoparticle size packets.It should be noted and may need to increase concentration step after liposome or nanoparticle are diluted by elution media.Column chromatography filler commonly uses glucosan as Sephadex G-50, also bibliographical information is had to use Sephadex G-25 and Sephadex G-200, concrete steps are: loading water or physiological saline or the swelling Sephadex G-50 of phosphate buffer in chromatographic column, by suspension upper prop, with water or physiological saline or phosphate buffer coutroi velocity wash-out.Select the speed of the kind of the particle size of gel, eluent, wash-out, temperature to have important impact to separation, need to make elution curve to determine best separating effect in concrete experiment.
Korea Spro waits people quietly and adopts when measuring the envelop rate of solid lipid nanoparticles containing volatile oil of Lignum dalbergia odoriferae column chromatography to be separated.Condition is: Sephadex G-50 post (16cm × 2cm), and eluent is distilled water, and flow velocity is 1ml/min, room temperature.Pipette dalbergia wood volatile oil solid nano grain 0.5ml upper prop, with column chromatography condition wash-out, every 3ml collects once.The HPLC condition that encapsulated medication amount application content of dispersion measures measures.
The Sephadex G-25 of swelling 12 hours is filled post by the people such as He Jun, uses 80ml water elution, flow velocity 1ml/min, and after collecting, 40ml eluent carries out measuring (2).The entrapment efficiency determination of taxol long circulating lipid nano particle selects Sephadex gel column equally, is eluent with water, accesses and wherein measures with the part of blue-opalescent.
Luan Libiao etc. find when measuring Ketoprofen gelatine microsphere envelop rate gel filtration chromatography method apart from accurately, convenient, particulate is survivable, outside high repeatability and other advantages, all right purifying microballoon, not only can remove the low molecular weight impurities such as medicine, inorganic salts of not wrapping up, and can Tween-20 be isolated.
Gao Xiaoli etc. screen the condition that dextrane gel chromatography measures liposome encapsulation.To glass column, the particle diameter of gel is not the smaller the better, if gel particle is too thin, larger liposome may be trapped on gel column, will consider molecular size and the character of separated compound when selecting.The gel (particle size 50-150 μm) of thick level in should selecting for multilamellar liposome, then can with the gel of any rank for small unilamellar vesicle.In column chromatographic process, the blade diameter length ratio of chromatographic column used, the flow velocity of eluent and the number of applied sample amount all affect separated free medicine from liposome, and should select to make liposome reach the elution requirement of maximum separation degree, guarantee is envelop rate accurately.It should also be noted that dextran surface also exists can be combined with liposome membrane and interactional minute sites.Although this effect does not affect the flow characteristics of liposome on gel column, but still can cause the loss of a small amount of lipid, film instability is increased, thus cause the change of membrane permeability and the seepage of encapsulate substances.This phenomenon should give special attention when lipid concentration is lower, generally by strengthening liposomal samples upper column quantity or solving saturated for pillar in advance with empty liposome.
2. dialysis
Dialysis utilizes liposome or nanoparticulate particles and drug molecule to vary in size, the method removed by free drug by the fenestra crown_interception of semipermeable membrane material.Liposome and nanoparticle more greatly can not through semi-permeable diaphragms, and free drug can pass through, and generally liposome and nanoparticle is placed in semi-permeable diaphragm, and conventional semipermeable membrane material has parchment, animal's bladder and collodion etc.Put neat solvent outside film, due to concentration difference factor, the free drug in film, constantly to film exosmosis, is often changed the solvent outside film, is made free drug be completely segregated out.This method is the most also the method (except macromolecular compound) of the most frequently used non-entrapped drug of removing.It does not need complicated technology, also without the need to the instrument of costliness, and can expanding production.All free drugs can be removed by constantly changing dialysis medium.But this method is very time-consuming, under general room temperature condition, the free drug that remove more than 95% at least needs replacing three dialysis media, and the time is at more than 10-24h.In addition, the osmotic strength of dialysis medium should be consistent with the concentration of liposome or nanoparticle suspension, otherwise will change the volume of liposome and nanoparticle suspension in dialysis, and may cause the seepage of encapsulate substances.
The separation application dialysis of insulin nanoparticles, insulin liposome pH7.4PBS is mixed with suitable concn, get 1ml and put into bag filter, pH7.4PBS10.0ml is dissolution medium, be placed in triangle tool plug flask, be placed in oscillator by Erlenmeyer flask and vibrate, constant temperature 37 DEG C, oscillation frequency is 150r/min.Get dislysate after 3h, measure its concentration.
Zhang Guifang etc. mensuration Buddhist nun not in liquid nano liposomes envelop rate by liposome solutions 1ml in processed bag filter (molecular weight 10000), bag filter is immersed bag filter (hydration medium used when namely preparing this liposome) 45ml, be placed on magnetic stirring apparatus and stir, dislysate is changed in timing.Because liposome particles is less in this experiment (about 30-150nm), centrifuge method separating effect is not fine, and the effectiveness comparison of dialysis is good.
After every bottle of lipid freeze-dry powder is added the hydration of 1ml redistilled water by Lv Wenli etc. in entrapment efficiency for liposomal formulation of breviscapine measures, precision pipettes 0.5ml, add in the bag filter of wound packages, put into the conical flask filling 100ml0.9%NaCl, magnetic agitation in 37 DEG C of water-baths.In preliminary experiment, determine that getting outer liquid at 4h measures.The people such as Xiong Fei apply reverse dialysis in the assay method of Breviscapinun nano liposomes envelop rate.Concrete grammar is placed in outside bag filter by liposome solutions, and hydration medium, in bag filter, stirs the outer liquid of bag filter, dialysis 16h.In accurate absorption bag filter, liquid measures.
Because the liposome of preparation is less, mean grain size 20.8nm, adopts sephadex chromatography method, exchanges different loading volume for and be all difficult to be separated liposome and free drug with mobile phase, and liposome is comparatively large from loading and complete wash-out extension rate, likely causes liposome seepage.The particle diameter of liposome is less, also cannot be separated liposome and free drug with the ultracentrifugation of long period.Conventional dialysis is placed in bag filter by liposome, dialysis material is placed in the outer liquid of bag filter, free drug can through bag filter, until in bag filter free drug concentration with dialysis medium in reach balance, but because the volume of the outer liquid of bag filter is generally the long-pending 20-50 of interior liquid doubly, when dialysing complete, around liposome, drug concentration can dilute larger multiple, may cause the seepage of liposome medicament in dialysis procedure because the mobile equilibrium of liposome and free drug is broken.So hyperfiltration effectively can avoid seepage.
3. centrifuge method
Under different centrifugal force, centrifuging is the effective ways being separated free drug in removing variety classes liposome or nanoparticle.In order to remove free drug completely, usually need to repeat to suspend with repeatedly centrifugal.Make liposome or the centrifugal force required for nanoparticle sinking depend on the size of liposome and nanoparticle, also depend on the coagulation of suspension to a certain extent.If liposome or the little and narrowly distributing of nanoparticle, just need high speed centrifugation and freezing conditions.Low speed (2000-4000r/min) is centrifugal can only make large liposome or nanoparticle sedimentation.The freezing centrifugal and consumed energy of high speed is utilized for a large amount of liposome and nanoparticle and costly, therefore this method is unsuitable for being separated small liposome or nanoparticle.
In bibliographical information, nanoparticle is separated with the multiplex centrifuge method of larger liposome.Ursolic Acid Phospholipid Nanoparticles is separated with its free drug by the centrifuge method such as Zhou little Ju, after low temperature ultracentrifugation (4 DEG C, 100000r/min, 60min), gets supernatant and measures.Aclarubicin A PLA milimicron particle, eye Norfloxacin milimicron particle, Praziquantel-Liposome etc. are all that application of cold temperature high speed centrifugation carrys out separated free medicine.The separation condition that the people such as Tasana Pitaksuteepong prepare in the nanoparticle of hydrophilic substance in water-in-oil microemulsion interfacial polymerization is: 51500 × g, 1h, 25 DEG C (14).For larger liposome, low-speed centrifugal can shorten the time and rarer liposome turbid liquor can be concentrated to required concentration simultaneously.In order to avoid liposome is destroyed, must be noted that the osmotic pressure ensureing to repeat suspension medium is consistent with the osmotic pressure of Liposomal suspensions.
4. ultrafiltration
Ultrafiltration (be called for short UF), is be expulsive force with pressure, utilizes the physics screening process that ultra filtration membrane different pore size is separated liquid.Its molecule cutting quantity (CWCO) is generally 6000 to 50 ten thousand, and aperture is 100nm(nanometer).Originating from is 1748, and Schmidt cotton glued membrane or fine jade film divide filter solution, and when applying certain pressure, solution (water) is through film, and the material such as protein, colloid is then retained down, and its filtering accuracy considerably beyond filter paper, therefore claims ultrafiltration.The separation characteristic of ultrafiltration has: 1. detachment process is without phase change, therefore economize energy; 2. being separated is carry out at normal temperatures, is suitable for the concentrated of some heat sensitivity materials (as fruit juice, medicine, biopreparate) and purifies; 3. the ultra filtration membrane of seriation, can carry out molecular-weight gradation by the macromolecular solution system of many components; 4. equipment is simple, is easy to operation, management and maintenance; 5. ultrafiltration is a uniform non-individual body be made up of high molecular polymer, and in use, film itself, without any chip or particles from getting loose, ensures through water pure.
In entrapment efficiency determination, ultrafilter is also used to be separated liposome or nanoparticle and free drug.Ultrafiltration is carried out with SS-5 hollow fiber membrane ultrafiltration device (retaining mean molecular weight 10000) in the research of camptothecine solid lipid nanoparticle.The red grade of Wang Zhun uses SS-14A type ultrafilter in the entrapment efficiency of Penciclovir liposome measures, ultra filtration membrane molecule interception 30,000.
Summary of the invention
Technical matters to be solved by this invention is: in prior art, measures envelop rate, and usually need liposome and not encapsulated medical separation, complicated operation, accuracy rate declines.
For solving this technical matters, the technical solution used in the present invention is:
The invention provides a kind of assay method of Doxil envelop rate, be divided into 3 steps:
(1) total drug monitoring: prepare certain density Doxil sample solution, measure the absorbance log of this sample solution,
In Doxorubicin, the concentration of Doxil controls as 0.00001mg/ml ~ 2mg/ml, and total drug monitoring wavelength is 249-259nm,
As preferably, following operation can be adopted, get Doxil, be diluted to 0.004mg/ml, be blank with methyl alcohol, utilize ultraviolet-visible photometer, measure absorbance log A at 254nm place
1;
(2) free drug measures: to being same batch with step (1), with in concentration Doxil solution, add excessive alkali reaction, after reaction terminates, measures absorbance log.
Wherein, alkali to be selected from NaOH, potassium hydroxide, lithium hydroxide, ammoniacal liquor one or more, and paper mill wastewater is 0.001mol/L ~ 3mol/L, and alkalescence is stronger, and the reaction time is shorter, reacts more complete,
Temperature of reaction is 0 DEG C ~ 55 DEG C, and temperature usury is in reaction, but liposome membrane has phase transition temperature, and under too high condition, film just becomes and is easy to penetrating, and such alkali can enter liposome center, thus affects measurement result.
Envelop rate of the present invention detection time is short is its distinguishing feature, and when alkali adds in liposome, free Doxorubicin reacts at once, and make system become blue, its reaction time is 0.001 hour ~ 0.5 hour.
In Doxorubicin, the concentration of Doxil controls as 0.001mg/ml ~ 2.5mg/ml, and it is 570-610nm that free drug measures wavelength,
As preferably, following operation can be adopted, get the Doxil 1ml of same batch of 2mg/ml, after diluting 500 times, add excessive alkali reaction, after reaction terminates, with the Doxil of same concentration for blank, utilize ultraviolet-visible photometer, measure absorbance log A at 600nm place
2;
(3) by correction factor computational envelope rate, envelop rate=(1-A
2* f/A
1) * 100%, consider the difference of testing tool and brand, correction factor f is 1.488 ~ 1.522, and measuring f in the present invention is 1.500.
Because liposome bilayer membrane has buffer action.When adding alkali lye in system, free Doxorubicin and alkali react, and free Doxorubicin absorbing wavelength is long moves, and is wrapped in the Doxorubicin in film, because the isolation of film does not react with alkali, keeps original absorbing wavelength, there is not interference.Thus directly can measure free drug, calculate envelop rate.
The invention has the beneficial effects as follows: the present invention is that liposome encapsulation mensuration provides a kind of novel method, when without the need to adopting separation means, have measure consuming time short, convenient, accurate, error is little, reappear, and is applicable to the feature of commercial process control.
Accompanying drawing explanation
Fig. 1 is the scintigram of doxorubicin hydrochloride, there is not absorption at 600nm place.
Fig. 2 is the doxorubicin hydrochloride scintigram after adding alkali, and obvious as seen exist absorption at 600nm place.
Fig. 3 is the Doxil scintigram of 70% envelop rate, there is not absorption at 600nm place.
Fig. 4 is the Doxil of 70% envelop rate, adds the scintigram after alkali, and obvious as seen exist absorption at 600nm place.
Embodiment
Embodiment 1
Doxil lot number 0344689 envelop rate about 80%
(1) mensuration of total medicine: the Doxil 1ml getting 2mg/ml, in the volumetric flask of 50ml, adds methyl alcohol and shakes up to scale.Get wherein 1ml, in the volumetric flask of 10ml, to add methyl alcohol to scale, shake up, to take methyl alcohol as blank measure absorbance log at 254nm place is A
1 is equal=0.382.
(2) free drug measures: get 2mg/ml with step (1) the Doxil 1ml that is same batch in the volumetric flask of 50ml, add water to scale and shake up.Get wherein that 1ml is in the volumetric flask of 10ml, the NaOH adding 0.1mol/L at 2 ~ 8 DEG C, to scale, shakes up, and reacts 5 minutes.
Getting the Doxil of same concentration (same batch), get 1ml in the volumetric flask of 50ml, add water to scale and shake up, then get wherein 1ml and, in the volumetric flask of 10ml, at room temperature, add water to scale, shake up, is blank.
Utilize ultraviolet-visible photometer, measuring absorbance log at 600nm place is A
2 is equal=0.051.
(3) by correction factor computational envelope rate, envelop rate=(1-A
2* f/A
1) * 100%, correction factor f be 1.5.
Measurement result is analyzed
Above-mentioned supercentrifugal process measures, and carries out with reference to State Food and Drug Administration's standard (YBH02522012).
Embodiment 2
Doxil lot number 0344466 envelop rate about 90%,
(1) mensuration of total medicine: the Doxil 2ml getting 2mg/ml, in the volumetric flask of 50ml, adds methyl alcohol and shakes up to scale.Get wherein 1ml, in the volumetric flask of 10ml, to add methyl alcohol to scale, shake up, to take methyl alcohol as blank measure absorbance log at 259nm place is A
1 is equal=0.453.
(2) free drug measures: get 2mg/ml with step (1) the Doxil 2ml that is same batch in the volumetric flask of 50ml, add water to scale and shake up.Get wherein that 1ml is in the volumetric flask of 10ml, at room temperature, the potassium hydroxide adding 1mol/L, to scale, shakes up, and measures immediately,
Getting the Doxil of same concentration (same batch), get 2ml in the volumetric flask of 50ml, add water to scale and shake up, then get wherein 1ml and, in the volumetric flask of 10ml, at room temperature, add water to scale, shake up, is blank.
Utilize ultraviolet-visible photometer, measuring absorbance log at 600nm place is A
2 is equal=0.030.
(3) by correction factor computational envelope rate, envelop rate=(1-A
2* f/A
1) * 100%, correction factor f be 1.5.
Measurement result is analyzed
Above-mentioned supercentrifugal process measures, and carries out with reference to State Food and Drug Administration's standard (YBH02522012).
Claims (1)
1. an assay method for Doxil envelop rate, is characterized in that: described assay method is,
(1) total drug monitoring: get the Doxil 1ml of 2mg/ml in the volumetric flask of 50ml, add methyl alcohol to shake up to scale, get wherein 1ml and, in the volumetric flask of 10ml, add methyl alcohol to scale, shake up, to take methyl alcohol as blank measure absorbance log at 254nm place is A
1 is equal=0.382;
(2) free drug measures: get 2mg/ml with step (1) the Doxil 1ml that is same batch in the volumetric flask of 50ml, add water to scale to shake up, get wherein 1ml in the volumetric flask of 10ml, the NaOH of 0.1mol/L is added to scale at 2 ~ 8 DEG C, shake up, react 5 minutes;
Getting the Doxil of same batch of same concentration, get 1ml in the volumetric flask of 50ml, add water to scale and shake up, then get wherein 1ml and, in the volumetric flask of 10ml, at room temperature, add water to scale, shake up, is blank;
Use ultraviolet-visible photometer, measuring absorbance log at 600nm place is A
2 is equal=0.051;
(3) by correction factor computational envelope rate, envelop rate=(1-A
2 is equal× f/A
1 is equal) × 100%, correction factor f is 1.5.
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