CN107854489A - Purposes of the disodium clodronate liposome in terms of tumour adriamycin chemotherapy auxiliary treatment - Google Patents
Purposes of the disodium clodronate liposome in terms of tumour adriamycin chemotherapy auxiliary treatment Download PDFInfo
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Abstract
The invention discloses purposes of the disodium clodronate liposome in terms of tumour adriamycin chemotherapy auxiliary treatment, after the present invention by appropriate cholesterol, lecithin by being placed in mixing, add chloroform methanol mixed liquor, uniform lipid dry film is prepared using rotating thin film evaporation, the phosphate buffer for adding disodium clodronate produces.The technical effects of the invention are that the disodium clodronate lipid that discovery prepares stability and high efficiency can weaken myocardium toxicity caused by adriamycin and increase therapeutic effect of the adriamycin to breast cancer.
Description
Technical field
The present invention relates to a kind of purposes of medicine, and in particular to the new application of disodium clodronate liposome.
Background technology
Heart failure has had become disease most common, maximum to patient's harm in cardiovascular disease, and causes the original of heart failure
Because again sufficiently complex various, therefore heart failure has turned into the emphasis and difficult point of cardiovascular disease research field.And in tumor therapeutic procedure
Cardiac toxic side effect can also cause the heart failure of patient, so as to have a strong impact on the life quality of tumor patient, it is often more important that, poison
Property development may cause the adjustment of antineoplaston scheme or even stop, influenceing existence (Binaschi M, the et of patient
al.,2001).Cardiac toxic performance is complicated various caused by antineoplastic, and common performance includes arrhythmia cordis, cardiac muscle lacks
Blood, coronary artery disease, hypertension and myocardial dysfunction.The common antineoplastic for causing cardiac toxic mainly has two big
Class：One kind is chemotherapeutics, including anthracycline (Doxorubicin, epirubicin, daunorubicin etc.), alkylating agent are (endoxan, different
Endoxan etc.), anti-cell micro-pipe agent (taxol), anti-metabolism (fluorouracil) etc., another kind of is targeted drug, such as bent appropriate
Pearl monoclonal antibody and Lapatinib etc..
Adriamycin, belong to broad-spectrum high efficacy antineoplastic, be a kind of clinically the most commonly used anthracene ring antitumor medicinal, but its
Cardiac toxic is serious.Adriamycin has unique affinity, the specific accumulation easily in heart to cardiac muscle cell, and is being metabolized
During produce active oxygen, excessive attack cardiac muscle cell, cause myocardium oxidative damage (Kim SY, et al., 2006).Research
Show, the generation in cardiac muscle cell can be increased and reduce the activity of antioxidant enzyme in cardiac muscle cell, cardiac muscle cell is in oxygen
Change stress situation, so as to cause cardiomyopathy and congestive heart failure.Studies have shown that doxorubicin cardiotoxicity is related to numerous simultaneously
Influencing factor, such as cause Apoptosis, autophagy, directly oxidative stress, destruction nucleic acid and albumen synthesis, injury of mitochondria, blood vessel
(Kwok JC, et al., 2003) such as reactive amines releases.Therefore, the research for many years on effectively preventing and treating cardiac toxic is standby always
Paid close attention to by researchers.
Disodium clodronate (clodronic acid) is first generation diphosphonate medicine, is clinically mainly used in caused by cancer
Osteolytic Bone tumour and osteoporosis, hypercalcinemia (Peter Seiler, et al., 1997).It can avoid or postpone by cancer
Osteolytic Bone tumour caused by disease, postpone or prevent that osteolytic Bone tumour canceration from continuing to develop, and can also reduce osteolytic bone
Pathologic fracture caused by transfer changes, and does not influence normal bone mineralization effect, prevents hypercalcinemia and keeps serum calcium dense
The normal level of degree.Research finds that internal macrophage can optionally be removed by being injected intravenously the liposome containing disodium clodronate
Cell (SM Zeisberger, et al., 2006).With its this characteristic, the liposome of disodium clodronate can be used for
The treatment of inflammation disease.
Therefore, for tumor patient, when carrying out antineoplaston with adriamycin, it is necessary to use myocardial protective agent.
Good myocardial protective agent should be that and can protection cardiac muscle cell is without prejudice in the case where not influenceing adriamycin antineoplastic action.
The content of the invention
In order to can induce cardiac muscle cell apoptosis, necrosis, the heart when solving and carrying out antineoplaston with adriamycin in the prior art
Myofibrosis increases, and myocardial contractive power reduces, and the problem of ultimately result in Ventricular Remodeling and congestive heart failure, the present invention carries
For application of the disodium clodronate liposome in preparing with tumour adriamycin chemotherapy auxiliary therapeutic action medicine, disodium clodronate
Liposome property is stable, and into after in vivo, degradation cycle is longer, lasting medicine, has preferable biocompatibility, and reported
Road disodium clodronate lipid physical efficiency suppresses the growth of tumour.Therefore, disodium clodronate liposome is to reducing the heart caused by adriamycin
Flesh toxic action high-efficiency low-toxicity.
In order to realize the above object technical scheme is as follows：
The present invention provides disodium clodronate liposome in preparing with tumour adriamycin chemotherapy auxiliary therapeutic action medicine
Application.
It is described to refer to tumour adriamycin chemotherapy auxiliary therapeutic action to tumour adriamycin chemotherapy with Synergy and attenuation
Effect.
It is described that there is tumour adriamycin chemotherapy auxiliary therapeutic action to refer to disodium clodronate liposome to caused by adriamycin
Myocardium toxicity has abated effect.
It is described that there is tumour adriamycin chemotherapy auxiliary therapeutic action to refer to that disodium clodronate liposome can increase adriamycin and resist
The effect of tumour.
Preferably, the preparation method of the disodium clodronate liposome is：Weigh cholesterol, lecithin is placed in container,
Chloroform-methanol mixed liquor is added, chloroform and methanol volume ratio=2 in the chloroform-methanol mixed liquor:1, in 50-60 DEG C of condition
Under, use rotating thin film evaporation to prepare lipid dry film of the thickness for 0.1-0.2mm, residual solvent is dried up with nitrogen, added
Dissolved with the phosphate buffer for the disodium clodronate that purity is 98%, lipid film is set fully to be swelled aquation, ultrasonic power 400W's
Under the conditions of according to ultrasound 5 seconds, stop frequency ultrasound 5min, the subsequent 22000rpm of 5 seconds, centrifuged 1 hour under the conditions of 10 DEG C, lower floor's fat
Plastid is resuspended with ph=7.2 phosphate buffered saline solution and produced；The cholesterol and lecithin mass ratio are cholesterol：Lecithin
=1:10；The disodium clodronate and lecithin mol ratio are disodium clodronate：Lecithin=1:10.
Preferably, disodium clodronate liposome therapeutic mode is local administration or oral in above-mentioned application.
The present invention proves that disodium clodronate liposome mitigates doxorubicin cardiotoxicity and increase adriamycin by following experiment
The effect of antitumor effect：
1. injecting adriamycin after disodium clodronate liposome pretreatment C57BL/6 mouse, myocardial enzymes are horizontal to be reduced；2. chlorine
Adriamycin is injected after the sodium lipidosome of phosphonic acids two pretreatment C57BL/6 mouse, mouse weight reduces trend and slowed down；3. disodium clodronate
Adriamycin is injected after the pretreated lotus knurl Balb/c mouse of liposome, myocardial enzymes are horizontal to be reduced, and gross tumor volume is with Clodronate
The concentration of two sodium lipidosomes increases and reduced.
The present invention has advantages below：
1) present invention prepares that disodium clodronate liposome technical maturity is reliable, and raw material sources are extensive and superior in quality.
2) the existing medicine for reducing heart failure can cause bone marrow suppression, Liver and kidney function exception etc., while the medicine can reduce
The anticancer drug effect of anthracene nucleus medicament and its is expensive.Disodium clodronate liposome property is stable, has preferable bio-compatible
Property, and have been reported disodium clodronate and can suppress the growth of tumour.Therefore, disodium clodronate liposome causes to reducing adriamycin
Cardiotoxicity high-efficiency low-toxicity.
3) while reduction myocardium toxicity is played, the bone that can also reduce tumour cell turns disodium clodronate liposome
Move.
4) after disodium clodronate liposome property stabilization enters in vivo, degradation cycle is longer, lasting medicine.
5) using disodium clodronate liposome as medicine, the Immunogenicity that connection aglucon can be avoided to bring, while greatly
Amplitude reduction pharmacy cost.
6) present invention uses conventional administration formulation, technology maturation, and simple production process is easy.
7) present invention uses conventional administration mode, convenient drug administration, no pain.
Brief description of the drawings
Fig. 1 disodium clodronate liposomes, which slow down mouse weight, reduces trend；
It is horizontal that Fig. 2 disodium clodronates liposome reduces myocardial enzymes；
Fig. 3 disodium clodronates liposome reduces breast cancer mouse gross tumor volume and quality with adriamycin combination；
Fig. 4 disodium clodronates liposome reduces breast cancer mouse myocardial enzymes level with adriamycin combination；
Embodiment
By combination accompanying drawing described further below it will be further appreciated that the features and advantages of the invention.The implementation provided
Example is only explanation to the inventive method, remaining content without limiting the invention in any way announcement.
【Embodiment 1】Disodium clodronate liposome preparation and sign detection
(1) disodium clodronate liposome preparation
1. preparation method：
Weigh cholesterol, lecithin and disodium clodronate to be placed in container, addition chloroform-methanol mixed liquor, the chloroform-
Chloroform and methanol volume ratio=2 in methyl alcohol mixed liquor:1, the rotating thin film evaporation rotation film 20- under the conditions of 50-60 DEG C
50min, uniform lipid dry film is made；The lipid thickness of dry film is 0.1-0.2mm；Residual solvent is dried up with nitrogen, then added
Enter the phosphonic acids buffer solution dissolved with disodium clodronate, lipid film is fully swelled aquation, it is ultrasonic under conditions of ultrasonic power 400W
5min, subsequent 22000rpm, centrifuge 1 hour under the conditions of 10 DEG C, lower floor's liposome is resuspended with ph=7.2 phosphate buffered saline solution
Produce；The cholesterol and lecithin mass ratio are cholesterol：Lecithin=1:10；The disodium clodronate and lecithin mole
Than for disodium clodronate：Lecithin=1:10.
The particle diameter of the above-mentioned disodium clodronate liposome being prepared is 224.8 ± 4.5nm, its envelop rate ＞
55%.
2. Formulation and optimization
Reference literature and single factor experiment prerun analysis, determine the factor and level of orthogonal experiment.Using entrapment efficiency as
Evaluation index, prescription screening and optimization are carried out using orthogonal experiment.
(2) disodium clodronate liposome characterizes
1. morphological observation and particle size measure
Using ordinary optical microscope and transmission electron microscope phosphotungstic acid negative staining observation liposome.Using instruments for measuring particle diameter by use of laser
Determine average grain diameter.
2. liposome encapsulation determines
1) uv scan
Medicine, drug containing liposome and blank liposome are used into methanol-distilled water (1 respectively:1, V/V) mixed liquor dissolved dilution
Afterwards, scanned in 200~500nm, medicine and drug containing liposome have absorption maximum at 215nm, and blank liposome is in the wavelength model
Enclose no absworption peak.
2) prepared by standard curve
Precision is weighed in 60 DEG C of dry disodium clodronate 1mg to constant weight put 10ml volumetric flasks, adds methanol to dissolve on a small quantity
And scale is diluted to as reference substance storing solution (100 μ gmL-1), accurately pipette standard liquid 0.125,0.25,0.5,0.75,
1.0ml is in 10mL volumetric flasks, with methanol-distilled water (1:1, V/V) mixed liquor is diluted to scale.It is horizontal stroke with concentration C (μ g/ml)
Coordinate, absorbance A are ordinate, draw standard curve.
3) entrapment efficiency determination
Dextran gel column chromatography.Column chromatography condition：Sephadex G-50 posts (2.6cm × 30cm), redistillation washing
It is de-, flow velocity 0.5mlmin-1, carry out at room temperature.The total dose of liposome (W is total) is first measured, then uses Gel-filtration
Separation drug containing liposome and free drug simultaneously determine the amount (W trips) of free drug, according to the Chinese Pharmacopoeia liposome bag of 2000 editions
Envelope rate calculation formula calculates, i.e.,：/ W is always × 100% by envelop rate ﹦ (total-W trips of W).W is total：The amount of total medicine, W trips：Lipid is not wrapped into
The amount of the free drug of body.Specifically it is summarized as follows：Precision measures liposome 5ml, and 25ml is diluted to double distilled water, after put
50mL volumetric flasks methanol dilution shakes up to be measured to scale.Disodium clodronate liposome 5ml upper props are taken again, double distilled water elutes,
Monitored with 215nm and collect free disodium clodronate eluting peak, be diluted to 25ml with double distilled water, then put 50ml volumetric flasks
With methanol dilution to scale and determine the amount of free drug, computational envelope rate.
4) rate of recovery is investigated
A series of disodium clodronate standard liquid of various concentrations is configured, pipettes 5ml upper props respectively, according to above-mentioned layer 3)
Analysis condition carries out column chromatography, collects free drug component, dilution, constant volume, absorption value is surveyed at 215nm, calculates the post rate of recovery.Match somebody with somebody
A series of disodium clodronate standard liquid of various concentrations is put, is mixed respectively with blank liposome, standard mixed liquor is obtained, moves respectively
5ml upper props are taken, the same terms column chromatography, the component absorption value of free drug is measured, calculates post average recovery.
5) study on the stability
3 batches of samples are put respectively under the natural conditions of room temperature and refrigerator in DEG C place 1,2,3 and investigate its stability June,
Specific inspection target is as follows：1. outward appearance：Liposome solutions belong to the thermodynamic unstable system of high degree of dispersion, grain in storage process
Son has the tendency such as self-assemble and fusion, causes liposomal particle size distribution to change, and long-term place can assemble, flocculate and be layered
Precipitation.Result is observed according to particle under sample appearance and microscope in experiment, it is evaluated.Liposome outward appearance is not stratified, without heavy
Form sediment, be designated as (-)；It is not stratified, there is a little flocculation resilient after shaking, be designated as (±) layering, there is irreversible precipitation to be designated as (+) degree；
2. pH value：For liposome during storage, phospholipid oxidation hydrolysis, which produces free aliphatic acid etc., declines pH value, it is therefore necessary to
The pH value of liposome is monitored, to reflect the stable envelop rate of liposome；3. envelop rate is the finger for evaluating lipid weight
One of mark, liposome is influenceed, easy to leak during storage by pharmaceutical properties and membrane stability etc., therefore the bag of liposome
Envelope rate can reflect its stability.
(3) result
1. Formulation and optimization
Reference literature and single factor experiment prerun analysis result, determine cholesterol：Lecithin (mass ratio), Clodronate two
Sodium:Lipid (mol ratio) and phosphate buffer pH value determine the horizontal extent of each factor, such as table as 3 investigation factors
1, using entrapment efficiency as evaluation index, design 9 prescriptions according to orthogonal design table and prepare liposome.The influence factor of envelop rate
Size is A>B>C, the optimal collocation of each factor is A3B1C3, i.e. cholesterol：Lecithin (mass ratio) is 1:10, Clodronate two
Sodium：Lipid (mol ratio) is 1:10, PBS pH value is 7.2.Therefore, the prescription that preliminary screening goes out is：
(1) cholesterol 20mg；
(2) lecithin 200mg；
(3) disodium clodronate 2.5g；
(4) pH value is 7.2 phosphate buffer 20ml, such as table 2.
Table 1, experimental factor and level
2. disodium clodronate liposome characterizes
1) morphological observation and particle size measure
It is 1% with mass fraction after the suitably dilution of disodium clodronate liposome turbid liquor from transmission electron microscope photo
Phosphotungstic acid negative staining, form is observed under transmission electron microscope, as a result visible lipid sees rounding in vitro, mostly spherical and spherical particle,
Size is more uniform.Particle size distribution range is narrow and meets normal distribution law, and particle diameter is 224.8 ± 4.5nm.
2) prepared by uv scan, standard curve, the rate of recovery is investigated
Medicine and drug containing liposome have absorption maximum at 215nm, and blank liposome is in the wave-length coverage without absworption peak.With
Concentration C (μ g/ml) is abscissa, and absorbance A is ordinate, draws standard curve, obtains λmaxAbsorbance A at=372nm wavelength
With drug concentration C (μ gmL-1) regression equation be：A=0.0456C+0.0066 (r=0.9991), linear range are：1.0
~5.0 μ gmL-1.The post rate of recovery, its average value are 100.35%, RSD 1.24%.Post average recovery, its average value are
99.66%, RSD 0.86%, such as table 3.
Table 2, orthogonal design and interpretation of result
Table 3, disodium clodronate liposome determination of recovery rates result (n=5)
3) entrapment efficiency determination
By Sephadex G-50 post separations in the disodium clodronate liposomal samples of preparation, free disodium clodronate is collected
Eluting peak, and the amount of medicine is determined, it is 55.73% (n=4) to obtain the average envelop rate of liposome by the calculation formula of envelop rate.
4) study on the stability
Liposome places 1,2,3 respectively at 4 DEG C and room temperature under the conditions of inflated with nitrogen and is showed no within 6 months layering cohesion etc. now
As being still homogenous suspension, and pH value and envelop rate prompt it to have good stability, such as table 4 without significant changes.
Table 4, disodium clodronate liposome stability investigate result (n=3)
Note：Liposome outward appearance is not stratified, no precipitation, is designated as (-)；It is not stratified, there is a little flocculation resilient after shaking, be designated as
(±) is layered, and has irreversible precipitation to be designated as (+) degree.
(4) conclusion
It is above-mentioned test result indicates that, the preparation method of disodium clodronate liposome is simple and easy, and success rate is higher, property
It is stable.
【Embodiment 2】Disodium clodronate liposome weakens the Effect study of Adriamycin cardiotoxicity
(1) animal packet and processing
6-8 weeks C57BL/6 male mice every group 10, is divided into Normal group, model control group, disodium clodronate lipid
Body treatment group.(1) normal saline is injected intraperitoneally in continuous 7 days in Normal group daily；(2) model control group carries the previous day abdomen
Chamber injects normal saline, the 2nd day intraperitoneal injection DOX (adriamycin) 20mg/kg；(3) disodium clodronate liposome low dosage
First day 5 μ l/g disodium clodronate liposome of intraperitoneal injection of experimental group, the 2nd day intraperitoneal injection DOX (adriamycin) 20mg/kg；(4)
First day 10 μ l/g disodium clodronate liposome of intraperitoneal injection of disodium clodronate liposome high dose experimental group, the 2nd day abdominal cavity note
Penetrate DOX (adriamycin) 20mg/kg；Mouse is put to death after 5 days, takes blood, heart, liver, kidney to be detected.
(2) experiment detection
1. detection mouse weight daily, observe mouse state and record；
2. myocardium enzyme CK, CK-MB, LDH, AST Concentration Testing
Collect mouse blood, according to the operating instruction of commercial reagents box detect serum myocardial zymogram concentration (kit by
Bioengineering Research Institute's offer is built up in Nanjing)；
(3) result
1. changes of weight
Disodium clodronate liposome pre-processes the Adriamycin cardiotoxicity model mice changes of weight curve of 5 days, as Fig. 1 can
See, increase over time, the mouse of disodium clodronate liposome pretreatment and the mould of unused disodium clodronate liposome-treated
The mouse of type group is slow compared to body weight reduction trend.
2. myocardium enzymic change
As shown in Figure 2, increase over time, myocardium toxicity model group serum center creatase CK, CK- of adriamycin processing
MB, LDH, AST concentration are apparently higher than Normal group, and the myocardium toxicity mouse cardiac muscle crossed with disodium clodronate liposome-treated
Enzyme concentration is remarkably decreased than the myocardium toxicity model group that adriamycin is handled.
(4) conclusion
It is above-mentioned test result indicates that, disodium clodronate liposome can by suppress the apoptosis of cardiac muscle cell so as to reach weaken
The effect of Adriamycin cardiotoxicity.
In summary result, the conclusion tested, it is believed that disodium clodronate liposome is to weaken Adriamycin cardiotoxicity
Active drug.
【Embodiment 3】Application of the disodium clodronate liposome in doxorubicin breast cancer
(1) animal packet and processing
4T1 breast cancer cells (1 × 10 are inoculated with 6-8 weeks Balb/c mammary gland of mouse fat pad6Individual/only), treat gross tumor volume
Up to 100mm3Shi Jiwei the 0th day, random packet, is divided into control group, model control group, disodium clodronate liposome by every group 10
Treatment group.(1) normal saline is injected intraperitoneally in Normal group daily；(2) model control group intraperitoneal injection equivalent life in the 1st day
Salt solution is managed, a physiological saline is injected weekly afterwards, the 2nd day intraperitoneal injection DOX (adriamycin) 4mg/kg, injects one weekly afterwards
Secondary adriamycin, continuous five weeks；(3) the 1st day 5 μ l/g disodium clodronates of intraperitoneal injection of disodium clodronate liposome low dosage experimental group
Liposome, inject an equivalent disodium clodronate liposome weekly afterwards, DOX (adriamycin) 4mg/kg is injected intraperitoneally within the 2nd day, it
Afterwards weekly inject an adriamycin, continuous five weeks；(4) disodium clodronate liposome high dose experimental group intraperitoneal injection 10 in first day
μ l/g disodium clodronate liposomes, afterwards weekly inject an equivalent disodium clodronate liposome, the 2nd day intraperitoneal injection DOX (Ah
Mycin) 4mg/kg, afterwards weekly inject an adriamycin, continuous five weeks；Detection knurl volume daily, puts to death mouse after five weeks, takes
Blood, heart, liver, kidney are to be detected, take knurl to weigh.
(2) experiment detection
1. observe and record mouse tumor volume, quality；
2. myocardium enzyme CK, CK-MB, LDH, AST Concentration Testing
Collect mouse blood, according to the operating instruction of commercial reagents box detect serum myocardial zymogram concentration (kit by
Bioengineering Research Institute's offer is built up in Nanjing)；
(3) result
1. as shown in Figure 3, the tumor-bearing mice gross tumor volume of Normal group and quality gradually increase with the time, model comparison
Group gross tumor volume has been reduced with respect to normal group, and with the gross tumor volume of the pretreated tumor-bearing mice of disodium clodronate liposome
Increase with the concentration of disodium clodronate liposome and reduce.
2. as shown in Figure 4, increase over time, the myocardium toxicity model group serum center creatase CK of adriamycin processing,
CK-MB, LDH, AST concentration are apparently higher than Normal group, and the myocardium toxicity mouse crossed with disodium clodronate liposome-treated
The myocardium toxicity model group of myocardium enzyme concentration ratio adriamycin processing is remarkably decreased.
(4) conclusion
It is above-mentioned test result indicates that, disodium clodronate liposome can increase the antitumor effect of adriamycin, while can lead to
Cross suppress cardiac muscle cell apoptosis so as to have the function that weaken Adriamycin cardiotoxicity.
In summary result, the conclusion tested, it is believed that disodium clodronate liposome is having for adriamycin Synergy and attenuation
Imitate medicine.
It should be appreciated that the part that this specification does not elaborate belongs to prior art.
It should be appreciated that the above-mentioned description for preferred embodiment is more detailed, therefore can not be considered to this
The limitation of invention patent protection scope, one of ordinary skill in the art are not departing from power of the present invention under the enlightenment of the present invention
Profit is required under protected ambit, can also be made replacement or deformation, be each fallen within protection scope of the present invention, this hair
It is bright scope is claimed to be determined by the appended claims.
Claims (6)
1. application of the disodium clodronate liposome in preparing with tumour adriamycin chemotherapy auxiliary therapeutic action medicine.
2. application according to claim 1, it is characterised in that described that there is tumour adriamycin chemotherapy auxiliary therapeutic action to be
Finger has the function that Synergy and attenuation to tumour adriamycin chemotherapy.
3. application according to claim 1, it is characterised in that described that there is tumour adriamycin chemotherapy auxiliary therapeutic action to be
Refer to disodium clodronate liposome has abated effect to myocardium toxicity caused by adriamycin.
4. application according to claim 1, it is characterised in that described that there is tumour adriamycin chemotherapy auxiliary therapeutic action to be
The antitumor effect of adriamycin can be increased by referring to disodium clodronate liposome.
5. the application described in claim any one of 1-4, it is characterised in that the preparation method of the disodium clodronate liposome
For：Weigh cholesterol, lecithin is placed in container, addition chloroform-methanol mixed liquor, chloroform in the chloroform-methanol mixed liquor
With methanol volume ratio=2:1, under the conditions of 50-60 DEG C, use rotating thin film evaporation to prepare lipid of the thickness for 0.1-0.2mm
Dry film, residual solvent is dried up with nitrogen, add the phosphate buffer dissolved with the disodium clodronate that purity is 98%, make lipid film
Fully swelling aquation, according to ultrasound 5 seconds under conditions of the W of ultrasonic power 400, stop the min of frequency ultrasound 5 of 5 seconds, then
22000 rpm, centrifuge 1 hour under the conditions of 10 DEG C, lower floor's liposome is resuspended with the phosphate buffered saline solution of ph=7.2 and produced；It is described
Cholesterol and lecithin mass ratio are cholesterol：Lecithin=1:10；The disodium clodronate and lecithin mol ratio are Clodronate
Disodium：Lecithin=1:10.
6. the application described in claim 5, it is characterised in that disodium clodronate liposome therapeutic mode is local administration or mouth
Clothes.
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| CN103040863A (en) * | 2012-12-17 | 2013-04-17 | 海南百思特医药科技有限公司 | Disodium clodronate liposome injection |
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| Title |
|---|
| JULIA K.L.WOODWARD等: "Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro", 《ANTI-CANCER DRUGS》 * |
| PAULA BERNARDO DE CARVALHO等: "Pamidronate Attenuates Oxidative Stress and Energetic Metabolism Changes but Worsens Functional Outcomes in Acute Doxorubicin-Induced Cardiotoxicity in Rats", 《CELL PHYSIOL BIOCHEM》 * |
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