CN103040863A - Disodium clodronate liposome injection - Google Patents
Disodium clodronate liposome injection Download PDFInfo
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- CN103040863A CN103040863A CN2012105478434A CN201210547843A CN103040863A CN 103040863 A CN103040863 A CN 103040863A CN 2012105478434 A CN2012105478434 A CN 2012105478434A CN 201210547843 A CN201210547843 A CN 201210547843A CN 103040863 A CN103040863 A CN 103040863A
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Abstract
The invention discloses disodium clodronate liposome injection and a preparation method thereof. The disodium clodronate liposome injection with excellent quality is made of disodium clodronate, distearoyl phosphatidyl glycerol, cholesterol, polyoxyethylene (40) hydrogenated castor oil according to specific weight ratio. Compared with the existing preparation, the injection has the advantages that the stability and the bioavailability of the injection are greatly improved, drug release is stable, the quality of injection products is improved, the toxic and side effect is reduced, and the curative effect is more obvious.
Description
Technical field
The present invention relates to a kind of novel formulation of disodium clodronate, be specifically related to a kind of disodium clodronate lipidosome injection and method for making thereof, belong to medical technical field.
Background technology
Malignant metastatic tumor of bone is one of late tumor common complication, and in a single day the patient bone transfer occurs and usually produce insufferable osteodynia, has a strong impact on patient's life quality.
Bisphosphonates is to treat at present bone to shift the active drug of generally acknowledging, in first and second,, bisphosphonates was in the recent decade successively after the listing in generation, become effective alleviation osteodynia, prevent the skeleton lesion growth, the quality of making the life better, prevent that the bone such as bone photo pass event generation from shifting the key player of palliative treatments.
Diphosphonate is one group of structure and the similar medicine of pyrophosphonate, and the latter is endogenous compound, can regulate deposition and the absorption of bone mineral.Identical with pyrophosphonate, diphosphonate is combined with hydroxyapatite crystal, but more is difficult for burnt phosphonic acids enzymatic degradation in the body than pyrophosphonate, and is stronger and stable with the osseous tissue affinity, affect the cohesive process of osteoclast and bone surface, stop growth and the decomposition of osseous tissue.Heavily absorb by suppressing bone, these medicines can produce favourable effect to cancer patient's bone metabolism.Therefore, bisphosphonates becomes the important selection of tumor patient treatment, can make the relevant hypercalcemia patient's of malignant tumor blood calcium recover normal, reduces bone photo and closes event, alleviates osteodynia, improves osteoporosis.
Disodium clodronate is the second filial generation bisphosphonates of this company's exploitation of Finland's roller, have oral and two kinds of dosage forms of vein use, got the Green Light at global majority state and closed the treatment of event for the metastatic bone cancer bone photo, some has also been ratified preventive use and has reduced the indication that Bone of Breast Cancer shifts generation.
Contain diphosphonate characteristic P-C-P structure in the disodium clodronate, this structure is highly stable, and is high temperature resistant, stable to many chemical substances, absorbs in vivo, stores and drain in the original shape mode.The disodium clodronate that has absorbed about 20% is adsorbed in bone, is distributed in bone formation more and enlivens the position, is adsorbed in disodium clodronate half-life on the bone than obviously prolonging in the blood.Kidney is high to the clearance rate of this medicine, mainly removes in the ultrafiltration mode, and oral or vein uses to have the similar plasma clearance half-life (2.44h and 2.31h), has 80% medicine to be discharged by urine during medication 48h.
The disodium clodronate lipotropy is low, can not transcellular transport, and oral administration biaavailability 2%, absorption site are mainly at small intestinal.Hydroxyl phosphine lime stone in P-C-P structure and the sclerotin is high affinity, and can be combined with metal ions such as calcium, ferrum, forms the insolubility complex.
The disodium clodronate dosage form of at present list marketing is capsule, injection and the three kinds of dosage forms of injectable powder that adopt common preparation technology of preparing to be prepared from, yet general formulation exists long-term shelf-stability relatively poor, content decrease, the problem such as bioavailability is low.
Liposome (liposomes) is to be proposed by biomembranous models of conduct research such as Britain Banghan nineteen sixty-five the earliest.Refer to drug encapsulation made spherical targeted drug carrier formulation of superminiature in the middle of the thin film that the lipoids bimolecular forms is belonged to a kind of novel form of targeting drug delivery system.Liposome has plurality of advantages as pharmaceutical carrier: can seal fat-soluble medicine such as liposome, can seal water soluble drug again; Alleviate allergy and immunoreation; Delay to discharge, reduce elimination speed in the body; Can effectively protect and be wrapped medicine, improve bioavailability; Change medicine distribution in vivo, and can the targeting release, the toxic and side effects of medicine can be reduced; Be fit to multipath administration etc.
People find by research, and liposome can be controlled the release of medicine as the carrier of medicine, improves target-oriented drug, reduces drug toxicity and side effect, improves curative effect of medication.
In order to improve the bioavailability of disodium clodronate, the inventor studies the lipidosome injection of disodium clodronate, obtain unforeseeable effect, overcome the series of problems that existing disodium clodronate preparation exists, improved dissolubility and the stability of medicine, prolong drug retention time in vivo, permanent performance drug effect improves bioavailability, reduces toxic and side effects, reduce the incidence rate of untoward reaction, improve treatment speed and therapeutic effect.
The challenge of preparation liposome is to select suitable liposome constituent and method for making.Because the character of liposome is directly closely related with the composition of liposome such as stability, envelop rate, onset time, in vivo circulation time, bioavailability and toxic and side effects etc., and the composition of liposome is directly closely related with the pharmaceutical properties that will seal, therefore, selecting which type of composition to form the disodium clodronate liposome with better quality is the primary problem that solves.
Summary of the invention
In order to form colory disodium clodronate lipidosome injection, can good compatible with disodium clodronate it well be sealed and non-leakage filmogen thereby importantly seek, and seek the excipient composition that can make liposome form the stable injectable agent.
To achieve these goals, large quantity research and test that the inventor carries out, find the disodium clodronate of specified weight proportioning, DSPG, cholesterol, polyoxyl 40 hydrogenated castor oil can be made the disodium clodronate lipidosome injection of excellent quality, wherein, envelop rate as the disodium clodronate of active constituents of medicine is high, the liposome particle diameter is little and be evenly distributed, compare with disodium clodronate injection of the prior art, the retention time significant prolongation of the active constituents of medicine of preparation of the present invention in the body circulation, the biocompatibility of medicine is high, bioavailability obviously improves, and curative effect obviously improves.
Clodronate disodium weight) and 0.3g (in clodronate disodium) disodium clodronate lipidosome injection described in the present invention, the specification of the disodium clodronate of its unit dose are 5ml:0.3g (injection volume:.
Disodium clodronate lipidosome injection provided by the invention, mainly made by the composition of following ratio of weight and number:
Preferably, disodium clodronate lipidosome injection according to the present invention is mainly made by the composition that comprises following weight proportion:
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.Natural phospholipid comprises PHOSPHATIDYL ETHANOLAMINE, Ovum Gallus domesticus Flavus lecithin, hydrogenation egg yolk lecithin, EPG, egg yolk lecithin acyl serine, PI, soybean lecithin, hydrogenated soya phosphatide, soybean phospholipid acyl glycerol, soy phosphatidylserine and soybean phospholipid acyl inositol etc.Synthetic phospholipid is DOPC, DSPC, dipalmitoyl phosphatidyl choline, DMPC, DLPC, DOPG, DSPG, DPPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, PE etc.
Among the present invention, according to the characteristics of disodium clodronate, find that DSPG is particularly suitable for as basic phospholipid filmogen.Soybean phospholipid acyl silk ammonia is as a kind of natural phospholipid, and its content is very high, obtains easily, and is cheap.The phase transition temperature of DSPC is higher, is easy to form stable liposome membrane.
When using other phospholipid, be difficult to form colory liposome, the character such as the envelop rate of liposome, stability and percolation ratio are poor.
In order to improve the stability of liposome, the purity of used DSPG is more than 98%, and is preferred more than 99%.
In disodium clodronate lipidosome injection of the present invention, for the disodium clodronate of 1 weight portion, the consumption of DSPG is the 1-2 weight portion.If the consumption of DSPG is lower than 1 weight portion, then can't form stable liposome; Otherwise if the consumption of the consumption of DSPG is higher than 2 weight portions, then the envelop rate as the disodium clodronate of active constituents of medicine descends, and the quality of injection and curative effect reduce.
In disodium clodronate lipidosome injection of the present invention, cholesterol and polyoxyl 40 hydrogenated castor oil are used for regulating the membrane stability of liposome.
Cholesterol is a kind of amphiphilic, combines with DSPG, stops it to be condensed into crystal structure.Cholesterol mixes the DSPG bilayer, is similar to " buffer agent " and equally plays the effect of regulating membrane structure " flowability ".When being lower than phase transition temperature, cholesterol can make film reduce ordered arrangement, increases mobile; When being higher than phase transition temperature, cholesterol can increase the ordered arrangement of film, thereby reduces the flowability of film.Cholesterol can make the liposome bi-layer membrane solidify, thereby reduces the generation of free radical, reduces oxidation level, and liposome stability is significantly strengthened.
Studies show that the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of disodium clodronate lipidosome injection of the present invention is high, is to cause one of high factor of drug bioavailability.
On the other hand, the inventor studies discovery, in disodium clodronate lipidosome injection of the present invention, for the disodium clodronate of 1 weight portion, the consumption of DSPG is the 1-2 weight portion, when cholesterol was the 0.2-1 weight portion, the envelop rate of formed disodium clodronate lipidosome injection was high.
In disodium clodronate lipidosome injection of the present invention, further improve the stability of liposome membrane with polyoxyl 40 hydrogenated castor oil.When polyoxyl 40 hydrogenated castor oil is used for the DSPC duplicature, can improve the chemical energy between this duplicature, thereby improve the chemical stability of liposome in waterborne liquid, and then improve the stability of disodium clodronate lipidosome injection.
In disodium clodronate lipidosome injection of the present invention, for the disodium clodronate of 1 weight portion, the consumption of polyoxyl 40 hydrogenated castor oil is the 0.1-0.5 weight portion.If the consumption of polyoxyl 40 hydrogenated castor oil is lower than 0.1 weight portion, then cause the stability improvement of disodium clodronate lipidosome injection inadequate owing to its consumption is excessively low, otherwise, if the consumption of polyoxyl 40 hydrogenated castor oil is higher than 0.5 weight portion, then cause liposome membrane to be easy to reveal owing to its consumption is too high.
Research is found, when the disodium clodronate that uses above-mentioned specified quantitative, DSPG, cholesterol and polyoxyl 40 hydrogenated castor oil, can obtain colory disodium clodronate liposome, its envelop rate and stability are all very high, toxicity is low, and bioavailability is high.
Clodronate disodium weight) and 0.3g (in clodronate disodium) disodium clodronate lipidosome injection of the present invention, wherein the specification of the disodium clodronate of unit dose is 5ml:0.3g (injection volume:.
On the other hand, the present invention also provides a kind of preparation method of disodium clodronate lipidosome injection, specifically comprises being prepared as follows step:
(1) DSPG, cholesterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) disodium clodronate is dissolved in an amount of buffer salt solution, then add in the above-mentioned lipid membrane, jolting, stirred 20 minutes, rotating speed is 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 5-10 of tissue mashing machine's high speed minute, rotating speed 10000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) use the water for injection standardize solution, 0.45 μ m filtering with microporous membrane, fill, sealing by fusing, sterilization; Or use the water for injection standardize solution, and 0.45 μ m filtering with microporous membrane, packing, lid is rolled in lyophilization.Namely get the disodium clodronate lipidosome injection.
Preparation method described above, wherein said organic solvent is selected from one or more in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, acetonitrile, benzyl alcohol, ethyl acetate, chloroform, normal hexane and the dichloromethane, is preferably chloroform.
Preparation method described above, wherein said buffer salt solution are selected from a kind of in phosphate buffered solution, citrate buffer solution, the borate buffer solution.
Preparation method described above, wherein said buffer salt solution are that pH is 6.4 citrate buffer solution.
The challenge of preparation liposome is how to make liposome membrane to form the high vesicle of envelop rate of suitable size, appropriate configuration material.And these materials do not spill at the formation liposome.
The inventor has obtained colory disodium clodronate lipidosome injection by selecting suitable material composition, adopting suitable preparation technology, and the liposome particle diameter is little, and particle size distribution is even, and envelop rate is high, and stability is high.
Research finds, the size of liposome is affect that liposome distributes in vivo and the principal element of the time of staying, and the particle diameter of liposome is less, and the interior time of staying of body is longer.Disodium clodronate liposome particles by the inventive method preparation is little, and particle size distribution is even, and this is one of its factor that metabolic rate is low in vivo, bioavailability is high.
Description of drawings
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail.Fig. 1 is the blood drug level-time graph of disodium clodronate lipidosome injection.The disodium clodronate lipidosome injection and the blood drug level of commercially available disodium clodronate injection and the relation curve of time that prepare among the disodium clodronate lipidosome injection for preparing among the expression embodiment 1-3, the Comparative Examples 1-3.
Wherein:
The specific embodiment
Following examples are to further specify of the present invention, but never limit the scope of the present invention.Further elaborate the present invention below with reference to embodiment, but it will be appreciated by those skilled in the art that the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
Embodiment 1 disodium clodronate lipidosome freeze-dried injection
Prescription:
Preparation technology:
(1) 600g DSPG, 150g cholesterol and 150g polyoxyl 40 hydrogenated castor oil are dissolved in the 2000ml chloroform, mix homogeneously, chloroform is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) the 300g disodium clodronate being dissolved in 1000mlpH is in 6.4 the citrate buffer solution, then add in the above-mentioned lipid membrane, jolting, stirred 20 minutes, rotating speed is 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 5-10 of tissue mashing machine's high speed minute, rotating speed 10000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) be settled to 2000ml with water for injection, 0.45 μ m filtering with microporous membrane, packing, every bottle of 2ml, lid is rolled in lyophilization, namely gets the disodium clodronate lipidosome freeze-dried injection.
Embodiment 2 disodium clodronate lipidosome injections
Prescription:
Preparation technology:
(1) 150g DSPG, 300g cholesterol and 30g polyoxyl 40 hydrogenated castor oil are dissolved in the 2000ml chloroform, mix homogeneously, chloroform is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) the 300g disodium clodronate being dissolved in 1000mlpH is in 6.4 the citrate buffer solution, then add in the above-mentioned lipid membrane, jolting, stirred 20 minutes, rotating speed is 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 5-10 of tissue mashing machine's high speed minute, rotating speed 10000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) be settled to 5000ml with water for injection, 0.45 μ m filtering with microporous membrane, fill, every 5ml, sealing by fusing, sterilization namely gets the disodium clodronate lipidosome injection.
Embodiment 3 disodium clodronate lipidosome injections
Prescription:
Preparation technology:
(1) 300g DSPG, 60g cholesterol and 60g polyoxyl 40 hydrogenated castor oil are dissolved in the 2000ml chloroform, mix homogeneously, chloroform is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) the 300g disodium clodronate being dissolved in 1000mlpH is in 6.4 the citrate buffer solution, then add in the above-mentioned lipid membrane, jolting, stirred 20 minutes, rotating speed is 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 5-10 of tissue mashing machine's high speed minute, rotating speed 10000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) be settled to 5000ml with water for injection, 0.45 μ m filtering with microporous membrane, fill, every 5ml, sealing by fusing, sterilization namely gets the disodium clodronate lipidosome injection.
The preparation of Comparative Examples 1-3 disodium clodronate lipidosome injection
Adopt respectively the production technology identical with embodiment 1-3, the composition in will the Comparative Examples 1-3 as shown in following table 1-3 is made respectively the disodium clodronate lipidosome injection:
Used composition among the table 1 Comparative Examples 1-3
The mensuration of test example 1 liposome particle diameter
Under the room temperature condition, get the disodium clodronate lipidosome injection of embodiment and Comparative Examples, be made into 0.1% solution with normal saline, place the sample cell of Submicron Particle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; Observe particle shape with projection electron microscope.Result such as table 2:
Table 2 particle diameter testing result
| Embodiment | Mean diameter | Outward appearance |
| Embodiment 1 | 193.5nm | Spherical, evenly |
| Embodiment 2 | 206.1nm | Spherical, evenly |
| Embodiment 3 | 218.3nm | Spherical, evenly |
| Comparative Examples 1 | 720.8nm | Inhomogeneous, mixed and disorderly |
| Comparative Examples 2 | 684.5nm | Inhomogeneous, mixed and disorderly |
| Comparative Examples 3 | 692.1nm | Inhomogeneous, mixed and disorderly |
By above result as can be known, the disodium clodronate liposome particle diameter that embodiment 1-3 makes is even, and is aobvious spherical, big or small homogeneous; The disodium clodronate liposome particle diameter that Comparative Examples 1-3 makes is inhomogeneous, and shape is indefinite, and is not of uniform size.
The mensuration of test example 2 envelop rates
The disodium clodronate Liposomal formulation thin up of embodiment and Comparative Examples preparation is become 0.1% solution, high speed centrifugation, 5000r/min, centrifugal 20 minutes, get supernatant, use dissolve with methanol, the HPLC method is measured disodium clodronate content, the computational envelope rate, and result such as table 3:
Table 3 entrapment efficiency determination result
As shown in Table 3, the envelop rate of the Liposomal formulation of embodiment 1-3 preparation is higher than the envelop rate of the Liposomal formulation of Comparative Examples 1-3 significantly.Illustrate that when using the used composition of the present invention composition in addition perhaps work as the composition consumption outside the composition amount ranges that the present invention limits, the liposome encapsulation of gained liposome is lower than the present invention.
Test example 3 study on the stability
Sample and listing disodium clodronate injection (lot number: 20110601 with embodiment of the invention 1-3 and Comparative Examples 1-3 preparation, Nanjing Pharmaceutical Factory Co., Ltd.) places respectively lower 6 months of the condition of 40 ℃ of high temperature, relative humidity 75%, carry out accelerated test and investigate, result of the test is shown in the following table 4.
Table 4 accelerated test result
By above result as can be known, when accelerating June, Comparative Examples and listing preparation become pale yellow powder or little yellow clear liquid, content, and related substance raises; And sample property of the present invention, content and related substance variation are all not obvious, illustrate that product stability of the present invention is good.
The test of test example 4 percolation ratios
Get the sample of test example 1-3 and Comparative Examples 1-3 preparation, under the room temperature condition, respectively at 0 day, 30 days, 60 days, 90 days and 180 days, make regular check on respectively, measure envelop rate, with the dose of sealing in 0 day relatively, calculate percolation ratio, the results are shown in Table 5
Table 5 percolation ratio result of the test
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 |
| 0 day | 0.37 | 0.36 | 0.43 | 1.80 | 1.51 | 1.21 |
| 30 days | 0.41 | 0.48 | 0.51 | 2.75 | 2.78 | 2.35 |
| 60 days | 0.59 | 0.67 | 0.65 | 4.53 | 4.46 | 5.03 |
| 90 days | 0.68 | 0.75 | 0.76 | 8.75 | 9.96 | 10.45 |
| 180 days | 0.83 | 0.96 | 0.91 | 15.97 | 18.59 | 19.57 |
By above result of the test as can be known, the sample of embodiment of the invention preparation changes little in the long middle percolation ratio of long term storage, and the sample percolation ratio of Comparative Examples increases gradually, and the liposome seepage is serious, and the disodium clodronate lipidosome injection of this explanation the present invention preparation has higher stability.
The mensuration of test example 5 blood drug level
42 rats are divided into 7 groups at random, every group of injection for preparing among intravenous administration embodiment 1-3 and the Comparative Examples 1-3 respectively, and commercially available disodium clodronate injection (lot number: 20110601, Nanjing Pharmaceutical Factory Co., Ltd.), injection volume is the 20mg clodronate disodium.Respectively at 0.5h, 1h, 1.5h, 2h, 3h, 6h, 8h, 12h and 24h, take a blood sample after the administration, blood sample is measured blood drug level with the HPLC-MS method after treatment.The disodium clodronate lipidosome injection and the blood drug level of commercially available injection disodium clodronate and the relation curve of time that prepare among the disodium clodronate lipidosome injection for preparing among the drafting embodiment 1-3, the Comparative Examples 1-3 are shown in the accompanying drawing 1.
As shown in Figure 1, compare with commercially available injection disodium clodronate with the disodium clodronate lipidosome injection for preparing among the Comparative Examples 1-3, the disodium clodronate lipidosome injection for preparing among the embodiment of the invention 1-3 has the following advantages: release rate in vivo slows down, distribution time prolongs in the body circulation, reached improved slow release effect, bioavailability increases.
Claims (8)
1. a disodium clodronate lipidosome injection is characterized in that mainly being made by disodium clodronate, DSPG, cholesterol and polyoxyl 40 hydrogenated castor oil.
Clodronate disodium weight) and 0.3g (in clodronate disodium) 2. disodium clodronate lipidosome injection according to claim 1, the specification that it is characterized in that the disodium clodronate of unit dose are 5ml:0.3g (injection volume:.
3. arbitrary described disodium clodronate lipidosome injection according to claim 1 and 2 is characterized in that being made by the composition of following ratio of weight and number:
4. arbitrary described disodium clodronate lipidosome injection according to claim 1-3 is characterized in that being made by the composition of following ratio of weight and number:
5. a method for preparing the disodium clodronate lipidosome injection is characterized in that comprising the steps:
(1) DSPG, cholesterol and polyoxyl 40 hydrogenated castor oil are dissolved in the organic solvent, mix homogeneously, organic solvent is removed in decompression on rotary film evaporator, obtains lipid membrane;
(2) disodium clodronate is dissolved in an amount of buffer salt solution, then add in the above-mentioned lipid membrane, jolting, stirred 20 minutes, rotating speed is 500-1000r/min, makes the complete aquation of immobilized artificial membrane, with the homogeneous emulsifying 5-10 of tissue mashing machine's high speed minute, rotating speed 10000r/min with 0.45 μ m filtering with microporous membrane, makes liposome turbid liquor;
(3) use the water for injection standardize solution, 0.45 μ m filtering with microporous membrane, fill, sealing by fusing, sterilization; Or use the water for injection standardize solution, and 0.45 μ m filtering with microporous membrane, packing, lid is rolled in lyophilization, namely gets the disodium clodronate lipidosome injection.
6. preparation method according to claim 5, it is characterized in that described organic solvent is selected from one or more in ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, acetonitrile, benzyl alcohol, ethyl acetate, chloroform, normal hexane and the dichloromethane, is preferably chloroform.
7. preparation method according to claim 5 is characterized in that described buffer salt solution is selected from a kind of in phosphate buffered solution, citrate buffer solution, the borate buffer solution.
8. preparation method according to claim 5 is characterized in that described buffer salt solution is that pH is 6.4 citrate buffer solution.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106361701A (en) * | 2016-08-31 | 2017-02-01 | 上海交通大学 | Liposome drug carrier and preparation method and application thereof |
| CN107693489A (en) * | 2017-09-12 | 2018-02-16 | 甘肃博睿生物科技有限公司 | Chlorine disodium hydrogen phosphate liposome enema and preparation method and its application in preventing and treating Colon and rectum inflammation and colorectal cancer |
| CN107854489A (en) * | 2017-12-19 | 2018-03-30 | 武汉大学 | Purposes of the disodium clodronate liposome in terms of tumour adriamycin chemotherapy auxiliary treatment |
-
2012
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Non-Patent Citations (1)
| Title |
|---|
| 张建新等: "氯膦酸二钠脂质体对大鼠腹腔巨噬细胞功能的影响", 《世界华人消化杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106361701A (en) * | 2016-08-31 | 2017-02-01 | 上海交通大学 | Liposome drug carrier and preparation method and application thereof |
| CN106361701B (en) * | 2016-08-31 | 2019-08-27 | 上海交通大学 | A kind of lipidosome drug carrier and its preparation method and application |
| CN107693489A (en) * | 2017-09-12 | 2018-02-16 | 甘肃博睿生物科技有限公司 | Chlorine disodium hydrogen phosphate liposome enema and preparation method and its application in preventing and treating Colon and rectum inflammation and colorectal cancer |
| CN107854489A (en) * | 2017-12-19 | 2018-03-30 | 武汉大学 | Purposes of the disodium clodronate liposome in terms of tumour adriamycin chemotherapy auxiliary treatment |
| CN107854489B (en) * | 2017-12-19 | 2020-04-10 | 武汉大学 | Application of disodium clodronate liposome in adjuvant therapy of tumor doxorubicin chemotherapy |
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