CN102274185A - Antitumor pH-sensitive liposome and freeze-dried powder injection thereof, and preparation methods thereof - Google Patents
Antitumor pH-sensitive liposome and freeze-dried powder injection thereof, and preparation methods thereof Download PDFInfo
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- CN102274185A CN102274185A CN2011102286230A CN201110228623A CN102274185A CN 102274185 A CN102274185 A CN 102274185A CN 2011102286230 A CN2011102286230 A CN 2011102286230A CN 201110228623 A CN201110228623 A CN 201110228623A CN 102274185 A CN102274185 A CN 102274185A
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Abstract
The invention relates to an antitumor pH-sensitive liposome and a freeze-dried powder injection thereof, and preparation methods thereof. The antitumor pH-sensitive liposome is mainly prepared from the following raw materials in parts by weight: 1 part of antitumor active medicine, 1-20 parts of phospholipid, 1-20 parts of cholesterol and 0.5-10 parts of oleic acid, wherein the phospholipid is one of phosphatidylethanolamine, dioleoyl phosphatidylethanolamine and hydrogenated phospholipid. In the invention, the phosphatidyl ethanolamine is used as the phospholipid; the polar groups of the phosphatidyl ethanolamine are protonized in an acid environment, causing structural change of liposome; and under the synergetic effects of the phospholipid and the oleic acid, the pH sensitivity of the antitumor pH-sensitive liposome is greatly enhanced, and the antitumor pH-sensitive liposome has good slow-release effect.
Description
Technical field:
The present invention relates to a kind of antitumor pH sensitive liposome body, particularly vinorelbine tartrate pH sensitive liposome body, its freeze-dried powder and their preparation method.
Background technology:
Vinorelbine tartrate (Vinorelbine Bitartrate, VB), it is a kind of semisynthetic vinca alkaloids, its mechanism of action and vincaleucoblastine (VLB) and vincristine (VCR) are basic identical, main by the microtubule formation in the retardance cell mitogen process, make cell division arrest mitosis metaphase, be cell cycle specific agents.The same with other vinblastine, vinorelbine tartrate also can suppress the circulation of aminoacid front and back and the metabolism of glutathion; Rely on the activity of the Ca-ATP enzyme of calmodulin; The biological oxidation of cell and nucleic acid and greasy biosynthesis; Clinical nonsmall-cell lung cancer, metastatic breast cancer, advanced ovarian cancer, the malignant lymphoma etc. of being mainly used in.But this medicine is after intravenous injection, and toxic and side effects is bigger, and common is bone marrow depression, gastrointestinal toxicity and alopecia etc., and in addition, weakness of the lower extremities can appear in long-term prescription.These toxic and side effects make the clinical practice of vinorelbine be subjected to considerable restraint.Urgent need is sought a kind of effective method, can be under the situation that does not increase drug dose, and the half-life of prolong drug, the antitumous effect of raising medicine, the toxic and side effects of minimizing medicine strengthens the clinical practice of medicine.
Liposome is a kind of targeted drug carrier, belongs to a kind of novel form of targeting drug delivery system.It can be engulfed medicine and activate the autoimmune function of body by the huge system of biting, and the interior distribution of the body that changes encapsulated medicine, drug main will be put aside in histoorgans such as liver, spleen, lung and bone marrow, thereby improve the therapeutic index of medicine, reduce the toxicity of the therapeutic dose and the reduction medicine of medicine.
Chinese patent CN1839800A discloses a kind of " Vinorelbine monotartrate liposome and freeze-dried powder thereof and preparation method ", the liposome of Vinorelbine monotartrate contains following composition: Vinorelbine monotartrate, phospholipid, cholesterol, vitamin E, the weight ratio between them are 1 part: 5-100 part: 1-15 part: 0.01-0.05 part.This kind liposome helps improving the antitumor action of medicine, but does not find the sensitivity that it changes the environment pH value.
Tumor tissues is when ischemia, unusual acidify phenomenon appears in mesenchyma stroma of tumors liquid, utilize the tumor organization pH 5.0-6.5 characteristic lower than normal structure, design and research stable p H responsive type liposome in physiological range, make it realize that under the meta-acid environment the prominent of medicine release, not only can further improve the targeting of liposome, and can realize that the Based Intelligent Control of medicine discharges.
Summary of the invention:
The purpose of this invention is to provide a kind of antitumor pH sensitive liposome body, its freeze-dried powder and their preparation method.
Antitumor pH sensitive liposome body, mainly be made up of the raw material of following weight part ratio: 1 part of anti-tumor activity medicine composition, phosphatidase 11-20 part, cholesterol 1-20 part and oleic acid 0.5-10 part, described phospholipid are a kind of in PHOSPHATIDYL ETHANOLAMINE, DOPE, the hydrogenated phospholipid.
Described antitumor pH sensitive liposome body, preferably be made up of the raw material of following weight part ratio: 1 part of anti-tumor activity medicine composition, phosphatidase 11-10 part, cholesterol 1-10 part and oleic acid 0.5-2 part, described phospholipid is PHOSPHATIDYL ETHANOLAMINE.
Above-mentioned anti-tumor activity medicine composition is selected from one or several in vinorelbine tartrate, vinorelbine, doxorubicin hydrochloride, Farmorubine Hydrochloride and the paclitaxel, preferred vinorelbine tartrate.
The freeze-dried powder of described antitumor pH sensitive liposome body comprises antitumor pH sensitive liposome body and acceptable carrier thereof.Described acceptable carrier comprises buffer solution, frozen-dried supporting agent and solvent for injection.
The preparation method of the freeze-dried powder of described antitumor pH sensitive liposome body, step is as follows:
1) takes by weighing anti-tumor activity medicine composition, phospholipid, cholesterol, oleic acid, be dissolved in organic solvent, mix homogeneously;
2) with mixed liquor on Rotary Evaporators, the decompression remove organic solvent, adding pH then is the phosphate buffer mixing of 6-8, liposome turbid liquor; Perhaps mixed liquor is added the phosphate buffer that pH is 6-8, emulsifying, organic solvent is removed in decompression on Rotary Evaporators then, gets liposome turbid liquor;
3) the gained liposome turbid liquor is carried out the high pressure breast and spare, reduce particle diameter promptly, an amount of frozen-dried supporting agent is dissolved in the liposome aseptic filtration.
4) be up to the standards, bottling, capping, lyophilizing gets product.
In the preparation method of the freeze-dried powder of above-mentioned antitumor pH sensitive liposome body, consumption of organic solvent is every 100mg matrix material with organic solvent 20ml (matrix material is meant phospholipid, cholesterol and oleic acid); The consumption of buffer solution is every 100mg matrix material buffer solution 20ml, and the consumption of frozen-dried supporting agent is 5% of a matrix material gross mass.Described organic solvent is chloroform and methanol mixture, and described frozen-dried supporting agent is selected from a kind of in mannitol, glucose, lactose, the sucrose.
Antitumor pH sensitive liposome body of the present invention can be made into injection, lyophilized injectable powder.
The invention has the beneficial effects as follows:
(1) utilize PHOSPHATIDYL ETHANOLAMINE to make phospholipid, this phospholipid polar group under sour environment takes place protonated, thereby causes the variation of liposome structure, by with oleic synergism, improved pH sensitivity greatly, have better slow release effect simultaneously;
(2) entrapment efficiency of liposome higher (envelop rate is 60-90%), stable performance, particle diameter is even, is 100-1000nm;
(3) Zhi Bei liposome has marked featurees such as passive targeting, intelligent controlled release, and it is good to have storage stability, and characteristics such as Drug therapy index height, toxic and side effects are low can be used for treating various neoplastic disease;
(4) Zhi Bei freeze-dried powder can make the liposome Chinese medicine continue to discharge, improve blood drug level, prolong drug circulation time in blood, improve bioavailability of medicament, can reduce the toxic and side effects of medicine simultaneously again, strengthen the effective pharmaceutical formulation of compliance of patients;
(5) preparation technology is simple.
Description of drawings
Fig. 1 is the electromicroscopic photograph of antitumor pH sensitive liposome body of the present invention;
Fig. 2 is the particle size distribution figure of antitumor pH sensitive liposome body of the present invention;
Fig. 3 is the electromicroscopic photograph of antitumor pH sensitive liposome body of the present invention behind high pressure homogenize;
Fig. 4 is the particle size distribution figure of antitumor pH sensitive liposome body of the present invention behind high pressure homogenize;
Fig. 5 is the seepage curve of antitumor pH sensitive liposome body of the present invention at the PBS of different pH buffer mesotartaric acid vinorelbine.
The specific embodiment
Below by experiment embodiment the present invention is specifically described; it is important to point out that present embodiment only is used for that the present invention will be further described; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can content according to the above description make some nonessential improvement and adjustment.Medicine material all can be bought from the market.
Embodiment 1
Take by weighing 30mg PHOSPHATIDYL ETHANOLAMINE, 30mg cholesterol, 10mg oleic acid and be dissolved in 10ml organic solvent (V
Chloroform: V
Methanol=9: 1), pressurization evaporate to dryness mixed solution is to forming the layer of even lipid membrane.The even suspension of drug solution (drug level is 5mg/ml) the ultrasonic formation of dissolving that adds the vinorelbine tartrate of 2ml pH=7.4; replenish with the PBS buffer of pH7.4 that to make final volume be 20ml; promptly get vinorelbine tartrate pH sensitive liposome body under 37 ℃ of water bath condition behind the hydration 30min; add mannitol 3.5mg as freeze drying protectant; the lyophilized powder that-80 ℃ of pre-freeze 12h lyophilizing afterwards promptly get vinorelbine tartrate faces with preceding and redissolves with normal saline.Prepared vinorelbine tartrate pH sensitive liposome body mean diameter is 290nm, transmission electron microscope photo as shown in Figure 1, particle size distribution is as shown in Figure 2.
Embodiment 2
Take by weighing 90mg PHOSPHATIDYL ETHANOLAMINE, 90mg cholesterol, 30mg oleic acid and be dissolved in 30ml organic solvent (V
Chloroform: V
Methanol=9: 1), pressurization evaporate to dryness mixed solution is to forming the layer of even lipid membrane.The even suspension of drug solution (drug level is 5mg/ml) the ultrasonic formation of dissolving that adds the vinorelbine tartrate of 6ml pH=7.4; replenish with the PBS buffer of pH7.4 that to make final volume be 60ml; carry out the even particle diameter that reduces of high pressure breast; promptly get vinorelbine tartrate pH sensitive liposome body under 37 ℃ of water bath condition behind the hydration 30min; add mannitol 10.5mg as freeze drying protectant; the lyophilized powder that-80 ℃ of pre-freeze 12h lyophilizing afterwards promptly get vinorelbine tartrate faces with preceding and redissolves with normal saline.Prepared vinorelbine tartrate pH sensitive liposome body mean diameter is 232nm, transmission electron microscope photo as shown in Figure 3, particle size distribution is as shown in Figure 4.
Embodiment 3
Take by weighing 150mg PHOSPHATIDYL ETHANOLAMINE, 150mg cholesterol, 15mg oleic acid and be dissolved in 30ml organic solvent (V
Chloroform: V
Methanol=9: 1), pressurization evaporate to dryness mixed solution is to forming the layer of even lipid membrane.The even suspension of drug solution (drug level is 5mg/ml) the ultrasonic formation of dissolving that adds the vinorelbine tartrate of 6ml pH=7.4; replenish with the PBS buffer of pH7.4 that to make final volume be 60ml; carry out the even particle diameter that reduces of high pressure breast; promptly get vinorelbine tartrate pH sensitive liposome body under 37 ℃ of water bath condition behind the hydration 30min; add mannitol 15.75mg as freeze drying protectant; the lyophilized powder that-80 ℃ of pre-freeze 12h lyophilizing afterwards promptly get vinorelbine tartrate faces with preceding and redissolves with normal saline.Prepared vinorelbine tartrate pH sensitive liposome body mean diameter is 252nm.
Embodiment 4
Take by weighing 300mg PHOSPHATIDYL ETHANOLAMINE, 300mg cholesterol, 60mg oleic acid and be dissolved in 30ml organic solvent (V
Chloroform: V
Methanol=9: 1), pressurization evaporate to dryness mixed solution is to forming the layer of even lipid membrane.The even suspension of drug solution (drug level is 5mg/ml) the ultrasonic formation of dissolving that adds the vinorelbine tartrate of 6ml pH=7.4; replenish with the PBS buffer of pH7.4 that to make final volume be 60ml; carry out the even particle diameter that reduces of high pressure breast; promptly get vinorelbine tartrate pH sensitive liposome body under 37 ℃ of water bath condition behind the hydration 30min; add mannitol 33mg as freeze drying protectant; the lyophilized powder that-80 ℃ of pre-freeze 12h lyophilizing afterwards promptly get vinorelbine tartrate faces with preceding and redissolves with normal saline.Prepared vinorelbine tartrate pH sensitive liposome body mean diameter is 270nm.
Performance test
Make vinorelbine tartrate pH sensitive liposome body by the foregoing description 2, utilize the Dynamic Membrane dialysis, investigate the release rule of preparation in different pH PBS, the gained release profiles as shown in Figure 5.
Claims (9)
1. antitumor pH sensitive liposome body is characterized in that, it mainly is made up of the raw material of following weight part ratio:
1 part of anti-tumor activity medicine composition, phosphatidase 11-20 part, cholesterol 1-20 part and oleic acid 0.5-10 part, described phospholipid are a kind of in PHOSPHATIDYL ETHANOLAMINE, DOPE, the hydrogenated phospholipid.
2. antitumor pH sensitive liposome body according to claim 1, it is characterized in that, it is made up of the raw material of following weight part ratio: 1 part of anti-tumor activity medicine composition, phosphatidase 11-10 part, cholesterol 1-10 part and oleic acid 0.5-2 part, described phospholipid is PHOSPHATIDYL ETHANOLAMINE.
3. antitumor pH sensitive liposome body according to claim 1 and 2 is characterized in that anti-tumor activity medicine composition is selected from one or several in vinorelbine tartrate, vinorelbine, doxorubicin hydrochloride, Farmorubine Hydrochloride and the paclitaxel.
4. antitumor pH sensitive liposome body according to claim 3 is characterized in that anti-tumor activity medicine composition is a vinorelbine tartrate.
5. the freeze-dried powder of the described antitumor pH of claim 1 sensitive liposome body comprises antitumor pH sensitive liposome body and acceptable carrier thereof.
6. the freeze-dried powder of antitumor pH sensitive liposome body according to claim 5 is characterized in that described acceptable carrier comprises buffer solution, frozen-dried supporting agent and solvent for injection.
7. the preparation method of the freeze-dried powder of the described antitumor pH of claim 5 sensitive liposome body is characterized in that step is as follows:
1) takes by weighing anti-tumor activity medicine composition, phospholipid, cholesterol, oleic acid, be dissolved in organic solvent, mix homogeneously;
2) with mixed liquor on Rotary Evaporators, the decompression remove organic solvent, adding pH then is the phosphate buffer mixing of 6-8, liposome turbid liquor; Perhaps mixed liquor is added the phosphate buffer that pH is 6-8, emulsifying, organic solvent is removed in decompression on Rotary Evaporators then, gets liposome turbid liquor;
3) the gained liposome turbid liquor is carried out the high pressure breast and spare, reduce particle diameter promptly, an amount of frozen-dried supporting agent is dissolved in the liposome aseptic filtration.
4) be up to the standards, bottling, capping, lyophilizing gets product.
8. the preparation method of the freeze-dried powder of antitumor pH sensitive liposome body according to claim 7 is characterized in that, consumption of organic solvent is every 100mg matrix material organic solvent 20ml; The consumption of buffer solution is every 100mg matrix material buffer solution 20ml, and the consumption of frozen-dried supporting agent is 5% of a matrix material gross mass.
9. according to the preparation method of the freeze-dried powder of claim 7 or 8 described antitumor pH sensitive liposome bodies, it is characterized in that, described organic solvent is that ether, chloroform or both mix, and described frozen-dried supporting agent is selected from a kind of in mannitol, glucose, lactose, the sucrose.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106309370A (en) * | 2016-09-20 | 2017-01-11 | 上海上药新亚药业有限公司 | Paclitaxel pH-sensitive long-circulation liposome and preparation method thereof |
| CN106924747A (en) * | 2017-03-17 | 2017-07-07 | 临沂大学 | Imitative lipoprotein structure pharmaceutical carrier of a kind of nanometer and its preparation method and application |
| CN108542884A (en) * | 2018-05-04 | 2018-09-18 | 重庆市人民医院 | A kind of sensitive medicament-carried liposomes of pH of SPIO tracers and preparation method thereof |
| CN112915106A (en) * | 2021-02-05 | 2021-06-08 | 张虎山 | Preparation and application of tumor immune microenvironment regulator |
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| WO2010096806A1 (en) * | 2009-02-23 | 2010-08-26 | Duke University | Methods for loading contrast agents into a liposome |
| US20100285611A1 (en) * | 2009-05-06 | 2010-11-11 | Ostafin Agnes E | Photobleaching resistant ph sensitive dye nanoreactors with dual wavelength emission |
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2011
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Patent Citations (4)
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| US4925661A (en) * | 1984-04-19 | 1990-05-15 | Leaf Huang | Target-specific cytotoxic liposomes |
| CN101557813A (en) * | 2006-08-02 | 2009-10-14 | 联合治疗公司 | Liposome treatment of viral infections |
| WO2010096806A1 (en) * | 2009-02-23 | 2010-08-26 | Duke University | Methods for loading contrast agents into a liposome |
| US20100285611A1 (en) * | 2009-05-06 | 2010-11-11 | Ostafin Agnes E | Photobleaching resistant ph sensitive dye nanoreactors with dual wavelength emission |
Non-Patent Citations (2)
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| TATSUHIRO ISHIDA等: "Development of pH-sensitive liposomes that efficiently retain encapsulated doxorubicin (DXR) in blood", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| V.P.TORCHILIN等: "Temperature-dependent aggregation of pH-sensitive phosphatidyl ethanolamine-oleic acid-cholesterol liposomes as measured by fluorescent spectroscopy", 《ANALYTICAL BIOCHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106309370A (en) * | 2016-09-20 | 2017-01-11 | 上海上药新亚药业有限公司 | Paclitaxel pH-sensitive long-circulation liposome and preparation method thereof |
| CN106924747A (en) * | 2017-03-17 | 2017-07-07 | 临沂大学 | Imitative lipoprotein structure pharmaceutical carrier of a kind of nanometer and its preparation method and application |
| CN108542884A (en) * | 2018-05-04 | 2018-09-18 | 重庆市人民医院 | A kind of sensitive medicament-carried liposomes of pH of SPIO tracers and preparation method thereof |
| CN112915106A (en) * | 2021-02-05 | 2021-06-08 | 张虎山 | Preparation and application of tumor immune microenvironment regulator |
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Application publication date: 20111214 |