CN102641244B - Method for improving liposome stability - Google Patents
Method for improving liposome stability Download PDFInfo
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- CN102641244B CN102641244B CN 201210136282 CN201210136282A CN102641244B CN 102641244 B CN102641244 B CN 102641244B CN 201210136282 CN201210136282 CN 201210136282 CN 201210136282 A CN201210136282 A CN 201210136282A CN 102641244 B CN102641244 B CN 102641244B
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Abstract
The invention relates to a method for improving liposome stability, which comprises the following steps of: firstly, measuring the following components by mass ratio: 1 part of silicon dioxide nanoparticle, 125-250 parts of water, 15-50 parts of hexadecyl trimethyl ammonium bromide, 1-10 parts of phosphatide and 100-200 parts of trichloromethane; secondly, uniformly mixing the silicon dioxide nanoparticle and the hexadecyl trimethyl ammonium bromide with the water, and performing ultrasonic dispersion for 5-20 minutes to obtain a mixed solution A; uniformly mixing the phosphatide with the trichloromethane to obtain a mixed solution B; thirdly, dropwise adding the mixed solution A to the mixed solution B to obtain a W/O emulsion; then, adding water to the W/O emulsion to obtain a W/O/W emulsion; and finally, performing vacuum evaporation to remove the trichloromethane to obtain liposome which encapsulates the silicon dioxide nanoparticle. According to liposome, the defects of easy fusion, fracture, precipitation and the like existing in conventional liposome are overcome, the liposome stability is improved, and drug release property improving and drug bioavailability increasing are facilitated.
Description
Technical field
The present invention relates to a kind of stable method of liposome that improves.Belong to medical technical field.
Background technology
Liposome is the vesicle of the near-spherical that formed by phospholipid molecule.Contain two hydrophobic fat acid chains and a hydrophilic head base in phospholipid molecule, when it was dispersed in water, phospholipid molecule formed the bilayer structure.Because the basic structure of organism plasma membrane is also phospholipid bilayer, liposome has the structure similar with biological cell, so it has good biocompatibility.Liposome enters the immunologic mechanism that inside of human body can start human body afterwards, by reticuloendothelial system phagocytic, thus targeting ground enrichment in the tissues such as liver, spleen, lung and bone marrow.Liposome preparation technology is simple, and biocompatibility is good, there is no immunoreation, liposome both can be sealed fat-soluble medicine in addition, also can seal water soluble drug, therefore, liposome can be used for drug loading, and the characteristics of utilizing liposome to merge with cell membrane are sent medicine into cell interior.There is lot of advantages in the liposome medicine carrying, and for example, drug encapsulation can be reduced in tissue diffusion and slowly discharges medicine in blood in liposome, thus prolong drug release time.In addition, the lipid physical ability optionally is distributed in some tissue and organ, increases medicine to lymphoid directionality, improves medicine in the treatment concentration of target site.And normal tissue and cell are without obvious detrimental effect.And, after some unsettled drug encapsulation are in liposome, be subject to the protection of phospholipid bilayer due to medicine, can significantly improve its stability.After simultaneously in entering body, due to the protection of liposome membrane, medicine can be avoided body enzyme system and immune degraded.Therefore, liposome is subject to extensive concern and the great attention of numerous researcheres as a kind of novel pharmaceutical carrier.At present, the report of related lipase plastid medicine carrying is a lot, for example, " a kind of Taxdol self assembled precusor liposome and preparation method thereof " (Chinese invention patent, the patent No.: 200610037637.3), " clopidogrel bisulfate liposome solid preparation " (Chinese invention patent application number: 201110272025.3, publication number: CN102397253A), and " anti-tumor multi-medicine resistant targeted liposome " (Chinese invention patent application number: 201110349033.3, publication number: CN102357074A) etc.Although liposome has possessed many advantage and disadvantages as the application of pharmaceutical carrier, yet, the shortcomings such as present conventional liposome ubiquity poor stability, make liposome preparation, deposit with use procedure in easily produce merge, break, the defective such as precipitation, this often causes medicine easy seepage from liposome before reaching targeting moiety, has greatly limited the practical application of liposome.
Summary of the invention
The object of the present invention is to provide a kind of method that improves liposome stability.With the liposome of the present invention preparation overcome present liposome preparation, deposit with use procedure in easily produce merge, break, the defective such as precipitation, improved the stability of liposome, reduce the seepage of medicine in liposome, helped to improve the releasing properties of medicine.
In order to achieve the above object, the present invention introduces Nano particles of silicon dioxide in the liposome preparation process, and Nano particles of silicon dioxide is encapsulated in liposome, utilizes Nano particles of silicon dioxide the supporting role of liposome to be improved the stability of liposome.Nano particles of silicon dioxide is the good nano material of biocompatibility, at aspects such as bio-sensing, neoplasm targeted therapies, potential application is arranged.Therefore, add during liposome Nano particles of silicon dioxide can improve the stability of liposome in preparation, can not affect again the biocompatibility of liposome.
Concrete technique is undertaken by following several steps:
First measure Nano particles of silicon dioxide according to mass ratio: water: cetyl trimethyl ammonium bromide: phospholipid: chloroform=1:125 ~ 250:15 ~ 50:1 ~ 10:100 ~ 200; Then the Nano particles of silicon dioxide that aforementioned proportion is measured, cetyl trimethyl ammonium bromide and water, mix homogeneously, ultra-sonic dispersion 5 ~ 20min obtains mixed solution A; With phospholipid and the chloroform that measures according to the above ratio, mix homogeneously obtains mixed solution B; Under stirring condition, mixed solution A is added drop-wise in mixed solution B, obtains Water in Oil emulsion; Then, add water in Water in Oil emulsion, obtain W/O/W type emulsion, the addition of above-mentioned water is 10 ~ 20 times of Water in Oil emulsion quality; At last W/O/W type emulsion reduction vaporization is removed chloroform, namely obtain sealing the liposome of Nano particles of silicon dioxide;
Above-mentioned phospholipid is a kind of in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, dipalmitoyl phosphatidyl choline, DPPE, distearoyl phosphatidylcholine;
The particle diameter of above-mentioned Nano particles of silicon dioxide is 5 ~ 200nm.
Test analysis shows, the liposome that gained is sealed Nano particles of silicon dioxide can reach more than 3 months the stable existence time, and the phenomenon such as conventional liposome often merges about month, breaks, precipitation.In addition, the bovine hemoglobin that conventional liposome is sealed as pharmaceutical carrier discharges end in 30h, and more than can reaching 60h the release time of the bovine hemoglobin that the liposome of sealing Nano particles of silicon dioxide is sealed as pharmaceutical carrier.
The present invention has the following advantages:
1. the liposome of sealing Nano particles of silicon dioxide that the present invention makes can reach more than 3 months the stable existence time, and the phenomenon such as conventional liposome often merges about month, breaks, precipitation.Therefore, introduce the stability that Nano particles of silicon dioxide has greatly improved liposome in liposome.
2. the liposome of sealing Nano particles of silicon dioxide that the present invention makes can effectively reduce the seepage of medicine in liposome owing to having good stability, helps to improve the releasing properties of medicine.
3. preparation technology of the present invention is simple, and the gained liposome is stable high, has a good application prospect.
The specific embodiment
Embodiment 1
The ratio that Nano particles of silicon dioxide, water, cetyl trimethyl ammonium bromide, Ovum Gallus domesticus Flavus lecithin and chloroform are 1:125:15:1:100 according to mass ratio measures.Measure according to the above ratio Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water, mix homogeneously, ultra-sonic dispersion 5min.Measure according to the above ratio phospholipid and chloroform, mix homogeneously.Under stirring condition, the mixed solution of Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water is added drop-wise in the mixed solution of phospholipid and chloroform, obtains Water in Oil emulsion.Then, add entry in the Water in Oil emulsion and obtain W/O/W type emulsion.The quality of the water that wherein adds is 10 times of Water in Oil emulsion quality.W/O/W type emulsion reduction vaporization is removed chloroform, namely obtain sealing the liposome of Nano particles of silicon dioxide.Test analysis shows, the liposome that gained is sealed Nano particles of silicon dioxide can reach more than 3 months the stable existence time.The release time of the bovine hemoglobin that the liposome of gained being sealed Nano particles of silicon dioxide is sealed as pharmaceutical carrier, more than can reaching 60h, and the bovine hemoglobin that conventional liposome is sealed as pharmaceutical carrier discharges end in 30h.
Embodiment 2
The ratio that Nano particles of silicon dioxide, water, cetyl trimethyl ammonium bromide, soybean lecithin and chloroform are 1:150:20:3:120 according to mass ratio measures.Measure according to the above ratio Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water, mix homogeneously, ultra-sonic dispersion 10min.Measure according to the above ratio phospholipid and chloroform, mix homogeneously.Under stirring condition, the mixed solution of Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water is added drop-wise in the mixed solution of phospholipid and chloroform, obtains Water in Oil emulsion.Then, add entry in the Water in Oil emulsion and obtain W/O/W type emulsion.The quality of the water that wherein adds is 15 times of Water in Oil emulsion quality.W/O/W type emulsion reduction vaporization is removed chloroform, namely obtain sealing the liposome of Nano particles of silicon dioxide.Test analysis shows, the liposome that gained is sealed Nano particles of silicon dioxide can reach more than 3 months the stable existence time.More than can reaching 60h the release time of the bovine hemoglobin that the liposome of sealing Nano particles of silicon dioxide is sealed as pharmaceutical carrier, and the bovine hemoglobin that conventional liposome is sealed as pharmaceutical carrier discharges end in 30h.
Embodiment 3
The ratio that Nano particles of silicon dioxide, water, cetyl trimethyl ammonium bromide, dipalmitoyl phosphatidyl choline and chloroform are 1:200:30:5:150 according to mass ratio measures.Measure according to the above ratio Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water, mix homogeneously, ultra-sonic dispersion 15min.Measure according to the above ratio phospholipid and chloroform, mix homogeneously.Under stirring condition, the mixed solution of Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water is added drop-wise in the mixed solution of phospholipid and chloroform, obtains Water in Oil emulsion.Then, add entry in Water in Oil emulsion, obtain W/O/W type emulsion.The quality of the water that wherein adds is 15 times of Water in Oil emulsion quality.W/O/W type emulsion reduction vaporization is removed chloroform, namely obtain sealing the liposome of Nano particles of silicon dioxide.Test analysis shows, the liposome that gained is sealed Nano particles of silicon dioxide can reach more than 3 months the stable existence time.More than can reaching 60h the release time of the bovine hemoglobin that the liposome of sealing Nano particles of silicon dioxide is sealed as pharmaceutical carrier, and the bovine hemoglobin that conventional liposome is sealed as pharmaceutical carrier discharges end in 30h.
Embodiment 4
The ratio that Nano particles of silicon dioxide, water, cetyl trimethyl ammonium bromide, DPPE and chloroform are 1:220:40:8:180 according to mass ratio measures.Measure according to the above ratio Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water, mix homogeneously, ultra-sonic dispersion 20min.Measure according to the above ratio phospholipid and chloroform, mix homogeneously.Under stirring condition, the mixed solution of Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water is added drop-wise in the mixed solution of phospholipid and chloroform, obtains Water in Oil emulsion.Then, add entry in the Water in Oil emulsion and obtain W/O/W type emulsion.The quality of the water that wherein adds is 20 times of Water in Oil emulsion quality.W/O/W type emulsion reduction vaporization is removed chloroform, namely obtain sealing the liposome of Nano particles of silicon dioxide.Test analysis shows, the liposome that gained is sealed Nano particles of silicon dioxide can reach more than 3 months the stable existence time.More than can reaching 60h the release time of the bovine hemoglobin that the liposome of sealing Nano particles of silicon dioxide is sealed as pharmaceutical carrier, and the bovine hemoglobin that conventional liposome is sealed as pharmaceutical carrier discharges end in 30h.
Embodiment 5
The ratio that Nano particles of silicon dioxide, water, cetyl trimethyl ammonium bromide, distearoyl phosphatidylcholine and chloroform are 1:250:50:10:200 according to mass ratio measures.Measure according to the above ratio Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water, mix homogeneously, ultra-sonic dispersion 20min.Measure according to the above ratio phospholipid and chloroform, mix homogeneously.Under stirring condition, the mixed solution of Nano particles of silicon dioxide, cetyl trimethyl ammonium bromide and water is added drop-wise in the mixed solution of phospholipid and chloroform, obtains oil
Water-in type emulsion.Then, add entry in the Water in Oil emulsion and obtain W/O/W type emulsion.The quality of the water that wherein adds is 20 times of Water in Oil emulsion quality.W/O/W type emulsion reduction vaporization is removed chloroform, namely obtain sealing the liposome of Nano particles of silicon dioxide.Test analysis shows, the liposome that gained is sealed Nano particles of silicon dioxide can reach more than 3 months the stable existence time.More than can reaching 60h the release time of the bovine hemoglobin that the liposome of sealing Nano particles of silicon dioxide is sealed as pharmaceutical carrier, and the bovine hemoglobin that conventional liposome is sealed as pharmaceutical carrier discharges end in 30h.
The particle diameter of the Nano particles of silicon dioxide of above-described embodiment 1-5 is 5 ~ 200nm.
The raw material of above-described embodiment 1-5 is commercial reagent level product.
Claims (1)
1. a method that improves liposome stability, is characterized in that: first measure Nano particles of silicon dioxide according to mass ratio: water: cetyl trimethyl ammonium bromide: phospholipid: chloroform=1:125 ~ 250:15 ~ 50:1 ~ 10:100 ~ 200; Then the Nano particles of silicon dioxide that aforementioned proportion is measured, cetyl trimethyl ammonium bromide and water, mix homogeneously, ultra-sonic dispersion 5 ~ 20min obtains mixed solution A; With phospholipid and the chloroform that measures according to the above ratio, mix homogeneously obtains mixed solution B; Under stirring condition, mixed solution A is added drop-wise in mixed solution B, obtains Water in Oil emulsion; Then, add water in Water in Oil emulsion, obtain W/O/W type emulsion, the addition of above-mentioned water is 10 ~ 20 times of Water in Oil emulsion quality; At last W/O/W type emulsion reduction vaporization is removed chloroform, namely obtain sealing the liposome of Nano particles of silicon dioxide;
Above-mentioned phospholipid is a kind of in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, dipalmitoyl phosphatidyl choline, DPPE, distearoyl phosphatidylcholine;
The particle diameter of above-mentioned Nano particles of silicon dioxide is 5 ~ 200nm.
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| CN 201210136282 CN102641244B (en) | 2012-05-03 | 2012-05-03 | Method for improving liposome stability |
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| CN 201210136282 CN102641244B (en) | 2012-05-03 | 2012-05-03 | Method for improving liposome stability |
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| CN104146987B (en) * | 2014-07-28 | 2016-08-24 | 陕西师范大学 | A kind of preparation method of liposome/silicon dioxide composite Nano microcapsule |
| CN106349719B (en) * | 2016-08-24 | 2019-11-05 | 江苏大学 | A kind of preparation method and purposes of the edible antimicrobial compound film of nano liposomes |
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Non-Patent Citations (4)
| Title |
|---|
| 冯炜炜等.固体脂质体纳米粒制备方法的研究进展.《中国医药生物技术》.2011,第6卷(第3期),218-220. |
| 吉顺莉等.脂质体纳米粒组装体作为药物载体的研究进展.《江苏大学学报(医学版)》.2010,第20卷(第2期),180-183. |
| 固体脂质体纳米粒制备方法的研究进展;冯炜炜等;《中国医药生物技术》;20110630;第6卷(第3期);218-220 * |
| 脂质体纳米粒组装体作为药物载体的研究进展;吉顺莉等;《江苏大学学报(医学版)》;20100331;第20卷(第2期);180-183 * |
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