Application of liposomes in medicine

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Targeted administered liposomes (Liposomes) are composed of phospholipid cholesterol coated into membrane materials. When phospholipids are dispersed in water, they can form multiple microcapsules, and each layer is a lipid bilayer, separated by water. This microcapsule is the liposomes. Liposomes can be divided into single compartment, multicompartment liposomes and contain surfactants. According to the performance liposomes can be divided into general liposomes (including the above single-compartment, multicompartment and heterogeneous liposomes, etc.) special performance liposomes, thermal-sensitive, PH-sensitive, ultrasonic-sensitive, photosensitive and magnetic liposomes. According to the charge, liposomes can be divided into neutral, negative electric, and positively electric liposomes.


Liposomes have great potential in targeted drug administration therapy of malignant tumors. In order to overcome the disadvantages of unsatisfactory targeting distribution and poor stability of liposomes as carriers, some novel liposomes, such as temperature-sensitive, PL-sensitive, immune, and aggregated membrane liposomes, have been developed recently. The proposal and study of the concept of precursor liposomes provide a better idea for overcoming liposome instability.

At present, there are many methods to prepare liposomes, such as film method, reverse phase evaporation, solvent injection and compound emulsion method. These methods are generally called passive drug loading, while pH gradient method, ammonium sulfate gradient method is generally called active drug loading.1 The common preparation methods of passive drug-carrying liposomes mainly include thin film dispersion method, reverse phase evaporation method, injection method, ultrasonic dispersion, etc. When Chen Jianming et al. [1] prepared drug-containing liposomes, they first dissolved the drug in the aqueous phase or organic phase, and then prepared drug-containing liposomes according to the appropriate method, which is suitable for drugs with strong fat-soluble properties, and the resulting liposomes have a high encapsulation rate.



Thin film dispersion method is the most primitive but also the most basic and widely used preparation method for liposomes. Phospholipids and cholesterol and other lipids and fat soluble drugs in organic solvent, and then put the solution in a large round bottom flask, spin pressure steam, phospholipids on the bottle wall will form a thin membrane, and then add a certain amount of buffer solution, fully oscillation the flask make lipid membrane hydration off, can get lipid body.


The organic solvent was removed by evaporation, and the remaining solution was sonicated to separate the liposomes. Ultrasonic method can be divided into two kinds of "water bath ultrasonic method and probe ultrasonic method". This method is a common method to prepare small liposomes, but ultrasound is easy to cause the degradation of drugs.


freeze-drying Liposomal suspension is prone to aggregation, fusion and drug leakage during storage, and phospholipids are easy to oxidation and hydrolysis, which is difficult to meet the requirements of the stability of pharmaceutical preparations. Currently, this method has become one of the more promising methods to improve the long-term stability of liposome preparations.


Freeze melting method

In this method, coated liposomes were prepared and then frozen. During the rapid freezing process, due to the formation of ice crystals, the formed liposome membrane breaks up, and the lamella of ice crystals exists simultaneously with the broken membrane. This state is unstable. During the slow melting process, the exposed lipid membranes fuse with each other to form the liposomes again. Methoxarin liposomes were prepared by reverse phase evaporation, emulsification and freeze-thawing, respectively.


Compound milk method

In the first step of this method, phospholipid is dissolved in organic solvent, and the solution of encapsulation is added to get W / O colostrum. In the second step, colostrum is added to 10 times the volume of water to get W / O / W emulsion, and then remove organic solvent at a certain temperature to get liposomes. The encapsulation rate of liposomes is relatively high, but the particle size is relatively large. It is found that the temperature of the second emulsification process and the removal of organic solvent has a relatively large impact on the particle size of the liposome, and the lower temperature is beneficial to reduce the particle size of the liposome. By controlling the temperature, the [2] with the particle size of 400 nm Wang Jiansong can be produced, and the encapsulation rate reaches 90%.


The injection method solves the lipid and lipid-soluble drugs in organic solvent (oil phase), and then the oil phase is evenly injected into the aqueous phase (containing water-soluble drugs), stirred to swing the organic solvent, and then milk evenly or sonicated to get the liposome. According to the different solvents, it can be divided into ethanol injection method and ether injection method.


reverse phase evaporation

General method is the phospholipid membrane material dissolved in organic solvent, short-time ultrasonic oscillation, until the formation of stable W / O emulsion, and then reduce pressure evaporation remove the organic solvent, reach the gel, drop buffer, rotary evaporation make the gel on the wall of the device fall off, then continue to evaporate under reduced pressure, make water-based suspension, remove the drug, namely a large single layer of liposomes. This method can wrap a large water volume, generally applicable to encapsulating water-soluble drugs, macromolecular bioactive substances, etc.


The supercritical law  

The traditional liposome preparation method must use chloroform, ether, methanol and other organic solvents, which is harmful to the environment and human body. Supercritical carbon dioxide is a non-toxic, inert and environmentally harmless reaction medium. Active drug loading has a great influence on amphiphilic drugs, such as some weak acids, the oil and water distribution coefficient medium pH and ionic strength, and the encapment rate of liposome obtained by passive drug loading is low. This method usually coats the acid buffer salt, and then turns the outer water phase to neutral to establish a pH gradient inside and outside the liposome. The drug exists in a lipophilic neutral form in the pH environment of the outer aqueous phase and is able to penetrate the liposome bilayer membrane. In the aqueous phase, the drug is protonated into an ionic form, which can no longer return to the outer aqueous phase through the liposome bilayer and is thus encapsulated in the lipossome.

Active drug loading method generally refers to the pH gradient method. Tomoko Nii And other [3] people have subdivided it into:

(1)       pH gradient method;

(2)       Ammonium sulfate gradient method;

(3)       Calcium acetate gradient method.

Among them, ammonium sulfate gradient and calcium acetate gradient are only two special forms of pH gradient.


1)       PH Gradient method pH gradient method by adjusting the pH value of the water phase inside and outside of the lipid body, forming a certain PH gradient difference, weak acid or weak alkali drugs along the pH gradient, across the phospholipid membrane in the molecular form of the membrane in the form of ions.

2)         Ammonium sulfate gradient method The ammonium sulfate gradient method indirectly uses the free ammonia to the liposomes, allowing the drug to accumulate into the liposomes. Compared with the pH gradient method, the ammonium sulfate gradient method does not need to change the pH value of the external aqueous phase, and the control gradient is easy to achieve. The whole process does not need buffer or pH titration, and only the pH gradient method of the internal aqueous phase is more conducive to the stability of liposomes.

3)       Calcium acetate gradient method

The calcium acetate gradient method produces a calcium acetate concentration gradient through the transmembrane movement of calcium acetate (inside than outside), allowing a large number of protons from the liposomes to the outside to generate a pH gradient.

Liposomes are being increasingly appreciated as a novel drug delivery system. The indexes to evaluate the liposome quality include appearance, particle size distribution and encapsulation rate, among which the encapsulation rate is an important indicator to measure the intrinsic quality of liposomes. According to the different preparation methods of [4], the particle size, structure and encapsulation rate of liposome are different. Passive drug loading method is suitable for fat-soluble drugs, with high encapsulation rate and not easy to leak. The active drug loading method is suitable for amphiphilic drugs, and its encapsulation rate is generally> 80%, which opens a new idea of preparing water-soluble drug liposomes with high encapsulation rate. Current research on liposomes and vesicles focuses on three areas: membrane membranes; controlled release of drugs and targeted administration in Hugh, and delivery of genes and other substances to cells in vitro culture. In addition, interesting progress has been made in the dissociation of water molecules using solar energy, the preparation of colloidal catalysts with high catalytic activity and selectivity, and the study of emulsion and bulk polymerization mechanisms. Recently, some companies specializing in liposome development have been established, and the anti-cancer drugs, new vaccines, various drugs, cosmetics, and sunscreen pesticides have also been put on the market. As a new drug carrier, liposomes can reduce drug toxicity, reduce drug dosage, conduct targeted drug administration, and improve drug efficacy. 



To improve the therapeutic index of the drug and reduce or reduce the adverse effects of the drug, lecithin and cholesterol were used as carrier materials for liposomes. If a water-insoluble oral drug is made into an intravenous injection, the particle size of the drug must be reduced to a sub-micron or nano state (below 1 μ m). The commonly used particle preparation methods include thin film evaporation-freeze-drying method, emulsifying heat curing method, dissolved coal evaporation method, etc. As the carrier of anti-cancer drugs, liposomes of anti-cancer drugs can be characterized by increasing the affinity with cancer cells, overcoming drug resistance, increasing the drug intake of cancer cells, reducing drug dose, improving efficacy and reducing toxic and side effects. Hormone drugs carrier anti-inflammatory sterol hormone after the liposome has great superiority, concentrated in inflammation to be swallowed by phagocytes, avoid free drugs and plasma protein, once reached inflammation can endocytic, fusion, at lower doses can play a curative effect, thus reducing sterol hormones caused by high dose of complications and side effects. Insulin was supported with liposomes to improve bioavailability and patient compliance. However, there are still some problems of low encapsulation rate and drug deactivation in the gastrointestinal tract. Liposomes contain insulin with a wrapping rate of 20.3%. Insulin liposomes are resistant to insulin degradation by trypsin.

3)The carrier of the enzyme

The natural targeting of liposomes brings the capping enzyme mainly to the liver. Liposomes are the best carriers for the treatment of zymogen storage drugs, and some people apply multicompartment liposomes coated with starch-glucurase for the treatment of type II glycogen storage.

4) The carrier of detoxification agent  

 EDTA or EDPA can dissolve the metal and treat the metal storage disease. However, because these chelates cannot pass through the cell membrane and affect their in vivo effects Yang Zhijun et al [5], if the chelates are made into liposome dosage form, the liposomes serve as the carrier to transport the integrates to the cells of the storage metal.

5)Vectors of the antiparasitic agents

Lipossome as a drug vehicle for the reticuloendothelial system is one of the most successful applications of liposomes. The natural targeting of liposomes can be used to treat reticular endothelial system diseases.

6)Carriers of the antimicrobial agents

Using 1 / 10 of the original dose of liposomes and biological cell membrane, MariaB and other [6] are available.

7) The vehicle for transdermal delivery

Liposomes have become a research hotspot for their good biocompatibility and promoting transdermal absorption properties as percutaneous delivery carriers.


The composition of lipids in liposomes has some effect on drug penetration. CroweJH And other [7] by polar close to the skin ceramide, cholesterol, fatty acid and cholesterol sulfate esters composed of the so-called cutin liposomes Liu Taoshi [8], can make the drug have greater skin permeability and stability, this is due to the same lipid with the cuticle, easy to fuse with each other. The fluidity of liposomal lipids also affects drug transdermal permeability. Solid liposomes bind less to the skin than liquid liposomes, which increase the fluidity of cuticular lipids, while solid liposomes reduce the fluidity of cuticular lipids. The liquid liposomes have a better effect in promoting the transdermis than solid liposomes Lu Xiaoqing and other [9].5 Prorecurliposomes (proliposome)


Also known as the precursor form of reconstructed liposomes, Zhang Xuenong and other [10] are usually a powder with good mobility ability, which can be dispersed or dissolved into liposomes before application. It has a series of characteristics of liposomal preparations, and can improve the efficacy of drugs, reduce the side effects of drugs, and increase the stability of preparations and high temperature sterilization, laying a foundation for the industrial production of liposomes.


1) The type of the precursor liposomes

The solid and liquid forms, the two forms of precursor liposomes Feng Zuozhen and other [11], have successfully solved a series of stability problems of liposomes stored in the form of suspension, such as drug leakage, particle aggregation, oxidation and degradation of phospholipids, which is conducive to the industrial production and commercialization of liposome preparations.

2) Composition of the precursor liposomes

The addition of different add-ons to the precursor liposome prescription can significantly affect the properties and functions of the generated liposomes.

3 ) Encompassing drugs

Precursor liposomes extensively PhillipsNC and other [12] to encapsulate various lipid-soluble and water-soluble drugs.


4)        Preparation of the precursor liposomes

Most precursor liposomes are prepared first and then treated for special treatment. At present, the more mature methods include freeze-thaw method, reconstruction method, spray method, spray drying method and rotary evaporation method, which are dry powder Moser C and other [13].

5) Study of the in vivo properties of the precursor liposomes

The properties of precursor liposomes obtained by various methods should be studied in depth. For example, particle size and particle size distribution, encapsulation rate, and investigate the specific influencing factors in different preparation methods, in order to improve the encapsulation rate of Sun Wanfeng and other [14], and enhance the efficacy. Other properties such as in vitro drug release, absorption distribution, metabolism, and precursor liposomes are similar to liposomes.

6)       The application of precursor liposomes in pharmacy, the continuous development of [15] biotechnology and the gradual improvement of the preparation process, and the previous body liposomes have a series of characteristics of liposomes, so that the precursor liposomes encapsulating drugs are more and more attention and widely used.


1 Antitumor drug carrier

The precursor liposomes, as the carrier of anticancer drugs, can increase the affinity with cancer cells. [16], overcome drug resistance, increase the intake of drugs by cancer cells, reduce the drug dose, improve the efficacy, and reduce the toxic and side effects. Carrying loaded chemotherapy drugs is the main application mode of precursor liposomes.

2 Drug carriers against the reticular endothelial system disease

Due to the natural targeting of liposomes, the organs and cells of the reticuloendothelial system become the target areas of [17]. After the precursor liposomes loaded into the body, the therapeutic drugs can be effectively transported to the diseased cells of the reticuloendothelial system to release the drugs.

3 Antibacterial and antiviral drug vectors

Using the characteristics of strong affinity of liposomes and biological cell membranes, wrapping antibiotics in precursor liposomes can improve the antibacterial and antiviral effects, and significantly reduce the toxicity of some drugs.


4 other

Precursor liposomes are also used for encapsulating hormones, enzymes, antidotes, immune activators, antituberculosis drugs, including Guo Xingru and other [18], especially for some drugs that can not be sealed with liposomes due to instability. In conclusion, liposomes are a promising new dosage form for targeted drug delivery systems. The application of liposomes as a drug carrier has many advantages and features. But there are still some defects and production and application limitations. With the deepening of liposome research, there will be new types of liposomes to overcome these deficiencies, giving them a broader application prospect.

[reference documentation] [1], Chen Jianming, Zhang Yangmei, Gao Shen, et al. Development and characterization of vitamin A precursor liposome [J]. Journal of the Second Military Medical University, 2003,24 (2): 207. [2], Wang Jiansong, Zhu Jiabi. Preparation of azithromycin liposome and its encapsulation rate determination [J]. Journal of China Pharmaceutical University, 2004,35 (6): 499. 3 Tomoko Nii,Akira Takamura,Kiminori Mohri,et al.Fcators affecting physicochemical propertise of liposomes prepared with hydrogenated purifide egg yolk lecithins by the microencapsulation vesicles method  J  .colloida and Surfaces B:Biointerfaces,2002:323. [4], Zheng Qingzhong, Liu Lijun.pH Preparation of oxidized matrine liposome by pH gradient method [J]. Chinese Journal of Pharmaceutical Industry, 2006,37:679. [5] Yang Zhijun, Hino knowledge witness, Kawashima Jiaming. Journal of China Pharmaceutical University, 1993,24 (3): 1616   MariaB , RichardME  Effectofsugaralcoholsanddisaccha-ridesininducingthehexagonalphaseandalteringmembraneproperties : implicationsfordiabetesmellitus  BiochimBio-physActa  1988  943  4857   CroweJH , CroweLM . ChapmanD  InfraredSpectroscopicStudiesonInteractionsofWaterandCarbohydrateswithaBio-logicalMembrane  ArchBiochemBiophys  1984  232  400

[8]       , Liu Taoshi, CAI Baochang, Huang Yaozhou, et al. Research on the preparation of solid liposomes by sorbitol carrier deposition and freeze-drying method [J]. Chinese patent medicine, 2005,27 (5): 509-511. [9], Lu Xiaoqing, Chen Baixiang, Yang Huiping, et al. The killing effect of glucolipids on hepatoma cells and its physicochemical properties [J]. Journal of Shanghai Tiedao University, 1998,19 (9): 24-26. [10] Zhang Xuenong, Sun Dianjia, Li Guanhai, et al. Preparation of dehydrogen camel and alkali lipids [J]. Chinese Journal of The Pharmaceutical Industry, 1994,25 (10): 441-444. [11] Feng Zuozhen, Guan Dongxiu, Zhang Xiaoting. Quality standard of Cordyceps sinensis polysaccharide lipid oral liquid [J]. Journal of Shenyang Pharmaceutical University, 2005,22 (3): 203-206. 12 PhillipsNC , MorasML , BernardJM  ActivationofAlveolarMacrophageTumoricidalAcivityandEradicationofExperi-mentalMetastasesbyFreeze-DriedLiposomesContainingaNewLipophilicMuramylPipetideDerivative  CancerRe-search  1985  45  128 13 Moser C, Metcalfe IC, Viret JF. Virosomal adjuvanted antigen delivery systems [J]. Expert Rev Vaccines, 2003, 2(2): 189-196. [14] Sun Wanfeng, Sun Rongling, Jiang Weiling, Lin Zhihui, Wang Chunjuan; clinical observation of compound Cordyceps sinensis polysaccharide lipid oral solution for chronic hepatitis B [J];, China pharmacist; 2003,7 (2), 14-17 [15] Chang Mingxiang, Chen Keli; Preparation of matrine lipid bodies [J]; Chinese Journal of Hospital Pharmacy; 2005,22 (8).229-242 [16] Cao Ningning, Enplants. Preparation method and research progress of liposomes, Journal of Tianjin Institute of Technology [J], 2003,19 (1), 30-35 [17] Lu Yancheng, Zhao Jinming. Observation of the efficacy of indomethacin liposomes on rabbit corneal perforation injury, Journal of Bethune University of Medical Sciences, 1997,23 (2), 139-140 [18] Guo Xingru, Wu Shaoxi. Research and application of diasycicin B, Chinese Journal of New Drugs, 1996,5 (4) 261-26

Created on:2023-03-14 23:14