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www.wjpr.net Vol 8, Issue 11, 2019.

Aditi et al. World Journal of Pharmaceutical Research

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REVIEW ON LIPOSOMAL DRUG DELIVERY SYSTEM AND ITS

APPLICATIONS

Aditi Gujrati*, Alok Sharma, Deepika Pandit and S. C. Mahajan

Mahakal Institute of Pharmaceutical Studies, Ujjain Behind Air Strip, Datana, Dewas Road,

Ujjain (M.P.) India-456664.

ABSTRACT

Liposomes, bubble or tiny vesicles consisting of one or more

phospholipid bilayers. Today, they are a very useful tool in various

scientific disciplines, including chemistry, colloid science,

biochemistry, biology & pharmaceutical science. Along with many

new drug delivery systems, liposomes distinguish and advanced

technology to transport active molecules to the site of action, and at

present, several dosage forms are in clinical use. This paper

summarizes exclusively focuses on classification, methods of

preparations, stability and applications concerning liposomal drug

formulations.

KEYWORDS: Liposomes, phospholipids, drug delivery system.

INTRODUCTION

The name of liposome is derived from two Greek words „Lipid‟ meaning fat and „Soma‟

meaning body.[1]

A liposome is a tiny vesicle, composed of the same material as a cell

membrane. It can be filled with drugs, and used as drugs deliver carrier for cancer and other

diseases. Structurally, they are concentric bleeder vesicles in which an aqueous volume is

entirely enclosed by a membraneous lipid bilayer. Membranes are generally prepared by

phospholipids, which are molecules that have a hydrophilic head group and a hydrophobic

tail group. The head is attracted to water, and the tail, which is prepared by long hydrocarbon

chain, is repelled by water.[2,3]

World Journal of Pharmaceutical Research SJIF Impact Factor 8.084

Volume 8, Issue 11, 1375-1391. Review Article ISSN 2277– 7105

Article Received on

20 August 2019,

Revised on 10 Sept. 2019,

Accepted on 01 Oct. 2019,

DOI: 10.20959/wjpr201911-15969

*Corresponding Author

Aditi Gujrati

Mahakal Institute of

Pharmaceutical Studies,

Ujjain Behind Air Strip,

Datana, Dewas Road, Ujjain

(M.P.) India-456664.



1376

Fig-Liposome.

The water soluble drugs are present in aqueous compartments whereas lipid soluble drugs

and amphilhilic drugs insert themselves in phospholipids bilayer. The liposomes containing

drugs can be administrated by many routes like intervenous, oral inhalation, ocular and local

application, used in the treatment of many diseases. It is satisfactory and advanced carrier and

has capability to encapsulate hydrophilic as well as lipophilic drugs and shield them from

degradation. In general, they are more effective and less toxic than conventional dosage form

due to the bilayer composition and structure. Liposomes are usually applied to the skin as

liquids or gels and hydrophilic polymers are considered to be suitable thickening agents.

Liposomes as a carriers are biocompatible, biodegradable, targeting, and stimulus-responsive.

Local anesthetics are also encapsulated into liposomes have longer duration of action,

decrease in circulating plasma levels, decrease central nervous system toxicity and

cardiovascular toxicity.[4-18]

The unfavorable interactions may occur between hydrophilic and hydrophobic phase which

prevent by folding into closed concentric vesicles. The large free energy difference develops

between the hydrophilic and hydrophobic environment is decreased by the formation of large

vesicle. The spherical structures have minimum surface tension and maximum stability.

Hence there is maximum stability of self assembled structure by forming vesicles.[19]

PROPERTIES OF LIPOSOMES[19]

1. Loading of drug and control of drug release rate.

2. Overcoming the rapid clearance of liposomes.

3. Intracellular delivery of drugs.

4. Receptor-mediated endocytosis of ligand-targeted liposomes.

5. Triggered release.

6. Delivery of nucleic acids and DNA.



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MERITS OF LIPOSOMES[1,4]

1. It increases efficacy and therapeutic index of drug.

2. It offer targeted drug delivery.

3. It can deliver both water and lipid soluble drugs.

4. It helps to reduce exposure of sensitive tissues to toxic drug.

5. It size may be wide-ranging to integrate smaller or larger drug molecules.

6. They are biocompatible, biodegradable, non-immunogenic and non toxic.

7. It can be administered through different routes.

DEMERITS OF LIPOSOMES[1,4]

1. They have Short half life.

2. Production cost of liposome is high.

3. They have stability problem.

4. They have Low solubility.

5. There may be possibilities of leakage and fusion of encapsulated drug/molecules.

6. Allergic reactions may occur to liposomal constituents.

7. The Phospholipids may undergo oxidation and hydrolysis.

STRUCTURAL COMPONENTS OF LIPOSOMES

The main components of liposomes are phospholipids which are stabilized by cholesterol,

with other stabilisers sometimes added to the mixture depending on the specific use of the

liposome.

Phospholipids

Phospholipids are the most important structural part of biological membranes. In the structure

of the phospholipids on the one end of the molecule are the hydrophobic acyl hydrocarbon

chains and the other end of the molecule is also called as phosphate head group, is

hydrophilic.[20]

It contains the choline group which is the most abundant lipids in nature. The phospholipid

mostly used for liposomes preparation is the phosphatidylcholine. Phosphatidylcholines are

the generally use due to their suitable stability and their ability to act against changes in pH or

salt concentrations in the product and biological environment.[21]



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Sphingolipids are the membrane components made up of sphingoid base.[22]

Natural

gangliosides class of sphingolipids are added in liposome preparation to provide a layer of

surface charged groups, to prolong the lifetime of liposomes in the blood and to prevent their

uptake by the reticuloendothelial system (RES). Sphingomyelins are important phospholipids

useful in regulation of cholesterol distribution within membranes.[23]

Cholesterol

Cholesterol is one of the chief components in liposomal formulations which increases the

rigidity of the lipid bilayer, improves fluidity of the membrane, increase stability and the time

of circulation in the blood stream.[24,25]

Cholesterol dose not by itself form bilayer structure,

but can be incorporated into phospholipid membranes in very high concentration upto 1:1 or

even 2:1 molar ration of cholesterol to phosphatidylcholine. Cholesterol enter into the

membrane with its hydroxyl group leaning towards the aqueous surface and aliphatic chain

aligent parallel to the acyl chains in the center of the bilayer.

LIPOSOMES CLASSIFICATION

Liposomes classification depend upon size (small, intermediate, or large), number of bilayers

(uni- and multi-lamellar), composition and mechanism of drug delivery.[26]

Small unilamellar vesicles consist of a single lipid bilayer with an average diameter ranging

from 25 to 100 nm. Large unilamellar vesicles also made up of one lipid bilayer and are

greater than 100 nm, on other hand multilamellar vesicles are made up of several concentric

lipid bilayers and measure of 1-5 μm.[27,28]

Fig- Liposomes classification based on size and lamellarity.

According to the composition and mechanism of drug delivery, the liposomes can be

classified as conventional liposomes, long-circulating liposomes, polymorphic liposomes

(pH-sensitive, thermo-sensitive, and cationic liposomes), and decorated liposomes (surface-

modified liposomes and immunoliposomes).



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1. Table 1: Based on structural parameters.

Type of vesicles Size

Multilamellar vesicle (MLV) >0.5μm

Oligolamellar vesicle (OLV) 0.1-1μm

Unilamellar vesicle (UV) All size range

Small unilamellar vesicle (SUV) 20-100nm

Large unilamellar vesicle (LUV) >100nm

Giant unilamellar vesicle (GUV) >1μm

Multi vesicular vesicle (MVV) >1μm

2. Table 2: Based on method of liposome preparation.

Type of vesicle Method

REV Reverse-phase evaporation method

MLV-REV Multilamellar vesicles made by reverse-phase

evaporation method

SPLV Stable plurilamellar vesicles

FATMLV Frozen and thawed MLV

VET Vesicles prepared by extrusion technique

DRV Dehyration-rehydration method

3. Table 3: Based on composition and application.

Type of vesicle Application

Conventional liposomes(CL) Neutral or negatively charged phospholipids and Chol

Fusogenic liposomes(RSVE) Reconstituted Sendai virus envelops

pH Sensitive liposomes Phospholipid such as PE or DOPE with either CHEMS

or OA

Cationic liposomes Cationic lipids with DOPE

Long circulatory (stealth)

liposomes (LCL)

Neutral high Tc°, Chol and 5-10% of PEG-DSPE or

GM1

Immuno-liposomes CL or LCL with attached monoclonal antibody or

recognition sequence

MECHANISM ACTION OF LIPOSOME[19]

A liposome consists of a region of aqueous solution inside a hydrophobic membrane.

Hydrophobic substances can be easily dissolved into the lipid membranes; in this way

liposomes are able to carry both hydrophilic and hydrophobic molecules. The extent of

location of the drug will depend upon its physiochemical characteristics and composition of

lipid. For the release of necessary drug molecules to the site of action, the lipid bilayers fuse

with other bilayers of the cell (cell membrane) to release the liposomal content.

Following steps involved in liposome action of drug delivery

1. Adsorption of liposomes to cell membranes causes its contact on the cell membrane.



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2. Adsorption of liposomes on the cell surface membrane followed by engulfment

(Endocytosis) and internalization into the liposomes.

3. Fusion of lipid bilayers of liposomes with the lipoidal cell membrane by lateral diffusion

and intermingling of lipids results in direct delivery of liposomal contents in the

cytoplasm.

4. Due to the similarity of liposomal lipid membrane with cell membrane phospholipids,

lipid transfer proteins in the cell membrane easily recognize liposomes and cause lipid

exchange.

THE LIPOSOME PREPARATION METHODS

A. Mechanical dispersion method

1. Lipid film hydration using hand shaking method

Initially a mixture of phospholipid and cholesterol were dispersed in organic solvent.

Afterward, the organic solvent was removed by evaporation generally a Rotary Evaporator

are used at reduced pressure. Finally, the dry lipidic film formed on the flask wall was

hydrated by addition of an aqueous buffer solution under agitation at temperature above the

lipid transition temperature. This method is most popularly used and easy to handle,

dispersed-phospholipids in aqueous buffer produce a population of multilamellar liposomes

(MLVs) differ both in size and shape (1–5nm diameter).[29]

2. Sonication method

This method generally decreases the size of the vesicles and impart Energy to lipid

suspension .This can be achieved by exposing the MLV to ultrasonic irradiation. There are

two methods of Sonication.

(a) Using bath sonicator.

(b) Using probe sonicator.

The probe sonicator is used for suspension which requires high energy in small volume. The

disadvantage of probe sonicator is contamination of preparation due to metal from tip of

probe. For large volume of dilute lipids bath sonicator is used. Generally by this method

small unilamellar vesicles are formed and their purification performed by ultracentrifugation.

The probe sonicators are used for the small volume which requires high energy while the bath

sonicators are employed for the large volume.[30]



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3. French Pressure Cell Method

In French Pressure Cell Method, extrusion of multilamellar vesicles occurs at 20,000 psi at

4°C through a small orifice. The method has several advantages over sonication method. This

method is simple, rapid, and reproducible. The resulting liposomes are somewhat larger than

sonicated small unilamellar vesicles. The disadvantages of the method are that the

temperature is difficult to achieve and the working volumes are relatively small (about 50 mL

maximum).[31]

4. Membrane Extrusion method

In membrane extrusion method lipids dissolve in chloroform and dried into thin film. The

dried lipid film is then added to buffer solution containing the interested drug. The lipid

solution is sonicated, freeze dried and subjected to extrusion through polycarbonate

membrane to form liposomes. Uniform sized liposomes are formed by this method.[20]

5. Freeze and Thawed method

Liposomes produced by the film method are whirled with the solute to be entrapped until the

entire film is suspended and then resulted MLVs are frozen in luke warm water and than

whirled again.[32]

After two cycles of freeze thaw and whirling the sample is extruded three

times. Then follow by six freeze thaw cycle and addition eight extrusions. This method of

ruptures and defuses small unilamellar vesicles in which the solute equilibrates between

inside and outside and liposome themselves combine and increase in size to form large

unilamellar vesicle by extrusion technique. For the encapsulation of protein this method is

widely used.[33]

B. Solvent Dispersion Methods

1. Ethanol Injection Method

An ethanolic lipid solution is quickly injected to a vast excess of buffer. The multilamellar

vesicles are immediately formed. The disadvantages of the process are that the population is

heterogeneous (30-110 nm), liposomes are very dilute, removal of all ethanol is difficult due

to formation of azeotrope with water and the possibility of various biologically active

macromolecules are inactivated due to presence of even low amounts of ethanol.[2]

2. Ether Injection Method

When a lipids solution dissolved in diethyl ether or in ether & methanol mixture is slowly

injected to an aqueous solution of the material to be encapsulated at 55-65°C or under



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reduced pressure. The successive removals of ether under vacuum lead to the liposomes

formation. The main disadvantages of the method are population is heterogeneous (70-190

nm) and the exposure of compounds to be encapsulated to organic solvents or high

temperature.[34]

3. Reverse Phase Evaporation Method

When sonication of a two phase system containing phospholipids in organic solvent like

diethylether or isopropylether and aqueous buffer formed water in oil emulsion. viscous gel is

formed when organic solvents are removed under reduced pressure. When residual solvent is

removed by continued rotary evaporation under reduced pressure then liposomes are

produced. By reverse phase evaporation method a high encapsulation efficiency up to 65%

can be obtained in a medium of low ionic strength like 0.01M NaCl. The method useful to

encapsulate small and large macromolecules. The main disadvantage of the method is the

exposure of the materials to be encapsulated to organic solvents and to short periods of

sonication.[35]

C. Detergent Removal method

The detergents can be removed by dialysis. The main benifits of detergent dialysis method

are exceptional reproducibility and formation of liposome populations which are homogenous

in size. The main disadvantages of the method are the retention of traces of detergents within

the liposomes. Other techniques have been used for the removal of detergents:

a) By using Gel Chromatography involving a column of Sephadex G- 2.[36]

b) By adsorption or binding of Triton X-100 (a detergent) to Bio-Beads SM-2.[37]

c) By binding of octyl glucoside (a detergent) to Amberlite XAD-2 beads.[38]

The detergents at their critical micelles concentrations are used to solubilize lipids. the

micelles become progressively richer in phospholipid as the detergent is removed and finally

combine to form LUVs.[36]



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Table 4: Passive diffusion loading techniques.

S.N Method Type

1 Mechanical dispersion

methods

1. Lipid film hydration by hand shaking, non-hand

shaking or freeze drying. 2. Micro-emulsification 3. Sonication 4. French pressure cell 5. Membrane extrusion

6. Dried reconstituted vesicles 7. Freeze-thawed liposomes

2 Solvent dispersion

methods

1. Ethanol injection

2. Ether injection

3. Double emulsion vesicles 4. Reverse phase evaporation vesicles

5. Stable plurilamellar vesicles

3 Detergent removal

methods

1. Dialysis 2. Column chromatography

3. Dilutions 4. Reconstituted sandal virus enveloped vesicles.

PURIFICATION OF LIPOSOME[39-41]

Liposomes are generally purified by Gel filtration chromatography, Dialysis, and

centrifugation separation, Sephadex-50 is most widely used. Hollow fibre dialysis cartridge

can be used in dialysis method. In centrifugation method, SUVs in normal saline may be

separated by centrifuging at 200000 g, for 10-20 hours. MLVs are separated by centrifuging

at 100000 g for less than one hour.

TARGETING OF LIPOSOME[42-47]

Two types of targeting

1. Passive Taregeting

Liposomes have been shown to be hastily cleared from the blood stream and taken up by the

RES in liver spleen by passive targeting. Thus capacity of the macrophages may be decreased

when the macrophages are to be targeted by liposomes. This has been confirmed by

successful delivery of liposomal antimicrobial agents to macrophages. Liposomes may be

used for targeting antigens to macrophages as a first step in the index of immunity.

2. Active Targeting

A pre-requisite for targeting is the targeting agents are situated on the liposomal surface such

that the contact with the target i.e., the receptor is tabulated such as a plug and socket device.

The liposome physically prepared such that the lipophilic part of the connector is anchor into



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the membrane for the duration of the formation of the membrane. The hydrophilic part on the

surface of the liposome, to which the targeting agent should be held in a stericaly right

position to bond to the receptor on the cell surface.

CHARACTERIZATION OF LIPOSOMES

Table 5: Chemical Characterization.

S.No. Characterization Parameters Analytical method

1. Chemical[48-49]

Phospholipids concentration HPLC/Barrlet assay

Cholesterol concentration HPLC/Cholesterol oxide assay

Phospholipids per oxidation U.V.observation

pH pH Meter

Osmolarity osmometer

Phospholipid hydrolysis HPLC & TLC

Drug Conc. Assay method

Cholesterol auto-oxidation HPLC & TLC

Table 6: Physical Characterization.

S.N. Characterization Parameters Analytical method

2. Physical[50-55]

Vesicle shape and surface morphology TEM and SEM

Vesicle size and Size distribution Dynamic light scattering TEM

Surface Charge Free flow electrophoresis

Electrical surface potential and surface

pH Zeta potential measurement and pH

sensitive probes.

Lamellarity p31

NMR

Phase behavior DSC , freeze fracture electron microscopy

Percent Capture Mini column centrifugation

Drug release Diffusion cell/ dialysis

Table 7: Biological Characterization.

S.N Characterization Parameters Analytical method

3. Biological[56]

Sterility Aerobic/Anaerobic Culture

Pyrogenicity Rabbit Fever Response

Animal toxicity Monitoring Survival Rats

LIPOSOMES STABILITY

The therapeutic efficacy of the drug molecule is evaluated by the stability of the liposomes

involving manufacturing steps, storage and delivery. A stable liposome formulation must

preserve the physical stability and chemical integrity of the active molecule during its

development and storage. Stability study contains the evaluation of its physical, chemical and

microbial parameters along with the assurance of integrity of the product during its

storage.[57]



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Physical stability

The fusion and breaking may occur due to leakage of drug from vesicles during storage. This

may decreases the physical stability of the liposomal drug product. Therefore, morphology

and size distribution of the vesicles are important parameters for assessing the physical

stability.[58]

To estimate the visual appearance (morphology and size of the vesicles) like light

scattering and electron microscopy used. Cholesterol give rigidness to lipid membrane but its

concentration not be more than 50% in the liposome. It is necessary for the stabilization and

maintenance of the bioactive molecule in the liposome.

Physical stability can be maintained by avoiding the excess unsaturation in the phospholipids,

by maintaining the pH conditions and must be stored at 4°C with no freezing and light

exposure.[40]

Chemical stability

The unsaturated fatty acids like Phospholipids are chemically, prone to oxidation and

hydrolysis, which may change the stability of the drug product. In maintaining a liposomal

formulation a key role played by pH, ionic strength, solvent system and buffered species.

Oxidation deterioration involves the formation of cyclic peroxides and hydroxy-peroxidases

due to the result of free radical generation in the oxidation process. Liposomes can be

prevented from oxidative degradation by protecting them from light, by adding anti-oxidants

such as α-tocopherol or butylated hydroxyl toluene (BHT), producing the product in an inert

environment (presence of nitrogen or Argon) or by adding EDTA to remove trace heavy

metals.[59]

The lyso-phosphatidylcholine is formed due to hydrolysis of the ester bond at C-4 position of

the glycerol moiety of phospholipids. This will increase the permeability of the liposomal

contents. Hence, control of lyso-phosphatidylcholine limit within the drug product of

lysosomes becomes important. It can be achieved by formulating lyso-phosphatidylcholine

free liposomes with phosphatidylcholine.[60]

APPLICATION OF LIPOSOMES

1. Site specific targeting

Delivery of a larger fraction of the drug to the desired site, reducing the drug‟s exposure to

normal tissues can be achieved by site specific targeting. On systemic administration, long



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circulating immunoliposomes are able to recognize and bind to target cells with greater

specificity.[61]

2. Sustained release drug delivery

To achieve the optimum therapeutic efficacy, which requires a prolonged plasma

concentration at therapeutic levels; liposomes provide sustained release of target drugs.[62]

The cytosine Arabinoside drug can be encapsulated in liposomes for sustained release and

optimized drug release rate in vivo.

3. Site-avoidance delivery

The cytotoxicity of anti-cancer drugs to normal tissues is attributed to their narrow

therapeutic index. Under such circumstances, the therapeutic index can be improved by

minimizing the delivery of drug to normal cells by encapsulating in liposomes. For eg

doxorubicin has a severe side effect of cardiac toxicity, but when formulated as liposomes,

the toxicity was reduced without any change in the therapeutic activity.[63]

4. Intracellular drug delivery

Increased delivery of potential drugs to the cytosol (where drug receptors are present) can be

accomplished by using liposomal drug delivery system. N-(phosphonacetyl)-L-aspartate

(PALA) is normally poorly taken up into cells. Such drugs when encapsulated within

liposomes, showed greater activity against ovarian tumor cell lines in comparison to free

drug.[64]

5. Intraperitoneal administration

Tumors that develop in the Intra-Peritoneal cavity can be treated by administering the drug to

Intra-Peritoneal cavity. But the rapid clearance of the drugs from the Intra-Peritoneal cavity

results in minimized amount of drug at the diseased site. However, liposomal encapsulated

drugs have lower clearance rate, when compared to free drug and can provide a maximum

fraction of drug in a prolonged manner to the target site.[65]

6. For Topical Drug Delivery

Skin treatment applications of liposomes are based on the similarity between the lipid

vesicles bilayer structure and natural membranes which includes the ability of lipid vesicles,

with specific lipid composition, to change cell membrane fluidity and to combine with them.



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In the dermatological field, liposomes were initially used because of their moisturizing and

restoring action.[66]

7. In Cosmetic Applications

The properties of liposomes can be utilized also in the delivery of ingredients in cosmetics.

Liposomes offer advantages because lipids are well hydrated and can reduce the dryness of

the skin which is a primary cause for ageing. Also, liposomes can supply replenish lipids and

importantly linolenic acid to the skin.[67]

8. As a Immunoliposomes

Among the various types of liposomes, immunoliposomes have gained wide attention due to

their targeting capabilities. Due to the presence of antibodies attached on to their surface,

these liposomes exhibit immunologic response.[68,69]

9. Liposomes for Gene Delivery

Liposomes, which can deliver DNA, anti-sense oligonucleotides, siRNA and other potential

agents into the nucleus. Specially engineered liposomes like cationic liposomes, pH sensitive

liposomes, fusogenic liposomes and genosomes are explored for gene delivery.[70]

10. Liposomes for Protein and Peptide Delivery

Proteins and peptides are potent therapeutic agents used in the treatment of various diseases.

However because of their unstable nature and degradation at physiological conditions the

delivery of these drugs at the targeted site is extremely complicated.[71]

11. Liposome as Anti-Infective Agents

Intracellular pathogen like protozoal, bacterial, and fungal reside in the liver and spleen and

thus to remove these pathogen the therapeutic agent may be targeted to these organ using

liposome as vehicle system. The disease like leishmaniasis, candidiasis, aspergelosis,

histoplasmosis, erythrococosis, gerardiasis, malaria and tuberculosis are targeted by the

respective therapeutic agent using liposome as a carrier.[72]

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