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www.wjpr.net Vol 8, Issue 11, 2019.
Aditi et al. World Journal of Pharmaceutical Research
1375
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.
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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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