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International Standard Serial Number (ISSN): 2319-8141 International Journal of Universal Pharmacy and Bio Sciences 1(1): September-October2012

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES

Pharmaceutical Sciences Review Article……!!!

Received: 18-10-2012; Accepted: 22-10-2012

RECENT ADVANCES ON LIPOSOMAL DRUG DELIVERY SYSTEM: A REVIEW

Gajanan R. Sarje *, Parvin Patil.a

Department of Pharmacetics, Indira college of pharmacy Vishnupuri, Nanded, Dist.Nanded,

Maharashtra, India

aDepartment of Biopharmaceutics, Government College of Pharmacy Karad, Dist. Satara.

KEYWORDS:

Liposomes,

Biodegradable,

Phosphatidylcholine.

For Correspondence:

Mr. Gajanan R. Sarje,

Department of

Pharmaceutics, Indira

college of pharmacy

Vishnupuri, Nanded,

Dist.Nanded, Maharashtra,

India.

E-mail:

gajusarje@rediffmail.com

ABSTRACT

A liposome is an artificially-prepared vesicle composed of

a lipid bilayer. The liposome can be used as a vehicle

for administration of nutrients and pharmaceutical.

Liposomes are composed of natural phospholipids, and may

also contain mixed lipid chains with surfactant properties.

The major types of liposomes are the multilamellar vesicle,

the small unilamellar vesicle, and the large unilamellar

vesicle. Liposomal formulations were significantly explored

over the last decade for the Anticancer Therapy, Respiratory

drug delivery system, Nucleic acid therapy, ophthalmic drug

delivery applications, Vaccine adjuvant, Anti-infective, Brain

Targeting therapy. These formulations are mainly composed

of phosphatidylcholine and other constituents such as

cholesterol and lipid-conjugated hydrophilic polymers.

Liposomes are biodegradable and biocompatible in nature. In

this review article we summarize information about some of

the key advantages of liposome, mechanism of liposomal

formation, classification of liposomes, and application of

liposome.

14 Full Text Available On www.ijupbs.com

International Standard Serial Number (ISSN): 2319-8141

1. INTRODUCTION :

Liposome is an artificially-prepared vesicle composed of a lipid bilayer. Liposomes are vesicles

having concentric phospholipid bilayers (See Fig. 1 and 2). Molecules from low molecular weight

(glucose) to high molecular weight (peptides and proteins) have been incorporated in liposomes.

The water soluble compounds/drugs are present in aqueous compartments while lipid soluble

compounds/drugs and amphiphilic compounds/drugs insert themselves in phospholipid bilayers.

The liposomes containing drugs can be administrated by many routes (intravenous, oral inhalation,

local application, ocular) and these can be used for the treatment of various diseases. The liposome

can be used as a vehicle for administration of nutrients and pharmaceutical drugs [1, 2].

Due to their structure, chemical composition and colloidal size, all of which can be well controlled

by preparation methods, liposomes exhibit several properties which may be useful in various

applications. The most important properties are colloidal size, i.e. rather uniform particle size

distributions in the range from 20 nm to 10 µm, and special membrane and surface characteristics.

They include bilayer phase behavior, its mechanical properties and permeability, charge density,

presence of surface bound or grafted polymers, or attachment of special ligands, respectively.

Additionally, due to their amphiphilic character, liposomes are a powerful solubilizing system for a

wide range of compounds. In addition to these physico-chemical properties, liposomes exhibit

many special biological characteristics, including (specific) interactions with biological membranes

and various cells [3].

This review highlights some of the key advantages of Liposomes, modes of liposome action,

mechanism of liposomal formation, classification of liposomes, and application of liposome.

2. ADVANTAGES OF LIPOSOME [4, 5]:

1) Biodegradable

2) Nontoxic

3) Controlled drug delivery system

4) Carry both hydrophilic and hydrophobic drugs

5) Prevent Oxidation

6) Deliver drug to the Site of action.

7) A special quality of liposomes is that they enable water soluble,

8) Water insoluble materials to be used together in a formulation without the use of surfactants

International Journal of Universal Pharmacy and Bio Sciences 1(1): September-October 2012

and emulsifier,

9) The liposome wall, being a phospholipid membrane,

10) Holds fat soluble materials such as oils.

11) Liposomes hold the normally immiscible materials together in a microsphere, with

controllable release of the encapsulated ingredients.

3. MECHANISM OF LIPOSOMAL FORMATION [5, 6]:

A liposome encapsulates a region of aqueous solution inside a hydrophobic membrane;

dissolved hydrophilic solutes cannot readily pass through the lipids. Hydrophobic

chemicals can be dissolved into the membrane, and in this way liposome can carry both

hydrophobic molecules and hydrophilic molecules. To deliver the molecules to sites of

action, the lipid bilayer can fuse with other bilayers such as the cell membrane, thus

delivering the liposome contents. By making liposomes in a solution

of DNA or drugs (which would normally be unable to diffuse through the membrane) they

can be (indiscriminately) delivered past the lipid bilayer.

Liposomes are formed open hydration of lipid molecules normally lipids are hydrated from

a dry state (Thin or Thick lipid film, spray dried powder), and stacks of crystalline bilayers

become fluid and swell myelin-long, thin cylinders grow and upon agitation detach self

close in to large, multilameller liposomes because this eliminates unfavorable interactions

at the edges. Once the large particles are formed they can be either broken by mechanical

treatment in to smaller bilayered fragments, which close into smaller liposomes. The size

of liposomes in the budding off mechanism is very difficult to calculate, in the self closing

bilayer mechanism the liposomes size depends, the bending elasticity of the bilayer and the

edge interactions of open fragments.

4. CLASSIFICATION OF LIPOSOMES [7]:

Liposomes are classified on the basis of:

Structure:

1) Unilamellar vesicle(UV): All size range.

2) Small Unilamellar vesicle (SUV) : 20-100 nm.

3) Medium Unilamellar vesicle (MUV): More than 100nm

4) Large Unilamellar vesicle (LUV): More than 100nm .

5) Giant Unilamellar vesicle(GUV) : More than 1 micro meter.

6) Oligolamellar vesicle(OLV): 0.1-1 micro meter.

7) Multilamellar vesicle (MLV): More than 0.5 micrometer.

8) Multi vesicular vesicle (MV) : More than 1 micrometer.

Based Upon Conventional Liposome

1) Stabilize natural lecithin (PC) mixtures

2) Synthetic identical, chain phospholipids

3) Glycolipids containing liposome.

Based Upon Speciality Liposome

1) Bipolar fatty acid

2) Antibody directed liposome.

3) Methyl/ Methylene x- linked liposome.

4) Lipoprotein coated liposome.

5) Carbohydrate coated liposome.

6) Multiple encapsulated liposome.

Conventional liposome:

1) Fusogenic liposome

2) Cationic liposome

3) Immuno liposome.

5. APPLICATION OF LIPOSOME:

The current deepening and widening of intrest in liposomes in many scientific disciplines,

and their application in medicine, immunology, diagnostics, cosmetics, ecology, cleansing

and the food industry are promising novel breakthrough and products. The field of

liposome research has expanded considerably over last 30 years. It is now possible to

engineer a wide range of liposome of varying size, phospholipids composition, cholesterol

composition, surface morphology suitable for wide range of application [8].

Liposomes interact with cells in many ways to cause liposomal components to be

associated with target cells. The liposome carrier can be targeted to liver and spleen and

distinction can be made between normal and tumors tissue using tomography. In case of

transdermal drug delivery system, liposome has a great application. Liposomal drug

delivery system when used to target

International Journal of Universal Pharmacy and Bio Sciences 1(1): September-October 2012 the tumor cells leads to reduction in the toxic effect and enhances the effectiveness of

drugs. The targeting of the liposome to the site of action takes place by the attachment of

amino acid fragment, such as antibody or protein or appropriate fragments that target

specific receptors cell. Liposomal DNA delivery vectors and further enhancement in the

form of LPDI -I and LPD-II are some of the safest and potential most versatile transfer

vectors which are used to date. DNA vaccination and improved efficiency of gene therapy

are just a few of the recent application of liposome. Several modes of drug delivery

application have been purposed for the liposomal drug delivery system, few of them are as

follows:

1. Enhance drug solublisation (Amphotericin-B, Minoxidil, Paclitaxels, and Cyclosporins)

2. Protection of sensitive drug molecules (Cytosine arabinosa, DNA, RNA, Anti-sense

oligo-nucleotides, Ribozymes)

3. Enhance intracellular uptake (Anticancer, anti viral and antimicrobial drugs)

4. Altered pharmacokinetics and bio-distribution (prolonged or sustained released drugs

with short circulatory half life). Several recent applications of liposomal drug delivery

system are as follows:

A. Liposome in Anticancer Therapy [9-13] :

The long term therapy of anticancer drug leads to several toxic side effect. The liposomal

therapy for the targeting to the tumour cell have been revolutionized the world of cancer

therapy with least side effect. It has been said that the small and stable liposome are

passively targeted to different tumour because they can circulate for longer time and they

can extra vasate in tissue with enhanced vascular permeability. Liposome macrophage

uptake by liver and spleen hampered the development of liposome as drug delivery for

aver 20 years.

Doxil is the liposomal formulation of doxorubicin, intravenous, chemotherapeutic agent.

Doxil is prepared by the new technology called stealth technology, stealth liposome. These

are the long circulatory liposome which is prepared by several means. Caelyx and myocet

are the liposomal formulations of doxorubicin. Caelyx is used for treatment of metastatic

ovarian cancer but now in now in advanced breast cancer. Myocet s approved for

metastatic breast cancer.

International Journal of Universal Pharmacy and Bio Sciences 1(1): September-October 2012 B. Liposome for Respiratory Drug Delivery System [14]:

Liposome is widely used in several types of respiratory disorders. Liposomal aerosol has several

advantages over ordinary aerosol which are as follows:

1. Sustained release

2. Prevention of local irritation

3. Reduced toxicity and

4. Improved stability in the large aqueous core.

Several injectable liposome based product are now in the market including ambisome, Fungisome

and Myocet. To be effective, liposomal drug delivery system for the lung is dependent on the

following parameters:

1. Lipid composition

2. Size

3. Charge

4. Drug and Lipid ratio and

5. Method of delivery

The recent use of liposome for the delivery of DNA to the lung means that a greater understanding

of their use in macromolecular delivery via inhalational is now emerging. Much of this new

knowledge, including new lipids and analytical techniques, can be used in the development of

liposome based protein formulations. For inhalation of liposome the liquid or dry form is taken and

the drug release occurs during nebulization. Drug powder liposome has been produced by milling

or by spry drying.

C. Liposome in Nucleic Acid Therapy [15-18]

Recombinant DNA technologies and studies of gene function and gene therapy all depends on the

successful delivery of nucleic acid into cells in vitro and in vivo. Non viral vectors will be developed

for the selective delivery of the gene to the malignant cells. The vector will exploit the increase

requirements of rapidly growing cells for more nutrients by attaching a nutrients ligand onto the

vector (liposome). The vector additionally will have a passively charged lipid to enhance nucleic

acid binding along with novel pH sensitive surfactants. The role of surfactants is to increase the

amount of nucleic acid escaping the endosome and correspondingly increase the transfection

efficiency. The vector system will be evaluated first in an animal model of cancer. Lipid based gene

delivery is the focus of several specialized high technology companies, of which Vical ( San Diago,

International Journal of Universal Pharmacy and Bio Sciences 1(1): September-October 2012 -CA, USA), Genzyme ( Farmington, MA, USA) and Megabios(Burhingam, CA, USA) have

products in clinical trials. Preliminary studies will be carried out using a marker gene (BETA

GALCTOSIDASE) with later experiments using a gene encoding for cytosine deaminase. Cytosine

deaminase can catalyze the conversion of the innocuous agent 5- Flourocytosine to the anticancer

agent 5- Fluorouracil. By selective delivery of this gene to only cancer cells, the therapeutic index

of 5-Flourouracil can then be increased. Some of the engineered liposomal and non liposomal

versions like pH sensitive cationic and anionic liposome, pH sensitiveimmuno-liposome, fusagenic

liposome, genosomes, lipofections and recently cochleats are being investigated as the major gene

vectors. This agent will become activated at endosomal pH, has membrane disrupting effects and

will be inactivated before reaching the lysosome. For this agent to work, the surfactant must enter

the cell by endocytosis. The soft surfactant will be incorporated into liposome that has shown to be

entering cell in this manner. The novelty of this delivery system stems from soft pH sensitive

surfactants (SPS). The pH sensitive liposomes have been reported as plasmid expression vectors

for the cytosolic delivery of DNA. It is also effective carrier for intracellular trafficking of anti

sense oligo-nucleotides.

D. Liposome in Opthalmic Disorders [19-23]:

Liposomes have been investigated for ophthalmic drug delivery since it offers advantages as a

carrier system. It is a biodegradable and biocompatible nanocarrier. It can enhance the permeation

of poorly absorbed drug molecules by binding to the corneal surface and improving residence time.

It can encapsulate both the hydrophilic and hydrophobic drug molecules. In addition, liposomes

can improve pharmacokinetic profile, enhance therapeutic effect, and reduce toxicity associated

with higher dose. Owing to their versatile nature, liposomes have been widely investigated for the

treatment of both anterior and posterior segment eye disorders. Current approaches for the anterior

segment drug delivery are focused on improving corneal adhesion and permeation by incorporating

various bioadhesive and penetration enhancing polymers. However, in the case of posterior

segment disorders, improvement of intravitreal half-life and targeted drug delivery to the retina is

necessary. Currently verteporfin is being used clinically in photodynamic therapy for the treatment

of subfoveal choroidal neovascularization (CNV), ocular histoplasmosis, or pathological myopia

effectively. Verteporfin is a light-activated drug which is administered by intravenous infusion. In

photodynamic therapy, after the drug is injected, a low-energy laser is applied to the retina through

the contact lens in order to activate verteporfin that results in closure of the abnormal blood

vessels. Unfortunately, photodynamic therapy usually does not permanently close the

abnormal vessels and choroidal neovessels reappear after several months. Another liposomal

photosensitizing agent, rostaporfin, was evaluated for the treatment

of age-related macular degeneration. It is now under phase 3 clinical trial. Rostaporfin

requires less frequent administration compared to verteporfin. Liposome technology has

been explored for ophthalmic drug delivery. However, there are some issues to be addressed

such as formulation, and storage of liposomes is very difficult, and they are known to cause

long-term side effects. Intravitreal administration of liposomes has resulted in vitreal

condensation, vitreal bodies in the lower part of eye, and retinal abnormalities. Therefore, all

these factors should be taken into account while developing liposomal formulation for

ophthalmic application.

E. Liposome as Vaccine Adjuvant [24-26]

Liposome has been firmly established as immuno-adjuvant, potentiating both cell mediated

and non cell mediated (humoral) immunity.

Liposome acts as immuno-adjuvant by the following therapeutic points of view:

1. Liposomes as an immunological (vaccine) adjuvant

2. Liposomal vaccines

3. Liposomes as carrier of immuno modulation for

4. Liposomes as a tool in immuno diagnostics

Liposomal immuno-adjuvant act by slowly releasing encapsulated antigen on intramuscular

injection and also by passively accumulating within regional lymph node. The accumulation

of liposome to lymphoid is done by the targeting of liposome with the help of phosphotidyl

serine. Liposomal vaccine can be prepared by inoculating microbes, soluble antigen,

cytokinesis of deoxyribonucleic acid with liposome. The latter stimulating an immune

response on expression of antigenic protein. Antigens can be covalently coupled to

liposomal membrane.

Liposomes which are encapsulating antigen are second time encapsulated within alginate

lysine microcapsules, to control antigen release and improve the antibodies responses.

Liposomal vaccines can be store at the refrigerated condition for about 12 months.

International Journal of Universal Pharmacy and Bio Sciences 1(1): September-October 2012 F. Liposomes for Brain Targeting [27-30]

The biocompatible and biodegradable behaviour of liposomes have recently led to their

exploration as drug delivery system to brain.

Liposomes with a small diameter (100 nm) as well as large diameter undergo free diffusion

through the Blood Brain Barrier (BBB). However it is possible that a small unilamellar

vesicles

(SUVS) coupled to brain drug transport vectors may be transported through the BBB by

receptor mediated or absorptive mediated trans-cytosis.

Similarly, cationic liposomes which were developed recently showed these structures to

undergo absorptive mediated endocytosis into cells. Whether cationic liposomes

successfully undergo absorptive mediated transcytosis through the BBB has not yet been

determined. The transport of substances through BBB by liposomes was extensively studied.

The important finding issues from their studies are that the addition of the sulphatide (a

sulphur ester of galactocerebroside) to liposome composition increases their several recent

applications ability to cross BBB. Wang et al. reported that liposomes coated with the

mannose reach brain tissue and the mannose coat assist transport of loaded drug through

BBB. The neutropeptides, leu-enkephaline and mefenkephalin kyoforphin normally do not

cross BBB when given systemically. The anti depressant amitriptylline normally penetrate

the BBB, due to versatility of this method. Nanoparticles (NP) were fabricated with different

stabilizers. It was found that amitriptylline level was significantly enhanced in brain when

the substance was adsorbed onto the NP and coated or particle stabilized with polysorbate

G. Liposome as Anti-Infective Agents [31-33]:

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 carrier.

CONCLUSION:

Liposome vesicles have drawn attention of researchers as potential carriers of various bioactive

molecules that could be used for therapeutic applications in human and animals. Many factors

contribute to their success as drug delivery vehicles. Liposomes solubilise lipophillic drug

candidates that would otherwise be difficult to administer intravenously.

The encapsulated drug is inaccessible to metabolizing enzyme; conversely, body component such

as erythrocyte and tissue injection site are not directly exposed to full dose of the drug. Liposomes

can cross the Blood brain barrier (BBB) because of the lipophillic nature of the phospholipids, so

even the hydrophilic drugs (which otherwise cannot easily cross the BBB) might be formulated as

liposomes. Liposome can prolong the drug action by slowly releasing the drug in the body.

Targeting option change the distribution of the drug in the body. They can also be used as adjuvant

in vaccine formulation. The new developments in the liposome are the specific binding properties

of a drug-carrying liposome to a target cell (tumor cell and specific molecules), stealth liposomes

for targeting hydrophilic (water soluble) anticancer drugs like doxorubicin, mitoxantrone which

leads to decrease in side effects because the drug is mostly concentrated at the site of action. Other

development is bisphosphonate-liposome mediated depletion of macrophages.

Several commercial liposomes have already been discovered, registered and introduced with great

success in pharmaceutical market. There is even greater promise in future for marketing of more

sophisticated and highly stabilized liposomal formulations. In future the liposomal drug delivery

system will revolutionize the vesicular systems with wide application especially in the treatment of

cancer and various disorders.

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Full Text Available On www.ijupbs.com

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Figure No. 1 Structure of Liposome

Figure No. 2 Liposome for Drug Delivery

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