About Authors:
Dr.Pushpendra Kumar Tripathi
(director of RITM(pharmacy), *Shipra srivastava
Rameshwaram  Institute Of Technology And Management

The goal of any drug delivery system is spatial placement and temporal delivery of the medicament. Research works are going on to prepare an ideal drug delivery system which satisfies these needs. Researches carried out by ALEC BINGHAM lead to the development of a new drug delivery system called as liposome. Liposomes are small vesicles (_100 nm) composed of various of lipid molecules which build their membrane bilayers. These formulations are mainly composed of phosphatidylcholine (PC) and other constituents such as cholesterol and lipid-conjugated hydrophilic polymers . Liposomes are biodegradable and biocompatible in nature.

Reference Id: PHARMATUTOR-ART-1348

Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by membrane composed of lipid molecules. Various amphipathic molecules have been used to form liposomes(1,2)

Single phospholipid with it's hydrophilic head and hydrophobic tail

Phospholipids are the major structural components of the biological membranes in the human body, where two types of phospholipids exist i.e. phosphodiglycerides and sphingolipids, together with their corresponding hydrolysis products. The way they work and form membranes are elegant and miraculous. Each phospholipid molecule has three major parts, one head and two tails. The head is made from three molecularcomponents: choline, phosphate, and glycerol. The head is hydrophilic— in otherwords, it is attracted to water. Each tail is a long, essential fatty acid chain. These fattyacids are hydrophobic— that is, they are repelled by water. The drug molecules can either be encapsulated in aqueous space or intercalated in to the lipid bilayers.
The number of components of the liposomes is varied; however phospholipids and cholesterol are the main components. The most commonly used phospholipids include phosphatidyl choline (PC). PC is an amphipathic molecule in which a glycerol bridge links a pair of hydrophobic acyl hydrocarbon chains, with a hydrophilic polar head group, phospho choline. Phosphatidyl choline, also known as “lecithin”, can be derived from natural and synthetic sources(3,4,5,6,7)

Generally phospholipid are represented as follows:

*Molecules of pc are not soluble in water.
*In aqueous media they align themselves closely in planner bilayers sheets in order to minimize the unfavorable action between the bulk aqueous phase and the long hydrocarbon fatty chain (i.e they orient themselves so that the fatty acid chains face each other and the polor heads face the aqueous phase –this reduces the instability which exists when the molecule exist alon
*Such unfavorable interactions are completely eliminated when the sheets fold on themselves to form closed sealed vesicle.

In short this is what happens:

Some other common phospholipids:
1.Naturally ocuring phospholipids


*Incorporation of sterols in liposome bilayer brings about major changes in preparation of these membrane.
*cholesterol by itself does not forms a bilayer structure .
*however cholesterol acts fluidity buffer i.e below the phase transition temperature it make the membrane less ordered and slightly more permeable while above the phase transition temperature it makes the membrane more odered and stable.
*it can be incorporated into phospholipid membrane in very high concentration upto 1:1 or even 2:1 molar ratio of cholesterol to pc.
*cholesterol insert into the membrane with its hydroxyl groups oriented towards the aqueous surface and aliphatic chain aligned parallel to the acyl chain in the center of the bilayer.

Mechanism of cholesterol acting as a fluidity buffer
*cholesterol incorporation increases the separation between the choline head groups and eliminates the normal electrostatic and hydrogen binding intractions thus pushing the phospholipids apart making the layer less ordered at lower temperature.
*However ,in the higher concentration that cholesterol is used ,the membrane area occupied by the combination of acyl chains and cholestrolis greater than that taken by phosphacholin head group .this differences in area retards chain tilt (the phenomena responsible for phase transition –i.e trans to gauche conformation changes ).above the transition temperature ,the reduction in the freedom of the acyl chains causes the membrane to remain condenced and rigiged with a reduction in  area through closer packing and resultant decrease in fluidity(8,9,10,11,12).

Phosphatidylcholine and cholesterol interaction

History of liposome:
*The story of success of liposomes was initiated by Bangham and his colleagues in the early 1960s who observed that smears of egg lecithin reacted with water to form quite intricate structures. They were analyzed by electron microscopy showing that a multitude of vesicles were formed spontaneously. These more or less homogenous lipid vesicles were first called smectic mesophases . Later on, a colleague of Bangham termed them—more euphoniously—liposomes .

* The physiochemical characterization of liposomes had been carried out in 1968-75. Moreover, thin lipid film hydration method had been developed to prepare multilamellar vesicles (MLVs). (13,14). Liposomes were widely used to study the nature of biological membrane because of close resemblance of bilayered membrane with the biological membrane.

*During the late 1970s and early ‘80s, liposomes were re-engineered to maintain their stability so they could circulate in the blood for longer periods of time. While this was accomplished and stealth™ liposomes – ideal for delivering pharmaceutical drugs directly to cells - were developed, theyremained very difficult to produce on a large scale.

* In 1975 – 85Liposome’s utility was improved following basic research that increased the understanding of their stability and interaction characteristic within the system (15). This period also dealt with the discovery of various alternative methods for the preparation of liposomes. Also, due to the availability of vast knowledge  about the physio-chemical properties of liposomes, their behavior within the body, their interaction  with the cells, attempts had been made to improve their performance as drug carrier systems (16,17,18).

*The development of liposomal drugs with clinical utilityrelied on the development of techniques, which allowed the rapid generation of homogeneous small liposomes and efficient accumulation of drugs into liposomes. This was made possible by the extrusion technique and the pH gradient loading techniques, which were developed in the late 1980s and early 1990s. The first liposomal drug formulation on the US market was the anticancer drug doxorubicin encapsulated in sterically stabilised liposomes (Doxil®). Doxil® was approved by the FDA in 1995. It should be noted that it can take between 5 - 10 years and 50 - 100 million US dollars to bring a liposomal drug from the research and development stage to the market.

*Today, liposomes are used successfully in various scientific disciplines, including mathematics and theoretical physics (topology of two-dimensional surfaces  floating in a three dimensional continuum), biophysics (properties of cell membranes and channels), chemistry (catalysis, energy conversion, photosynthesis), colloid science (stability, thermodynamic of finite systems), biochemistry (function of membrane proteins) and biology (excretion, cell function, trafficking and signaling, gene delivery and function). AmbisomeTM, a parenteral amphotericin-B based liposomal product was first in the race, followed by number of other products which are either at the stage of clinical trials or are already in the market . Moreover, renaissance in the liposome research is promising many more products to come in the near future( 18).



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