liposomes ppt


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informarttionabout liposomes


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LIPOSOMES 12/02/2010 1 karpagam college of phamacy

Slide 2: 

What is a liposome? Spherical vesicles with a phospholipid bilayer Hydrophilic Hydrophobic 12/02/2010 2 karpagam college of phamacy

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Phospholipids Polar Head Groups Three carbon glycerol 12/02/2010 3 karpagam college of phamacy

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Classification of liposomes 1.Based on the size and number of lamellae Type of vesicles Unit of size (nm) Multilamellar vesciles (MLVs) 500 Oligolamellar vesicles (OLVs) 100 to 1000 Unilamellar vesicles (ULVs) 20 to >1000 Multi Vesicular system (MVs) >1000 Double liposomes >1000 Depofoam >1000 12/02/2010 4 karpagam college of phamacy

2. Based on the method of liposome preparation : 

2. Based on the method of liposome preparation 12/02/2010 5 karpagam college of phamacy

3.Based on composition and application : 

3.Based on composition and application 12/02/2010 6 karpagam college of phamacy

Slide 7: 

Classes of Liposomes Conventional Long circulating Immuno Cationic 12/02/2010 7 karpagam college of phamacy

Liposomes Help Improve : 

Liposomes Help Improve Therapeutic index Rapid metabolism Unfavorable pharmokinetics Low solubility Lack of stability Irritation 12/02/2010 8 karpagam college of phamacy

Liposomes manufacturing : 

Liposomes manufacturing Liposomes are manufactured in majority using various procedures in which the water soluble (hydrophilic materials are entrapped by using aqueous solution of these materials as hydrating fluid or by addition of drug/drug solution at some stage during manufacturing of Liposomes. And lipid soluble materials are solubilised in the organic solution of the constitutive lipids 12/02/2010 9 karpagam college of phamacy

Generally two methods are followed1.Passive loading 2.Remote loading : 

Generally two methods are followed1.Passive loading 2.Remote loading Passive loading This method involves the loading of the entrapped agents before (or) during the manufacture procedure. Remote loading Certain types of compounds with ionisable groups, and those, which display both lipid and water solubility, can be introduced into the liposomes after the formation of intact vesicles. 12/02/2010 10 karpagam college of phamacy

Passive loading techniques. : 

Passive loading techniques. It includes three different groups of methods working on different principles. Mechanical dispersion Solvent dispersion Detergent solubilisation 12/02/2010 11 karpagam college of phamacy

Mechanical dispersion : 

Mechanical dispersion This method begin with lipid soln in organic solvent and end up with lipid dispersion in water Various components are typically combined by co-dissolving the lipids in an organic solvent and the organic solvent is then removed by film deposition under vaccum. When all the solvent is removed, the solid lipid mixture is hydrated using aqueous buffer The lipids spontaneously swell and hydrate to form liposomes 12/02/2010 12 karpagam college of phamacy

Thin film hydration using hand shaking (MLVs) and non – shaking (ULVs) : 

Thin film hydration using hand shaking (MLVs) and non – shaking (ULVs) The lipids are casted as stacks of film from their organic soln using rotary flash evaporator under reduced pressure & then the casted film is dispersed in an aqueous medium Upon hydration the lipids swell and peel off from the wall of the round bottom flask and vesiculate forming multilamellar vesicles. The mechanical energy required for the swelling of lipids and dispersion of casted lipid film is impacted by minimal agitation 12/02/2010 13 karpagam college of phamacy

Slide 14: 

By exposing the film to a stream of water – saturated nitrogen for 15 min followed by swelling in aqueous medium without shaking (non- shaken vesicles) The percentage of encapsulation efficiency as high as 30% is achieved. 12/02/2010 14 karpagam college of phamacy

Slide 15: 

Liposome Preparation 12/02/2010 15 karpagam college of phamacy

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Liposome Preparation 12/02/2010 16 karpagam college of phamacy

Proliposomes : 

Proliposomes To increase the surface area of dried lipid film and to facilitate instantaneous hydration, the lipid is dried over a finely divided particulate support. Powdered Nacl, (or) sorbitol (or) other polysaccharides. Proliposomes form dispersion of MLVs on adding water into them, where support is rapidly dissolved and lipid film hydrates to form MLVs. This method overcomes the stability problems of liposomes encountered during their storage as dispersion such as dry (or) frozen form. 12/02/2010 17 karpagam college of phamacy

Mechanical treatment of MLVs : 

Mechanical treatment of MLVs Multilamellar vesicles formed on hydration of dried lipids could be further engineered (or) modified for their size & other characteristics No. of methods are devised to reduce their size and to convert liposomes of the large size range into smaller homogenous vesicles These include techniques such as microemulsification, extrusion, ultrasonication and use of french pressure cell 12/02/2010 18 karpagam college of phamacy

Slide 19: 

Second set of methods is designed to increase the entrapment volume of hydrated lipids (or) reduce lamellarity of the vesicles formed. Include procedures such as freeze drying, freeze thawing (or) induction of vesiculation dry ions (or) PH change 12/02/2010 19 karpagam college of phamacy

Sonicated unilamellar vesicles (SUVs) : 

Sonicated unilamellar vesicles (SUVs) At high energy level, the average size of the vesicles is further reduced. This was first achieved on exposure of MLVs to ultrasonic irradiation & most widely used for producing small vesicles. Probe (or) Bath sonicator. Probe is employed for dispersions, which require high energy in a small volume eg ; high concentration of lipids (or) viscous aqueous phase 12/02/2010 20 karpagam college of phamacy

Slide 21: 

Bath is more suitable for large volumes of diluted lipids. Probe tip sonicator supply a high energy input to the lipid dispersion but suffer from overheating of the liposomal dispersion causing lipid degradation Sonication tips also tend to release titanium particles into the liposome dispersion, which must be removed by centrifugation prior to use For these reasons, bath sonicators are most widely used for the preparation of SUVs. 12/02/2010 21 karpagam college of phamacy

Slide 22: 

Liposomes dispersion after sonication is placed in a clear plastic walled ultracentrifuge tube. Dispersion is generally centrifuged to sediment titanium particle and large MLVs followed by higher speed centrifugation After spining the tube is carefully removed from the rotor and with the help of a pasteur pipette, the liquid with top clear layer is decanted leaving the central oplaescent layer The top layer constitutes pure dispersion of SUVs with varying diameter 12/02/2010 22 karpagam college of phamacy

French pressure cell liposome's : 

French pressure cell liposome's The ultrasonic radiation not only degrades the lipids but also macromolecules & other sensitive compounds, which are to be entrapped in liposomes. It is very useful methods developed in extrusion of preformed large liposomes in a french press under very high pressure. This technique yields rather uni (or) oligo-lamellar liposomes of intermediate size depending upon pressure applied. 12/02/2010 23 karpagam college of phamacy

Slide 24: 

Draw back are high initial cost of the press that consists of an electric hydraulic press and pressure cell French press cell 12/02/2010 24 karpagam college of phamacy

Dried reconstituted vesciles (DRVs) : 

Dried reconstituted vesciles (DRVs) This method starts with freeze drying of empty SUVs and then rehydrating it with the aqueous fluid containing the material to be entrapped This leads to a dispersion of solid lipids in finely subdivided form. The step of freeze-drying is used to freeze and lyophilize a preformed SUVs dispersion rather than to dry the lipids from an organic solution. The water-soluble materials to be entrapped are added to the dispersion of empty SUVs and the dried together . Uni- or oligo- lamellar of the order of 1.0 µm or less in diameter. 12/02/2010 25 karpagam college of phamacy

Freeze Thaw Sonication (FTS) Methods : 

Freeze Thaw Sonication (FTS) Methods FTS method is an extension of classical DRV method. The method is based upon freezing of a unilamellar dispersion and then thawing by standing at room temperature for 15 min and finally subjecting to a brief sonication cycle. The process ruptures and re-fuses SUVs during which the solute equilibrates between inside and outside, and the liposomes themselves fuse and increase markedly in size. 12/02/2010 26 karpagam college of phamacy

Slide 27: 

In order to prepare giant vesicles of diameter between 10 and 50 µm, the freeze thaw technique has been modified to incorporate a dialysis step against hypo-osmolar buffer in place of second step sonication First mixed with salt solution followed by freeze thawing several times. During subsequent dialysis, the large vesicles formed by freeze thawing swell and rupture as a result of osmotic lyses where upon they fuse with each other to yield a large no. of giant vesicles. 12/02/2010 27 karpagam college of phamacy

Liposomes from preformed vesicles : 

Liposomes from preformed vesicles pH induced vesiculation This method is used to transform MLVs to LUVs using a change in the pH of the dispersion thus avoiding the use the sonication or high –pressure application This process is electrostatic event and termed “pH induced vesiculation”. The transient change in pH brings about an increase in the surface charge density of the lipid bilayer, which induces spontaneous vesiculation 12/02/2010 28 karpagam college of phamacy

Calcium induced fusion : 

Calcium induced fusion Principally based on the concept of aggregation and fusion of acid phospholipid vesicles in the presence of calcium In this method, SUVs are formed using sonication buffer as the hydrating fluid. The large particles are removed by centrifugation CaCl2 is added to phospholipids Incubated and pellet is obtained by spinning to EDTA Again incubated and Ca-EDTA complex is removed by dialysis. 12/02/2010 29 karpagam college of phamacy

Solvent dispersion methods for passive loading : 

Solvent dispersion methods for passive loading In this method, lipids are first dissolved in an organic soln, which then brought into contact with an aqueous phase containing materials to be entrapped within the Liposomes. 12/02/2010 30 karpagam college of phamacy

Ethanol injection : 

Ethanol injection This method is used one of the alternative used for the preparation of SUVs without sonication An ethanol solution of lipids is injected rapidly through a fine needle into an excess of saline or other aqueous medium. The procedure yields a high proportion of SUVs (~25nm) This method is extremely simple and has low risk of degradation of sensitive lipids 12/02/2010 31 karpagam college of phamacy

Ether injection : 

Ether injection It is similar to the ethanol injection. It involves injecting the immiscible organic soln very slowly into an aqueous phase through a narrow needle at the temperature of vapourising the organic solvent. This method may also treat sensitive lipids very gently. It has little risk of causing oxidative degradation provided ether is free from peroxides. 12/02/2010 32 karpagam college of phamacy

Rapid solvent exchange vesicles(RSEVs) : 

Rapid solvent exchange vesicles(RSEVs) The lipid mixture is quickly transferred between an essentially pure solvent environment and a pure aqueous enivornment The method involves passing the organic soln of the lipids through the orifice of blue-tipped syringe under the vaccum into a tube containing aqueous buffer The tube is mounted on the vortexer. Bulk solvent vapourises and is removed within seconds before coming in contact with aqueous environment 12/02/2010 33 karpagam college of phamacy

Reverse phase evaporation vesciles : 

Reverse phase evaporation vesciles In this method removal of solvent from an emulsion by evaporation. The droplets are formed by bath sonication of mixture of two phases. And the emulsion is dried down to a semisolid gel in a rotatory evaporater under reduced pressure. And bringing water droplets to collapse by vigorous mechanical shaking using a vortex mixer. The aqueous content of the collapsed droplet provides the medium required for dispersion of these newly formed liposomes. And then conversion of gel into a homogenous free flowing fluid. And the vesicles generally formed are unilamellar. 12/02/2010 34 karpagam college of phamacy

Stable plurilamellar vesicles (SPLVs) : 

Stable plurilamellar vesicles (SPLVs) In this method preparation of water-in-organic phase dispersion with an excess of lipid followed by drying under continued bath sonication with an intermittent stream of nitrogen. The redistribution and equilibration of aqueous solvent and solute occurs in between the various bilayers in each plurilamellar vescile. 12/02/2010 35 karpagam college of phamacy

Remote (active) loading : 

Remote (active) loading Which load a drug molecules into preformed Liposomes using pH gradients and potential difference across liposomal membranes. A concentration difference in proton concentration across the membrane of Liposomes can drive the loading of amphipathic molecules. 12/02/2010 36 karpagam college of phamacy

Advantages over a passive encapsulation techniques : 

Advantages over a passive encapsulation techniques High encapsulation efficiency and capacity Reduced leakage of the encapsulated compounds Flexibilty for the use of constitutive lipids, as drug is loaded after the formation of carrier units Avoidance of biologically active compounds during preparation steps in the dispersion thus reducing safety hazards.. 12/02/2010 37 karpagam college of phamacy

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12/02/2010 38 karpagam college of phamacy

Slide 39: 

DOXIL® Structure Doxorubicin Encapsulated in STEALTH® Liposomes Small (~100 nm) Pegylated Lipid Membrane (Phospholipid + Cholesterol) Doxorubicin Polyethylene Glycol 12/02/2010 39 karpagam college of phamacy

Slide 40: 

Morphology of DOXIL® Liposomes Cryo-Electron Micrograph of DOXIL liposome doxorubicin sulfate precipitate 12/02/2010 40 karpagam college of phamacy

Slide 41: 

Extravasation of STEALTH® Liposomes Normal Endothelium Gaps in Tumor Endothelium Liposome Extravasation Flat edges, cobblestone pattern, tight junctions Tumor vessels often have defects, gaps as large as several hundred nanometers, with poorly formed or missing basement membrane STEALTH® (arrows) can pass from lumen (L) through endothelial gaps and basement membrane into tumor parenchyma (T) T L 12/02/2010 41 karpagam college of phamacy

Modes of Liposome/Cell Interaction : 

Modes of Liposome/Cell Interaction Adsorption Endocytosis Fusion Lipid transfer 12/02/2010 42 karpagam college of phamacy

Why Use Liposomes in Drug Delivery? : 

Why Use Liposomes in Drug Delivery? Inactive: Unmodified liposomes gather in specific tissue reticuloendothelial system Active: alter liposome surface with ligand (antibodies, enzymes, protein A, sugars) Directly to site Physical: temperature or pH sensitive liposomes Drug Targeting 12/02/2010 43 karpagam college of phamacy

Uses of Liposomes : 

Uses of Liposomes Chelation therapy for treatment of heavy metal poisoning Enzyme replacement Diagnostic imaging of tumors Study of membranes Cosmetics 12/02/2010 44 karpagam college of phamacy

Slide 45: 

liposomal drug Type of Agents Examples Anticancer Drugs Anti bacterial Antiviral DNA material Enzymes Radionuclide Fungicides Vaccines Malaria merozoite, Malaria sporozoite Hepatitis B antigen, Rabies virus glycoprotein Amphotericin B In-111, Tc-99m Hexosaminidase A Glucocerebrosidase, Peroxidase Duanorubicin, Doxorubicin, Epirubicin Methotrexate, Cisplatin, Cytarabin Triclosan, Clindamycin hydrochloride, Ampicillin, peperacillin, rifamicin AZT cDNA - CFTR 12/02/2010 45 karpagam college of phamacy

Slide 46: 

e Problems with Liposomal Preparations of Drugs $$$$ Fungizone $40.58 Amphotec $2334 Doxil $1200 per treatment, twice the cost of normal protocol of chemotherapy and drugs Lack long term stability (short shelf life) Freeze dry and pH adjustment Low “Pay Load” - poor encapsulation Physical and chemical instability Polar drugs and drugs without opposite charge Modifications 12/02/2010 46 karpagam college of phamacy

Slide 47: 

Liposomes 12/02/2010 47 karpagam college of phamacy

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