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Ashish shukla feb 13, 2013 Liposomes: Improving drug delivery

What is liposomes?:

What is liposomes? Spherical vesicles with a phospholipid bilayer Hydrophilic Hydrophobic

What is liposomes?:

What is liposomes? Liposomes are defined as structure consisting of one or more concentric spheres of lipid bilayers separated by water or aqueous buffer compartments. Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid bilayers.


discovery Liposomes were first described by British haematologist Dr Alec D Bangham in 1961 (published 1964 ) The word liposome derives from two Greek words: lipo ("fat") and soma ("body"); it is so named because its composition is primarily of phospholipid.


advantage Provide controlled drug delivery Biodegradable, biocompatible, flexible Non ionic Can carry both water and lipid soluble drugs Drugs can be stabilized from oxidation Improve protein stabilization Controlled hydration Provide sustained release

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Targeted drug delivery or site specific drug delivery Stabilization of entrapped drug from hostile environment Alter pharmacokinetics and pharmacodynamics of drugs Can be administered through various routes Can incorporate micro and macro molecules Act as reservoir of drug Therapeutic index of drugs is increased Can modulate the distribution of drug


disadvantages Less stability Low solubility Short half life Phospholipid undergoes oxidation, hydrolysis Leakage and fusion High production cost Quick uptake by cells of R.E.S Allergic reactions may occur to liposomal constituents Problem to targeting to various tissue due to their large size

Structural component of liposome:

Structural component of liposome 1. Phospholipids 2. Sphignolipids 3. Sterols 4. Synthetic phospholipid 5. Polymeric material 6. Cationic lipids 7. Other subastances


Phospholipids Polar Head Groups Three carbon glycerol

Cell Membrane:

Cell Membrane

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Glycerol containing phospholipids are most common use. These are derived from Phosphatidic acid. Example of phospholipid are- Phosphatidyl choline (Lecithin) – PC Phosphatidyl ethanolamine (cephalin) – PE Phosphatidyl serine (PS) Phosphatidyl inositol (PI) Phosphatidyl Glycerol ( PG) For stable liposomes, saturated fatly acids are used. Unsaturated fatty acids are not used generally.


sphingolipids These are important constituents of plant and animal cells. This contain 3 characteristic building blocks A mol of F.A A mol of sphingosine A head group that can vary from simple alcohols such as choline to very complex carbohydrates. Most common Sphingolipids – Sphingomyelin. Glycosphingo lipids.


sterols Cholesterol & its derivatives are often included in liposomes for decreasing the fluidity or microviscosity of the bilayer reducing the permeability of the membrane to water soluble molecules Stabilizing the membrane in the presence of biological fluids such as plasma . Liposomes without cholesterol are known to interact rapidly with plasma protein such as albumin, transferrin, and macroglobulin.

Synthetic phospholipid:

Synthetic phospholipid E.g.: for saturated phospholipids are Dipalmitoyl phosphatidyl choline (DPPC) Distearoyl phosphatidyl choline (DSPC) Dipalmitoyl phosphatidyl ethanolamine (DPPE) Dipalmitoyl phosphatidyl serine (DPPS) Dipalmitoyl phosphatidic acid (DPPA) Dipalmitoyl phosphatidyl glycerol (DPPG) E .g.: for unsaturated phospholipids Dioleoyl phosphatidyl choline (DOPC) Dioleoyl phosphatidyl glycerol (DOPG)

Mechanism :

Mechanism 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.


classification A. Based on composition and mode of drug delivery 1. Conventional liposomes 2. pH sensitive liposomes 7. Cationic Liposomes 3. Long circulating or stealth liposomes 4. Immuno liposomes 5. Magnetic Liposomes 6. Temperature (or) heat sensitive liposomes

Classes of Liposomes:

Classes of Liposomes Conventional Long circulating Immuno Cationic

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B. Based on Size and Number of Lamellae 1. Multi lamellar vesicles ( M.L.V) -It contain many layer of phospholipids 2. Oligo lamellar vesicle (O.L.V) -It contain 2 to 10 layer of phospholipids 3. Uni lamellar vesicle (S.L.V.) These may be -SUV(20 to 40 nm) -MUV(40 to 80 nm) -LUV(100 to 1000 nm)


PHARMACOKINETICS OF LIPOSOMES Liposomal drugs can be applied through various routes, but mainly i.v. and topical administration is preferred. After reaching in the systemic circulation or in the local area, a liposome can interact with the cell by any of the following methods . 1. Endocytosis by Phagocytotic cells of the R.E.S such as macrophages and Neutrophils 2 . Adsorption to the cell surface either by non specific weak hydrophobic or electrostatic forces or by specific interaction with cell surface components

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3.Fusion with the plasma cell membrane by insertion of lipid bilayer of liposome into plasma membrane with simultaneous release of liposomal contents into the cytoplasm . 4.Transfer of liposomal lipids to cellular or sub cellular membrane or vice versa without any association of the liposome contents. It is often difficult to determine what mechanism is operative and more than one may operate at the same time.

Modes of Liposome/Cell Interaction :

Modes of Liposome/Cell Interaction Adsorption Endocytosis Fusion Lipid transfer

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Plasma Interaction If cholesterol is not present, liposomes interact rapidly with plasma proteins such as albumin, transferrin and macroglobulin. These proteins extract bulk phospholipids from liposomes, there by depleting outer monolayer of vesicles leading to physical instability. Liposomes with different surface charges bind different arrays of plasma proteins.

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Clearance and Distribution of Liposomes The size and surface charge of liposomes are 2 major determinants of liposomes clearance. Thus small U.L.V persist in the circulation for longer periods than large multilammellar vesicles of the same composition . Hall life (T1/2 ) T1/2 of drug increases by making liposome

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Factors affecting clearance and distribution 1. Particle size and charge 2. Chemical composition 3. Dose or lode of liposome administered 4. Structure of capillary endothelium 5. Fluidity of liposomal membrane


meTHODS OF PREPARATION OF LIPOSOMES 1 ) Hydration of lipids in presence of solvent 2) Ultrasonication 3) French Pressure cell 4) Solvent injection method a) Ether injection method b) Ethanol injection 7) High pressure extrusion

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8) Miscellaneous methods a) Slow swelling in Non electrolyte solution b) Removal of Chaotropic ion c) Freeze-Thawing

Applications of liposomeS:

Applications of liposomeS Chemotherapy Gene therapy As a carrier for vaccines For topical application For pulmonary delivery Metal storage disease Opthalmic delivery of drugs Cell biological application

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Protection Decrease harmful side effects Pharmokinetics - efficacy and toxicity Changes the absorbance and biodistribution Change where drug accumulates in the body Protects drug Deliver drug in desired form Multidrug resistance Why Use Liposomes in Drug Delivery?

Current liposomal drug preparations:

Current liposomal drug preparations Type of Agents Examples Anticancer Drugs Anti bacterial Antiviral DNA material Enzymes Radionuclide Fungicides Vaccines *Currently in Clinical Trials or Approved for Clinical Use 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*

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References Journals Allen, Theresa M. "Liposomal Drug Formulations: Rationale for Development and What We Can Expect for the Future." Drugs 56: 747-756, 1998. Allen, Theresa M. "Long-circulating ( sterically stabilized) liposomes for targeted drug delivery ." TiPs 15: 214-219, 1994. Allen, Theresa M. "Opportunities in Drug Delivery." Drugs 54 Suppl. 4: 8-14, 1997 Janknegt , Robert. "Liposomal and Lipid Formulations of Amphotericin B." Clinical Pharmacokinetics. 23(4): 279-291, 1992. Kim, Anna et al. "Pharmacodynamics of insulin in polyethylene glycol-coated liposomes." International Journal of Pharmaceutics. 180: 75-81, 1999. Quilitz , Rod. "Oncology Pharmacotherapy: The Use of Lipid Formulations of Amphotericin B in Cancer Patients." Cancer Control. 5:439-449, 1998. Ranade , Vasant V. "Drug Delivery Systems: Site-Specific Drug Delivery Using Liposomes as Carriers." Pharmacology. 29: 685-694, 1989. Storm, Gert and Daan J.A. Crommelin . " Liposomes:quo vadi ?" PSTT 1: 19-31, 1998. Taylor, KMG and JM Newton. "Liposomes as a vecicle for drug delivery." British Journal of Hospital Medicine. 51: 55-59, 1994

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