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Liposomes in drug delivery


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Liposomes Gadade D. D. Shri Bhagwan College of Pharmacy, Aurangabad


CONTENTS Introduction Classification of liposome Prepration of liposome Characterization of liposomes Formulation Application of liposome Recent Trends 2


INTRODUCTION Liposomes, vesicles composed of endogenous phospholipids with or without cholesterol, are capable of entrapping an extensive range of solutes from hydrophilic entities dissolved in the internalised aqueous compartments to hydrophobic species partitioned within the lipid bilayers. available in sizes ranging from 20 nm to greater than 1 μ m diameter and of apparent low toxicity 3

Advantages & Disadvantages:

Advantages & Disadvantages Advantages Increase efficacy Therapeutic index Increase drug stability Reduce drug toxicity Improve pharmacokinetics Provides selective passive targeting Easy scale up procedures Disadvantages Lack long term stability Low encapsulation capacity Possibility of new side effect 4

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Phospholipid bilayer Aqueous cavity Drug 5

Structural Components:

Structural Components Main components are: Phospholipids Cholesterol The most common phospholipid used is phosphatidylcholine ,is an amphipathic molecule in which exist -a hydrophilic polar head group. -a glycerol bridge -a pair of hydrophobic hydrocarbon chains . 6


Polar head group Glycerol 7

Structural Components:

Structural Components The molecules of phosphlipids are not soluble in water . In aqueous media they align themselves closely in a planar bilayer sheet They orient themselves so that the fatty acids chain face each other and the polar head face the aqueous phase. This reduces the instability which exist when the molecule exist alone. 8

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Conti… Phosphtidylcholine can be derived from natural and synthetic sources Naturally occuring PC: phosphatidylcholein PE: phosphatidylethanolamine PS: phosphatidylserine Synthetic DOPC:diolylphosphtidylcholein DOPE:diolylphosphatidylethanolamine DSPC:distearoylphosphatidylcholine 10


Cholesterol Incoportion of sterols in liposome bilayer brings about major changes in Prepration of these membranes Cholesterol it self does not form a bilayer structure. Cholesterol act as a fluidity buffer . It can be incorporated in to phospholipid membrane in very high concentration up to 1:1 or 2:1. 11

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-A lamella is flat plate like structure appears during formation of liposome -Phospholipid bilayer first exist as lamella then convert in to sphere. -Several lamella of phospholipid bilayer are form liposome of multilamellar structure. 12

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General method of preparation All the method of Prepration involve following common stages 16

Mechanical dispersion method:

Mechanical dispersion method All method under this start with a lipid solution in organic solvent end up with lipid dispersion in water. Dissolving lipid in organic solvent, organic solvent is removed by film deposition Solid-lipid mixture is hydrated using aqueous buffer The lipid spontaneously swell and hydrate to form liposome. At this stage incorporate some diverge processing parameter in various ways to modify their ultimate properties. 17

Basic method of mechanical dispersion:

Basic method of mechanical dispersion Hand shaking multilamellar vesicles Non shaking vesicles Pro-liposome Freeze drying After these method other processing method are used to modify the size and other characteristics are: -Microemulsification liposome -Sonicated unilamellar vesicles -French pressure cell liposome -Membrane extrusion liposome -Dried reconstituted vesicles -Freeze thaw sonication -Ph induced vasiculation 18

1)Hand shaking multilamellar vesicles :

1) Hand shaking multilamellar vesicles Simple and most widely used Basic steps are: 19 Lipid mixture charge Chloroform:methanol Drying of film Dispersion in an aqueous film Lipid swell and peel of the wall of flask evaporation hydration

Hand shaken method in general:

Hand shaken method in general 20

2)Non shaking vesicle:

21 2) Non shaking vesicle lipid Chloroform:mehanol(1:2, in flat bottom conical flask ) evaporation 15 to 20min 0.2 M sucrose (10 to 20 ml) Keep 2hr at 37ºc N2 flushed Centrifugation 12,000 rpm Bulk fluid (swelling) 10 min Water saturated nitrogen flow LUV’s

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22 BUCHI Rotary evaporator R type (pro-liposome )


23 3) Pro-liposome Lipid sol. In chloroform +sorbitol powder 100 ml flask fit to evaporator Add 5 ml lipid sol. Introduce in flask by inlet tube Second aliquot introduce again Lyophilize overnight (600mg) Powder 10ml glass vial Water bath 50 to 5ºc vacuum develop Solvent absorbed completely by powder

4)Freeze drying:

4) Freeze drying 24 Lipid+org. solvent Dry lipid Water or saline added MLV’S (above phase transition temp.) Freeze dry

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25 Microemulsification liposome

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26 Sonicated unilamellar vesicle

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27 French pressure Cell Liposomes

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28 Membrane exclusion liposome

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29 Dried reconstituted vesicle

Solvent dispersion method :

Solvent dispersion method Lipid +organic solvent aqueous phase (containing material) Phospholipids align themselves in to a monolayer which form basis for half of bilayer of liposome Fall in one of three categories: 1)Organic solvent miscible with organic phase 2)Organic solvent immiscible with inorganic phase 3)org.solvent in large excess and is immiscible with aqueous phase 30

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31 a)Ethanol /Ether injection method

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32 b)Reverse phase evaporation

Detergent solubilisation:

Detergent solubilisation Phospholipid brought in contact with aqueous phase via detergents. Structure formed called micelle Shape ,size dependent on chemical nature of detergents. Concentration of detergent in water at which micelles just start to form is known as cmc To remove the detergents two method can be employed: -Dialysis -column chromatography. -centrifugation method. 33

Active loading:

Active loading Drug molecule load in liposomes using pH gradient and potential difference across membrane. Some weak acids or bases can be transported through the membrane due to various transmembrane gradient Such as electrical, ionic or salt specific Advantage: -high encapsulation efficiency -reduced leakage 34

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CHARACTERIZATION OF LIPOSOME Physical Properties : 1)size and its distribution -Microscopic method -laser light scattering -Gel permeation 2)Surface charge 3)percent drug capture 4)Entrapped drug volume 5)Lamellarity 6)percent drug release 36


Cont… Chemical properties 1) Quntative determination of phospholipids. 2) Phospholipid hydrolysis 3) Phospholipid oxidation 4) Cholesterol analysis 37

Modes of Liposome/Cell Interaction :

Modes of Liposome/Cell Interaction Adsorption Endocytosis Fusion Lipid transfer 38


FORMULATION Doxil Chemotherapy, drug doxorubin side effects like anemia, damage to veins and tissue at injection, decrease platelet and WBC count, toxic to heart. Treats Kaposi’s sarcoma lesions or cancer tumors Modifications of liposome - keeps doxorubin in blood for 50 hours instead of 20 minutes -concentrates at KS lesions and tumors 39


FORMULATION Amphotericin B Systemic fungal infections in immune compromised patients AmB - kills ergosterol-containing fungal cells, also kills cholesterol-containing human cells Side effects: nephrotoxicity, chills, and fevers 40

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Mechanism of liposome action: Diffusion Lipid transfer -It decrease in toxicity -No decrease in effectiveness of drug against fungi AmB Lipid 41

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Liposomal drug preparations Type of Agents Examples Anticancer Drugs Anti bacterial Antiviral DNA material Enzymes Fungicides Vaccines Duanorubicin, Doxorubicin, Epirubicin Methotrexate, Cisplatin, Cytarabin Triclosan, Clindamycin hydrochloride, Ampicillin, peperacillin, rifamicin AZT cDNA - CFTR Hexosaminidase A Glucocerebrosidase, Peroxidase Amphotericin B Malaria merozoite, Malaria sporozoite Hepatitis B antigen, Rabies virus glycoprotein 42


APPLICATION OF LIPOSOME Liposome as drug/protein vehicle Liposome used in tumor therapy. Used in dermatology and Cosmetology Used in antimicrobial,antiviral,antifungal therapy. Used in gene therapy As a radiopharmaceutical and radiodiagnostic carrier As a red cell substituent and artificial RBCs Chelation therapy for treatment of heavy metal poisoning Enzyme immobilization. 43 -Controlled sustain drug release -Altered pharmacokinetics -Enzyme replacement therapy


RECENT TRENDS Now a days Liposome several novel application for drug delivery mainly in anticancer , antifungal, antibiotics, and also in other categories of drugs Liposome for carcinoma targeting lactoferrin to treat hepatic cancer. Docetaxel loaded liposome prepared by solvent injection method to enhance treatment of brain tumor. Polycation liposome developed as a novel gene tranfection vector to overcome barriers and achieve high transfection efficiency. 44


REFERENCES: Kellaway I.W. and Farr S.J. Liposomal drug delivery, Advanced Drug Delivery Reviews, 5 (1990) 149-161 Vays S.P. and Khar R.K., Targated and Controlled drug delivery Novel carrier system, I st eds., CBS publisher and distributor, New Delhi. Jain N.K., Controlled and novel drug delivery, 3 rd Eds. CBS publisher and distributors, New Delhi. Vemuri S., Rhodes C.T., Preparation and characterization of liposomes as therapeutic delivery systems: a review, Pharmaceutics Acta Helvetiae 70 (1995) 95-111 45

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