l iposomes :a n ovel drug delivery system 1. i ntroduction liposomes were discovered in the early...
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LIPOSOMES :A NOVEL DRUG DELIVERY SYSTEM
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INTRODUCTION
Liposomes were discovered in the early 1960’s by British Haemalogist Dr. A.D.Bangham.
Subsequently studied as cell membrane models.
The particle size of liposomes ranges from 20nm to10μm in diameter.
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LIPOSOMESLiposomes are simple microscopic vesicle in which an
aqueous volume is entirely enclosed by membrane composed of a lipid molecules.
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WHY USE LIPOSOMES IN DRUG DELIVERY SYSTEM
Pharmacokinetics:- Efficacy & toxicity.1. Changes the Absorbance & Bio-distribution.2. Deliver drug in desired form.3. Multidrug resistance.
Protection:-1. Decreases harmful side effects.2. Change where drug accumulates in the body.3. Protects drug.
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WHY USE LIPOSOMES IN DRUG DELIVERY SYSTEMRelease:-1. Affect the time in which the drug is released. 2. Prolong time- Increases duration of action &
Decreases administration interval period of time.
Dependent on drug & liposome properties:-1. Liposomes composition, pH, osmotic gradient &
environment.
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MODES OF LIPOSOME/CELL INTERACTION
Adsorption Endocytosis
Fusion Lipid transfer
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LIPOSOMES HELPS TO IMPROVE……
Therapeutic Index.Rapid metabolismUnfavorable Pharmacokinetics.Low solubility.Lack of stability. Irritation.
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ADVANTAGESTargeting drug delivery or site specific drug delivery. Increased efficacy and therapeutic index. Increased stability via encapsulation.Reduction in toxicity of the encapsulated agents.Site avoidance effect. Improved pharmacokinetic effects .Administered by various routes.Can act as reservoir for drug.
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DISADVANTAGESProduction cost is high Leakage and fusion of encapsulated drug /
molecules. Sometimes phospholipid undergoes reaction like
oxidation and hydrolysis Short half-life Low solubility Lower stables.Allergic reactions may occur due to liposomal
constituents
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COMPOSITION OF LIPOSOMES
The main components of liposomes are:
1) Phospholipids
2) Cholesterol
3) Sphingolipids
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PHOSPHOLIPIDS Phospholipids are the major structural
components of biological membranes such as the cell membrane.
Natural Synthetic
Phospholipids
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GENERALLY PHOSPHOLIPIDS ARE REPRESENTED AS FOLLOWS,
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MECHANISM OF PHOSPHOLIPIDS:
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CHOLESTEROLCholesterol by it self does not form a bilayer.
However, cholesterol acts as a fluidity buffer. i.e. below the phase transition temperature, it makes the membrane less ordered & slightly more permeable, while above the phase transition temperature, it makes the membrane more ordered & stable.
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SPHINGOLIPIDSBackbone sphingolipid is sphingosine or related
base.
This contains 3 characteristic building blocks…1. A mol of fatty acid2. A mol of sphingosine3. A head group that can vary from simple alcohols
such as choline to very complex carbohydrates.
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PHYSICAL CHARACTERIZATION OF LIPOSOME
Sr. no.
Characterization parameters
Analytical method/Instrument
1. Vesicle shape and surface morphology
Transmission electron microscopy,
Freeze-fracture electron microscopy
2. Vesicle size and size distribution
Dynamic light scattering, zeta sizer, laser light scattering
3. Surface charge Free-flow electrophoresis
4. Electrical surface potential and surface pH
Zeta-potential measurements & pH sensitive probes
5. Drug release Diffusion cell/ dialysis
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CHEMICAL CHARACTERIZATIONSr. No
Characterization parameters
Analytical method/Instrument
1… Phospholipid concentration
HPLC
2. Cholesterol concentration Cholesterol oxidase assay and HPLC
3. Phopholipid peroxidation UV absorbance, Iodometric and GLC
4. Phospholipid hydrolysis, Cholesterol auto-oxidation.
HPLC and TLC
5. Osmolarity Osmometer
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BIOLOGICAL CHARACTERIZATION
Sr. No
Characterization parameters
Analytical method/Instrument
1. Sterility Aerobic or anaerobic cultures
2. Pyrogenicity Limulus Amebocyte Lysate (LAL) test
3. Animal toxicity Monitoring survival rates, histology and pathology
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CLASSIFICATION OF LIPOSOMES
Liposomes are classified on the basis of….1. Structural parameters. 2. Method of preparation.3. Composition and application.4. Conventional liposome.
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Based on structural parameter
MLVMultilamellar vesicle(>0.5u
m)
OLVOligolamellar vesicle(0.1-
1um)
UVUnilamellar vesicle(all
size ranges)
MUVMediam
unilamellar vesicle
SUVSmall unilamellar vesicle
GUVGiant unilamllar vesicle
LUVLarge unilamellar vesicle
MVV/MVMultivesicula
r vesicle(>1um)
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Based on Method of
Preparation
REV SUVs/OLVs
Reveres-Phase
Evaporation Method
MLV-REVMLV’s made by Reverse
Phase Evaporation
Method
SPLV Stable
Plurilamellar Vesicle
FAT-MLVFrozen and
Thawed MLVs
VETVesicle
Prepared by Extrusion Technique
DRVDehydrated - Rehydration
Method
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Based on composition & application
pH Sensitive Liposome
Immuno-Liposome
Long Circulatory Liposome
(LCL)
Convention-al Liposome
Fusogenic Liposome
Cationic Liposome
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Based on Conventi
onal Liposom
e
Stabilize Natural
lacithin (PC) Mixture
Synthetic Identical
chain Phospholipi
d
Glycolipid containing Liposome
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PREPARATION OF LIPOSOMESMethod of Liposome Preparation
Passive LoadingInvolves loading of
entrapped agent before or during the mfg procedure
Active or remote Loading:Certain types of compounds with ionized groups & those
with both lipid & water solubility, can be introduced into the liposomes after the
formation of the intact vesicle
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Method of preparation of Liposomes
Passive Loading Techniques Active Loading Techniques
Mechanical Dispersion Methods
Solvent Dispersion Methods
Detergent Removal Methods
•Lipid Film Hydration•Micro Emulsification• Sonication Methods•French Pressure cell•Membrane Extrusion•Dried reconstituted vesicles•Freeze thawed Liposome
•Ethanol Injection•Ether Injection•Double Emulsion Vesicles•Reverse Phase Evaporation Vesicles•Stable Plurilamellar Vesicles
•Detergent•Dialysis•Column Chromatography•Dilution•Reconstituted Sendal Virus Enveloped Vesicles
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GENERAL METHOD OF PREPARATION OF LIPOSOMEAll the methods of preparing liposomes involve 3-4
basic steps:
Drying down lipids from organic solvent
Dispersion of lipid in aqueous medium
Purification of resultant Liposomes
Analysis of final product
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Cholesterol Lacithin Charge
Solution in Organic Solvent
Thin Film
Liposome Suspension
Drying
Dispersion (Hydration)
Fig: Common Stages of all the Method of Preparation of Liposomes
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HANDLING OF LIPOSOMES
Unsaturated lipids:- Susceptible to oxidation.
Volatile solvents:- Tend to evaporate from the container, such as chloroform.
Store:- In an inert atmosphere of nitrogen & in dark place, in glass vessels.
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1) METHOD OF PHYSICAL DISPERSION/ MECHANICAL DISPERSION: Basic methods of physical dispersion… 1. Hand-Shaken Multilamellar Vesicles2. Non-Shaking Vesicles3. Pro-liposomes4. Freeze Drying
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HAND SHAKEN METHOD IN GENERAL
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NON-HAND SHAKING METHOD: Method described by:- Reeves & Dowben in 1969 for
LUVs.
Lipid
Chloroform:Methanol
Agitation
Stream of Nitrogen
Spread over bottom of
flaskEvaporate at room temp.
Flow Through Nitrogen
Passed Through
Saturated Nitrogen
Hydration
(Drying)
LUVs liposomes
Swelling Milky suspension
2hrs at 37⁰C
+
Add bulk fluid
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PRO-LIPOSOMES:Method increases surface of the dry lipid (at low
aqueous volume). s
Lipid +
Chloroform
Powdered sorbitol,
NaCl,
Swelling Lipid
Pro-Liposome
Transfer to flask
Evaporation
50-55⁰C
Add 5ml lipid
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FREEZE DRYING:
The solvent choice depend on the freezing point drug which is to be entrapped.
Finely divided lipid
Freeze dried lipid
Organic solvent
Aqueoussolvent Dissolve in
With rapid mixing above phase
transition temp.
Add water or saline
MLVs liposomes
Milky suspension
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PROCESSING OF HYDRATED LIPID BY PHYSICAL METHOD OR MECHANICAL METHOD:
Sonicated unilamellar vesicles (SUVs).French Pressure cell method.Membrane Extrusion method.Dried-reconstitution vesicles (DRVs).Freeze and thawed technique ((FAT).pH Induced Vesiculation.Calcium induced Fusion.
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SONICATED UNILAMELLAR VESICLES (SUVS):
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FRENCH PRESSURE CELL LIPOSOMES:
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MEMBRANE EXTRUSION LIPOSOMES:
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DRIED RECONSTITUTED VESICLES (DRVS) & FREEZE THAW SONICATION (FTS):
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PH INDUCED VESICULATION:
In this method ULVs is prepared from MLVs without sonication or high pressure application.
It is an electrostatic phenomenon.Exposure of phospholipid to high pH is less than 2
mins.
Dry film Minimum quantity of
water
Material added to be entrapped
HydrationLiposomes15⁰C
NaCL
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2) SOLVENT DISPERSION METHOD:
Methods depends on one of three categories….1. Organic solvent miscible with aqueous phase.
E.g - Ethanol.2. Organic solvent immiscible with aqueous phase, the
latter being in large excess.3. Organic solvent is in large excess & again with
immiscible aqueous phase
Lipid
Organic solvent
+Aqueous phase
containing materialLiposome
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ETHANOL/ETHER INJECTION METHOD:
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DOUBLE EMULSION VESICLES:The outer portion of the liposome membrane is
created at a second interface between two phases by emulsification of an organic solution in water.
Also described as W/O/W system or double emulsion.
These vesicles are suspended in aqueous medium.
Organic solvent
Water droplets
Multi-compartment
vesicle+
Mechanical
Dispersion
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REVERSE PHASE EVAPORATION METHOD:
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STABLE PLURILAMELLA VESICLES (SPVS) (SONICATION METHOD):
In this method, drying in accompanied by continued bath sonication with the stream of nitrogen.
The internal structure of SPVs is different from MUV.
The percent entrapment is normally 60%.
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Their shape and size depend upon chemical nature of detergent, the concentration & other lipids involved.
The concentration of detergent in water at which micelles just start to form is known as critical micelle concentration (CMC).
3) DETERGENT REMOVAL METHOD:
Phospholipid
Aqueous Phase
Micelles+Detergents
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REMOTE OR ACTIVE LOADINGLipid bilayer membrane is impermeable to ions or
large hydrophilic molecules.
Advantages:1. Provides high encapsulation efficiency & capacity.2. Reduce leakage of encapsulated compounds.
Weak bases such as…3. Doxorubacin4. Vincristine5. Modified peptides & insulin
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PHARMACEUTICAL APPLICATIONS 1. Cell -liposome interaction2. Localized drug effect3. Enhanced drug uptake4. Flexibility in structural characteristics 5. Enzyme Replacement.6. Diagnostic imaging of tumors.7. Study of membranes.8. Targeted gene delivery to specific cells.9. Ligand mediated targeted drug delivery by long
circulating liposomes.
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MEDICAL APPLICATION OF LIPOSOMES:
AIDS Therapy Malaria Therapy Infectious Diseases Dermatology Heavy metal poisoning
(chelation therapy).
Cancer Therapy Lung therapyCosmetology Radiodiagnostic Carriers
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MARKETED PREPARATION: Product Drug Uses
Doxil Doxorubicin Brest & ovarian cancer
Marqiobo Vincristine Cancer
Arikace Amikacin Bacterial Infection
Amphotec Amphotericin B Fungal Infection
Lipoplastin Cisplastin Lung, head ,neck Ovarian Cancer
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REFERENCES: D.M.Bramhankar & Sunil B. Jaiswal Biopharmaceutics &
Pharmacokinetics(First edition 2005) pg.no- 360-361
International Journal of Pharmaceutical Studies and Research.
S.P. Vyas and R.K. Khar “Target and Oontrolled Drug Delivery - Novel Carrier Systems”.
Sanjay K. Jain & N. K. Jain “Controlled and Novel Drug Delivery Systems”
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