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NAME: V.SPANDANA
REGISTRATION NUMBER: 133H1S1103
BRANCH: PHARMACEUTICAL TECHNOLOGY
COLLEGE: SRI SAI ADITYA INSTITUTE OF PHARMACEUTICAL
SCIENCES & RESEARCH
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INTRODUCTION
MECHANISM OF LIPOSOME FORMATION
TYPES OF PHOSPHOLIPIDS
CLASSIFICATION
BIOLOGICAL FATE OF LIPOSOMES
ADVANTAGES & DISADVANTAGES
METHODS OF PREPARATION
CHARACTERIZATION OF LIPOSOMES
STABILITY OF LIPOSOMES
LIPOSOMAL PHARMACOKINETICS
APPLICATIONS
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Liposomes were discovered by Bhangam and co-workers in
1960’s.
Liposomes are simple microscopic , concentric bi-layered vesicles
in which an aqueous volume is entirely enclosed by a
membranous lipid bi-layer mainly composed of phospholipids
and cholesterol.
The exact location of the drug in the liposome depends up on the
physicochemical characterization of the drug and the composition
of the lipid content.
Stable liposomes from phospholipids are formed only as
temperature above the “gel to liquid crystalline” phase transition
temperature (Tc)
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Vesicles are formed by hydrophobic effect.
Ratio of hydrophilic and hydrophobic moieties.
Critical packing parameter (CPP)
If CPP value is less than 0.5 then liposomes are formed by
hydrophobic effect.
If CPP value is more than 0.5 then liposomes are formed by
hydrophilic effect.
If CPP value is between 0.5 – 1 then liposomes are formed by
surfactant effect.
CPP = v / lc Ap = Ahp / Ap
Where:
v = hydrophobic group volume
lc = hydrophobic group length
AP = cross sectional area of hydrophilic head group
Ahp = cross sectional area of hydrophobic head group
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The phospholipids used in liposomes are
Phosphotidyl choline
Phosphotidyl ethanolamine
Phosphotidyl serine
Phosphotidyl glycerol
Cholesterol alone cannot form liposome but with lipids it
intercalates i.e., Hydroxyl group aligns towards water surface and
aliphatic chain parallel to acyl chains in the center of bi-layer.
Widely used polar phospholipids is phosphotidyl choline which is
used alone and in combination with cholesterol.
Cholesterol condenses the packing of phospholipids in bi-layer
above the phase transition temperature
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BASED ON STRUCTURE :
Multi-lamellar large vesicles (>0.5 µm) MLV
Oligo-lamellar vesicles (0.1 – 1µm) OLV
Uni-lamellar vesicles ( All size ranges) UV
Small uni-lamellar vesicles (20 – 100 nm) SUV
Medium size uni-lamellar vesicles (>100 nm) MUV
Large uni-lamellar vesicles (>100 nm) LUV
Giant uni-lamellar vesicles (>1 µm) GUV
Multi-vesicular vesicles (>1 µm) MV
BAESD ON LIPOSOMAL FORMATION:
Reverse phase evaporation REV
Multi-lamellar vesicle by REV MLV-REV
Stable plurilamellar vesicle SPLV
Frozen and thawed MLV FATLV
Vesicles prepared by extrusion techniques VET
Dried reconstituted vesicles DRV
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Liposomes in blood stream taken up by reticulo- endothelial
system.
The macrophages engulf the liposomes which are taken by the
reticulo-endothelial system (endocytosis).
Then phagosome and lysosome combine and form as a
phagolysosome.
The membrane of phagolysosome have proton pumps which
decrease the pH of phagolysosome and the enzyme phospholipase
destruct the liposomal membrane and releases the drug from
destructed liposome.
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ADVANTAGES:
Biocompatibility and Biodegradability.
Easy manufacture.
Targeted drug delivery
Prolonged circulation in stealth mode
Able to protect encapsulated drug from degradation.
DISADVANTAGES:
Poor stability
High manufacturing cost
Poor loading capacity
Challenging sterilization
Poor reproducibility
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Liposomes are prepared by two methods. They are:-
Passive Loading Technique
Active Loading Technique
PASSIVE LOADING TECHNIQUE:
The passive loading technique again subdivided into 3methods.
Mechanical Dispersion Method
Lipid Film Hydration
• Hand Shaking
• Non Hand Shaking
• Freeze Drying
Microemulsion
Sonication
French Pressure cell
Membrane Extrusion
Dried reconstituted Vesicles
Freeze Thawed Liposomes
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SOLVENT DISPERSION METHODS
Ethanol injection
Ether injection
Double Emulsion Vesicles
Reverse Phase Evaporation
Stable Plurilamellar Vesicles
DETERGENT REMOVAL METHODS
Detergent ( cholate,alkyl glycoside) removal from micelles by
dialysis
Column Chromatography
Dilution
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Visual appearance
Vesicle shape and lamellarity (No.of bi-layers):
• Sample + 31p NMR + Manganese ( affect signal intensity)
• If intensity is decreased by 50% it forms unilamellar vesicles.
• If intensity is decreased by more intensity Multilamellar vesicles
are formed.
• Freeze fracture electron microscopy
• Optical microscopy
Vesicle size
• Light microscopy
• Fluorescent microscopy
• Electron microscopy :SEM,TEM
• Laser light scattering
• Gel permeation
• Ultracentrifugation
• Optical microscopy
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Liposome stability : Determined by physical , biological and
chemical methods.
Surface charge : Determined by Electrophoresis(Zeta potential)
Drug release : Dissolution
Entrapped volume : (water content is determined)
• Water is replaced with deuterium oxide & is analyzed by NMR.
Encapsulation efficiency :
Protamine aggregation method :
• Liposome + protamine = precipitation
• Centrifuge(2000 rpm), remove supernatant
• Liposome pellet + Trixon x-100 (surface breaker)
• The encapsulation efficiency can be determined (Analytically)
Mini column centrifugation
Chemical characterization
• Quantitative determination of phospholipids
• Phospholipid hydrolysis
• Phospholipid oxidation
• Cholesterol analysis
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Phospholipid determination: (Bartlett assay)
• Phospholipid phosphorus + Hydrolysis = Inorganic phosphate
• Inorganic phosphate + ammonium molybdate = Phosphomolybdic
acid
• Phosphomolybdic acid + Amino naphthyl sulfonic acid = reduced
to blue color whose intensity is measured and compared with
standard
Phospholipid Hydrolysis:
• Phospholipids + Hydrolysis = Lysolecithin
• One chain is lost by deesterification
• Determined by HPLC
Phospholipid oxidation:
• Free radical determination by UV, Iodometric method, GLC etc.
Cholesterol analysis:
• Cholesterol + Iron + Reagent ( Ferric perchlorate, ethyl acetate
sulfuric acid = purple complex , which is determined at 610 nm).
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Liposomes stability can be done in two ways.
• In vitro stability
• In vivo stability
IN VITRO STABILITY:
Liposomes are not thermodynamically stable but they represents a
metastable state.
Liposomal vesicles possess excess energy.
Phospholipids are prone to oxidation and hydrolysis leads to their
degradation.
The method of preparation, nature of amphipile and the
encapsulated drug effects membrane fluidity/rigidity and
permeability characteristics.
Drug leakage from aqueous domains of lipid bilayers i.e.,
Hydrophilic drugs.
Physicochemical and bio environmental stimuli.
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IN VIVO STABILITY:
Rapid RES uptake fast biodegradation.
Gastric stability for orally administered liposomes
LIPOSOMAL PHAMACOKINETICS:
Protection of drug from metabolism and inactivation in plasma.
Decreased volume of distribution and hence decrease in non
specific localization of drug.
High therapeutic index.
Decreased amount and type of non specific toxicity.
Increase in concentration of drug at target site.
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Formulation of antineoplastic drugs into liposomes will
significantly enhances systemic circulation time.
Decreased toxicity by reducing free drug levels in plasma.
Increased EPR (Enhanced permeability &retention effect).
Decreased cardio-toxicity of Doxorubicin by liposomal
encapsulation.
Positively charged liposomes have enhanced immunogenic
properties for vaccines and hypersensitivity responses.
PEGylated liposomes are recent advancement in brain targeted
drug delivery systems.
Liposomes used as drug carriers for efficient treatment of neuronal
inflammation (Methyl prednisolone) & others exhibited superior
anti inflammatory activity than
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BRAND NAME DRUG CATEGORY ROUTE
Doxil Doxorubicin Anticancer Intravenous
Daunoxome Daunorubicin Anticancer Intravenous
Epaxel Hepatitis A
vaccine
Protection against
Hepatitis
Subcutaneous
Elamax Lidocaine Local anesthetic Topical
Mikasome Amikacine Antibacterial Intravenous
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DRUGS CATEGORY ROUTE OF
ADMINISTRATION
Oleonolic acid Anticancer Oral
Midazolam Sedative Oral
Diclofenac sodium Arthritis Topical
Cytarabine Anticancer Parentral
Insulin Diabetes Mellitus Pulmonary
Acyclovir Genital Herpes Vaginal
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Liposomes are extremely useful drug carrier systems , additives
and tools in various scientific domains.
Specially for drug delivery and targeting in pharmaceutical fields.
The use of liposomes in delivery of drugs and genes to tumour
sites are more promising and may serve as a major area for focus
of future research.
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www.slideshare.com
www.authorstream.com
Targetted & controlled Drug delivery Novel carrier systems
- S.P.Vyas
- R.K.Khar
Novel drug delivery systems by N.K.Jain
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