Vesicular drug delivery system

B.K.Mody Government Pharmacy College,Rajkot. 1
Vesicular Drug Delivery System

• Introduction :
• Vesicles are colloidal particles in which a concentric bilayer
made-up of amphiphilic molecules surrounds an aqueous
compartment.
• Useful vehicle for drug delivery of both hydrophobic drugs,
which associate with the lipid bilayer and hydrophilic drugs,
which are encapsulated in the interior aqueous compartment.
• In general, vesicles made of natural or synthetic phospholipids
are called liposomes whereas those made of nonionic
surfactants (e.g. alkyl ethers and alkyl esters) and cholesterol
constitute a nonionic surfactant vesicular system called
niosomes.

• Vesicular system includes…
.
• LIPOSOME
.
• NIOSOME
.
• PHARMACOSOMES
.
• ETHOSOMES
.
• TRANSFEROSOMES
.
• ENZYMOSOMES

.
• VIROSOMES
.
• EMULSOMES
.
• AQUASOMES
.
• BILOSOMES
.
• SPHINGOSOMES

First described by British haematologist Dr. Alec D
Bangham in 1961 (published 1964) .
Name liposome is derived from two Greek words
- 'Lipid' means fat and 'Soma' means body.
Size of liposomes ranges from 20 nm to 10 μm.
Liposomes are a form of vesicles that consist either of many,
few or just one phospholipid bilayers.

Bangham et al.,1965 : Simple microscopic vesicles in
which an aqueous volume is entirely enclosed by a
membrane composed of lipid molecule.
Weiner N. et al.,1989 : As a microstructure consisting
of one or more concentric spheres of lipid bilayer
separated by water or aqueous buffer compartments.
• DEFINITION :

• ADVANTAGES OF LIPOSOMES :
• Biocompatible ,biodegradable, non-toxic, flexible and
nonimmunogenic for systemic and non-systemic administrations.
• Suitable for delivery of hydrophobic and hydrophilic drugs and
agents.
• Protection of encapsulated drug from the external environment and
act as sustained release depots (Propranolol, Cyclosporin).
• Provides selective passive targeting to tumor tissues ( liposomal
doxorubicin)

• Could encapsulate not only small molecules but also
macromolecules like superoxide dismutase, haemoglobin,
erythropoietin, interleukin-2 and interferon.
• Reduced toxicity and increased stability of entrapped drug via
encapsulation. (Amphotericin B).
• Liposomes help to reduce exposure of sensitive tissues to toxic
drugs.
• Flexibility to couple with site-specific ligands to achieve active
targeting (Anticancer and Antimicrobial drugs).

• Can be formulated as a suspension/aerosol/semisolid
form(gel, cream and lotion).
• Can be administered through most routes of
administration including ocular, pulmonary, nasal, oral,
intramuscular, subcutaneous, topical and intravenous.
• Alter the pharmacokinetic property of drugs (reduced
elimination, increased circulation life time).

• DISADVANTAGES OF LIPOSOMES :
Production cost is high.
Leakage and fusion of encapsulated drug / molecules
Phospholipid undergoes oxidation and hydrolysis
like reaction.
Short half-life, Low solubility.

• FORMULATION/STRUCTURAL ASPECT :
• Composed of mainly 2 components
 Cholesterol
 Phospholipids
1. CHOLESTEROL :
• Not form bilayer structure
• Can be incorporated in very high concentration upto 1:1 or even
2:1 molar ratios of cholesterol to PC.
• It acts as a fluidity buffer
 Below phase transition temp. :it makes the membrane less ordered
and slightly more permeable
 Above phase transition temp. :It makes the membrane more
ordered and stable

2. PHOSPHOLIPIDS :
• Major components of biological membranes
• 2 types of phospholipids exist – phosphoglycerides and
sphingolipids, together with their corresponding hydrolysis
products.
• Common PL is phosphotidylcholine (PC).
• PC is an amphipathic molecule in which
a glycerol bridge links a pair of
hydrophobic acyl hydrocarbon chains,
with a hydrophilic polar headgroup,
phosphor choline.

• PC molecule are not soluble in water and aqueous media,they
align themselves closely in planar bilayer sheets in order to
minimize the unfavourable action between the bulk aqueous
phase and the long hydrocarbon fatty chain.
• Such unfavorable interactions are completely eliminated when
the sheets fold on themselves to form closed sealed vesicles.
• Phosphatidylcholine (PC) is routinely used as a bulk neutral
phospholipid .

• Finally , if it is desirable to reduce the permeability of “fluid
crystalline state” bilayers, cholesterol is added to bilayer
structure.
• Sometimes lipids with a special affinity for certain target
cells in the body are deliberately inserted in bilayer.
• Ex-when hepatocytic delivery was aimed for and
lactosylceramide, a ligand with a special affinity for
hepatocytes, was included in the liposomal bilayer.

• TYPES OF PHOSPHOLIPIDS :
PL from natural source
Modified natural PL
Semisynthetic PL
PL with non-natural head group
Fully synthetic PL

• TYPES OF LIPOSOME :
Based on
structural
parameters
ULV
SUV(20-
100nm)
MUV
LUV(>100
nm)
GUV(>1µ
m)
OLV(0.1-
1µm)
MLV(>0.5
µm)
MVV(>1µ
m)

Based on
method of
preparation
VET
Vesicle prepare
by extrusion
DRV
Dehydration-
rehydration
method
FATMLV
Frozen and
thawed MLVs
SPLV
Stable
plurilamellar
vesicles
REV
SUV/OLV prepare
by reverse phase
evaporation
MLV-REV

Based on
composition and
application
Conventional
liposome
Fusogenic
liposome
pH-sensitive
liposome
Cationic liposome
Long
circulatory(stealth)
liposome
Immunoliposome

• Preparation of liposomes :

 General methods of preparation of liposomes :
• Drying down lipids from organic solvent,
• Dispersion of lipids in aqueous media,
• Purification of resultant liposomes,
• Analysis of final product.
Cholesterol + Lecithin + Charge
Dissolve in organic solvent
Drying of solution(thin film)
Dispersion/hydration of thin film
Liposomal suspension

• Mechanical dispersion methods for passive loading:
• Lipid hydration method :
• Sonication method :

• Microfluidization / Microemulsification method :
Microfluidizer pumps fluid at very high pressure through a 5μm
screen. Then forced along defined micro channels which direct two
streams of fluid to collide together at right angles at a very high
velocity, thereby effecting a very efficient transfer of energy.
 The lipid can be introduced into the fluidizer, either as a suspension
of large MLVs, or as a slurry of unhydrated lipid in a organic
medium. The fluid collected can be recycled through the pump and
interaction chamber until vesicles of the spherical dimension are
obtained.
 Advantages:
Excellent size reduction up to 0.2mm
High rate of production

• French pressure cell method :
• Liquid sample of preformed MLVs are introduced into the
sample cavity, then the position of piston and pressure is set up
to fill sample upto the outlet hole.
• At high pressure (2000 psi) and at 40ºC, MLVs are extruded
through small orifice, which is collected in suitable container.
• This technique yields uni- or oligo lamellar liposome of
intermediate size. More stable than they obtained by sonication
method and also leakage of the content from the liposomes are
lesser.
• Drawback: High cost.

• Membrane extrusion method :
• Size of prepared liposomes is reduced by gentley passing
them through membrane filter of defined pore size and this
can be achieved at much lower pressure.
• In this process,vesicles content are extruded with the
dispersion medium during breaking and resealing of
phospholipids as they pass through the polycarbonate
membrane in order to achieve high entrapment.
• Liposomes produced by this method termed as LUVETs and
30% encapsulation can be obtained using high lipid
concentration.

• Dried reconstituted vesicles :
• For mfg. of uni/oligo lamellar (1.0μm D or less).
• Advantages: high entrapment of water soluble content
• Use of mild condition for preparation & loading of bioactive.

• Freeze thaw sonication method :
• Freezing of unilamellar dispersion and thawing (melting) by
standing at RT for 15 min. and finally subjected to a sonication
cycle.
• This process ruptures and refuses SUVs during which the solute
equilibrates between inside and outside, and liposomes
themselves fuse and markedly increase in size.
• The second step of the sonication considerably reduces the
permeability of the liposome membrane, by accelerating the
rate at which the packing defects are eliminated.
• To produce giant vesicles (10 – 50 μm),sonication step is
replaced by dialysis against hypo-osmolar buffer.

• In this case, SUVs are mixed with salt solution followed
by freeze thawing. During this dialysis, the large vesicles
formed by freeze thawing swell and rupture as a result of
the osmotic lysis, where they fuse and prepare as giant
vesicles.
• Disadvantage:
 Lesser encapsulation efficiency
• Advantage:
 Simple, rapid, result in proportion of large unilamellar
vesicles formation.

• Solvent dispersion method:
Ethanol injection method :
• Disadvantage :
• Method is restricted to the production of relatively dilute SUVs
suspension. Removal of residual ethanol is also present a
problem(can be done by ultrafiltration or vacuum distillation).

• Ether infusion method :
• Drawbacks: Heterogeneous size (70 - 190μm), exposure of
compounds to organic solvents or high temperature.
• Stable plurilamellar vesicles :
• w/o dispersion is prepared as described in REV method with
excess lipid, but drying process is accompanied by continued
bath sonication with a stream of nitrogen. The redistribution and
equilibration of aqueous solvent and solute occur during this
time in between the various bilayer in each plurilamellar vesicle.
• Entrapment percentage: 30%.

• Double emulsion vesicles :
• When organic solution which already contain water droplet, is
introduced into excess aqueous phase followed by mechanical
dispersion, multi compartment vesicles are obtained.
• The ordered dispersion so obtained is desirable as a w/o/w
system. The vesicles with aqueous core are suspended in aqueous
medium. So two aqueous compartments being separated from
each other by pair of phospholipids monolayer whose
hydrophobic surface face each other across a thin film of organic
solvent.
• Removal of this solvent clearly results in intermediate sized
unilamellar vesicle. The theoretical entrapment may reach up to
90%.

• Reversed phase evaporation vesicles :
• Encapsulation percentage: upto 50%

• Detergent solubilization for passive loading:-
• PL are brought into intimate contact with the aqueous phase via the
intermediary of detergents, which associate with phospholipid
molecules and serve to screen the hydrophobic portions of the
molecule from water.
• Detergents can be depleted from a mixed detergent-lipid micelles by
various techniques which leads to the formation of very homogeneous
liposomes.
1. Dialysis
2. Adsorption using bio beads
3. Gel filtration
• The most popular detergent is sodium cholate, alkyl(thio)glucoside,
and alkyloxypolyethylenes.
• The use of different detergents results in different ratios of large
unilamellar vesicles/ oligolamellar vesicles/multilamellar vesicles.

• ACTIVE (REMOTE) LOADING TECHNIQUE:
• Certain types of drugs with ionisable groups and those with both
lipid and water solubility can be introduced into liposomes after
the formation of the intact vesicles.
• Remote loading method loads the drug molecules into preformed
liposomes using pH gradients and potential difference across the
membrane of liposomes can drive the loading of amphipathic
molecules.
• The membrane from lipid bilayer is in general impermeable to
ions and larger hydrophilic molecules. Ions transport can be
regulated by the ionophores while permeation of neutral and
weakly hydrophobic molecules can be controlled by
concentration gradients.

• Characterisation of liposome :

• OccularApplication :
• Eye protection by three highly efficient mechanisms
(a) an epithelial layer
(b) tear flow
(c) the blinking reflex.
• This mechanisms are responsible for poor drug penetration into
deeper layers of cornea and aqueous humour and for the rapid wash
out of drugs from the corneal surface.
• Enhanced efficacy of liposomes encapsulated idoxuridine in herpes
simplex infected corneal lesions in rabbits was first reported in 1981.
• Ganglioside‐containing liposomes and wheat germ agglutinin, a lectin
that has a high binding affinity for both cornea and ganglioside, were
tested for corneal adhesion.Corneal binding as well as accumulation
and transcorneal flux of carbachol was enhanced 2.5 to 3 fold over 90
min exposure times.

• PulmonaryApplication :
• Liposomes has been explored as a target selective alternative to
systemic administration of antiasthamatic and antiallergic
compounds and for antibiotics used against pulmonary infections.
• Liposomes are useful tools for pulmonary delivery of drugs due to
their solubilization capacity for poorly water soluble substances
rendering them more practical for aerolisation.
• Their biodegradability allows for prolonged pulmonary residence
times without danger of allergic or other side effects.
• The targeting capacity to infected or immunologically impaired
alveolar macrophages is a unique feature of liposomes.
• Padmanabhan et al demonstrated high enzyme activity and
prolonged tissue protection following pulmonary instillation of
liposome incorporated superoxide dismutase and catalase although
the mechanism responsible for the observed protection remained
obscure.

• Antimicrobial Therapy :
• Incorporation of rifabutin in liposomes resulted in a significant
enhancement of activity against Mycobacterium avium infection
compared to free rifabutin. Moreover, the antitubercular activity of
rifampin was considerably increased when encapsulated in egg
phosphatidylcholine liposomes.
• A further increase in the activity was observed when the macrophage
activator tetrapeptide tuftsin was grafted on the surface of drug‐loaded
liposomes. Rifampin delivered twice weekly for two weeks in
tuftsin‐bearing liposomes was at least 2,000 times more effective than
the free drug in lowering the load of lung bacilli in infected animals.
• Entrapment of ciprofloxacin in liposomes increases the circulation
half‐life of the drug when given by intravenous route in mice, which is
associated with enhanced delivery of the drug to the liver, spleen,
kidneys, and lungs.

• CancerTherapy :
• Cytotoxic drugs can distribute non‐specifically throughout the body,
lead to death of normal as well as malignant cells, thereby giving rise
to a variety of toxic side effects.
• Entrapment of these drugs into liposomes resulted in increased
circulation lifetime, enhanced deposition in the infected tissues,
protection from the drug metabolic degradation, altered tissue
distribution of the drug, with its enhanced uptake in organs rich in
mononuclear phagocytic cells (liver, spleen and bone marrow) and
decreased uptake in the kidney, myocardium and brain.

• Many research efforts have been directed towards improving the
safety profile of the anthracycline cytotoxics, doxorubicin (DXR)
and daunorubicin (DNR), along with vincristine (VCR), which are
associated with severe cardiotoxic side effects, although acute
gastrointestinal effects and other toxicities may also occur.
Liposomal entrapment of these drugs showed reduced
cardiotoxicity, dermal toxicity and better survival of experimental
animals compared to the controls receiving free drugs.
• DXR hydrochloride constitutes the first liposomal product
(DoxilTM) to be licensed in the United States.

• Surface grafted methoxypolyethylene glycol (MPEG) provides the
hydrophilic stealth coating, which allows the DoxilTM liposomes to
circulate in the blood stream for prolonged periods.
• The lipid matrix and an internal buffer system combine to keep
virtually all the DXR encapsulated during liposome residence in the
circulation. This means that the drug is not free to exert its toxic
effects.
• Liposome association alters the drug pharmacokinetics and thus the
liposome has a half‐life of approximately 55 hours in humans,
whereas the free drug distributes to the tissues within a few minutes
and is entirely cleared from circulation within 24 hours.

• Liposomes in Dermatology and Cosmetology :
• In the past, the beauty enhancements expected from cosmetic
products were obtained simply by combining the moisturizing,
bleaching, or cell generating agents with the cosmetic base. Now
cosmetic products have reached the stage where liposomes can
encapsulate active ingredients thought to be necessary for the skin so
they may be directly applied to the skin cells.
• The liposome wall is very similar, physiologically, to the material of
cell membranes. When cosmetic containing liposomes is applied to
the skin, it will deposited on the skin and begin to merge with the
cellular membranes.

• In the process, the liposomes release their payload of active
materials into the cells. As a consequence, not only is delivery of the
actives very specific directly into the intended cells but the delivery
takes place over a longer period of time.
• Today, most of the experts working in the field of liposomal
dispersions agree that liposomes do not penetrate as intact vesicles
into the skin or permeate through the skin. Liposomes are believed
to be deformed and transformed into fragments as a rule.
• The multifunctional properties of phosphatidylcholines lead to a
number of different applications.

• So, formulations with unsaturated phosphatidylcholine are
preferred to support skin regeneration, antiaging, acne preventing,
and penetrating other active agents like vitamins and their
derivatives into the skin.
• A patent involves a skin whitening lotion in which liposomes,
consisting of vitamin E and complex lipids are dispersed in alcohol
and water. The patent claims that vitamin E remains stable long
enough to exhibit reducing action.

• RecentAdvances :
Provesicles in drug delivery systems :
• To overcome the limitations (especially chemical and physical
stability) of vesicular drug delivery systems like liposomes,
niosomes.
• This includes-
1. Proliposomes :
• Proliposomes are the products which are mixed with water phase
containing drug before use, liposomes formed automatically and
load the drug.
2. Dry granular liposomes :
• Dry, free flowing granular product, which can be hydrated
immediately before use.
• Composed of water soluble porous powder coated with drug and
lipids.

• Dry granular type of liposomes has been studied for effective
delivery of various drugs like 5-fluorourasil, ibuprofen,
indomethacin, adriamycin, doxorubicin, glyburide, and
hydrocortisone
3. Mixed micellar proliposomes :
• Mixed micelles contain bile salts, cholesterol, and phospholipids,
which upon dilution, undergo micelles to vesicle transition to form
liposomes.
4. Lipopolyplexes :
• A combination of DNA, polymers and liposomes has been prepared
with a view to enhance transfection ability by utilization of their
individual properties.
• It has been reported that this method has resulted in better gene
transfer and lower toxicity as compare to cationic liposomes alone.

• Marketed liposome preparation :
• AmBisome® (Gilead Sciences / Fujisawa Healthcare)
• Amphotericin B
• Membrane intercalated
• DaunoXome® (Gilead Sciences)
• Daunorubicin
• Encapsulated
• DOXIL® (J&J ALZA)
• Doxorubicin
• Encapsulated
• Myocet® (Elan) [Approved in Europe]
• Doxorubicin
• Encapsulated

• Reference :
S.P.vyas,R.K.khar,targeted and controlled drug delivery novel carrier
systems,CBS publishers,pg.no.173
Priyanka r kulkarni*, jaydeep d yadav, kumar a vaidya, liposomes: a novel
drug delivery system, international journal of current pharmaceutical
research, vol 3, issue 2, 2011
 Sunil kamboj*, vipin saini, nancy magon, suman bala , vikas
jhawat,vesicular drug delivery systems: a novel approach for drug
targeting, international journal of drug delivery 5 (2013) 121-130
 Saurabh bansal, chandan prasad kashyap, geeta aggarwal and
harikumar,a comparative review on vesicular drug delivery system and
stability issues, international journal of research in pharmacy and
chemistry, 2012, 2(3)
 www.pharmainfo.com (Sanjay S. Patel, Liposomes: A versatile platform
for targeted delivery of drugs, volume 4. Issue 5, 2006)

• Study question:
• Discuss Sonication and French Pressure Cell (with the help of
diagram) in context to methods of preparation of liposomes. (may-
2012)
• Define Liposomes, classify them (based on structural parameters)
and discuss the applications of the same.(may-2012)
• Enlist materials used in preparation of liposomes. Discuss about
lipid characterization and control of liposomes.(jan-2011)
• Discuss the critical problems associated with Liposome’s drug
delivery system(may-2014)
• Describe methods for preparation of liposome.(nov-2012)

Thank
you…

Vesicular drug delivery system

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