Niosomes – An Overview
Dr. Rajesh Z. Mujariya*, Dr.
Avijit Muzumdar
CMJ College of Pharmacy, CMJ
University, Shillong, Meghalaya. India
ABSTRACT:
Non-ionic surfactant vesicles (or niosomes) are now widely studied as alternates to liposomes. An increasing number of non-ionic surfactant has
been found to form vesicles, capable of entrapping hydrophilic and hydrophobic
molecules. The drug disposition by niosomal drug
delivery proved that the drug accumulated in visceral organs (lung, kidney,
liver, spleen) was lower than free drug.
Niosomes are uni
or multilamellar vesicles formed from synthetic,
non-ionic surfactant of alkyl or dialkyl poly
glycerol ether class, offering an alternative to liposomes
as drug carriers. Niosomes can entrap solutes in a
manner analogous to liposomes, are relatively more stable in vitro and
can improve the stability of entrapped drug as compared with stability in
conventional dosage forms
KEYWORDS: Non-ionic surfactant, liposomes, visceral
organs, multilamellar vesicles, niosomes, entrapped
drug.
INTRODUCTION:
Niosomes are a novel drug delivery system, in
which the medication is encapsulated in a vesicle. The vesicle is composed of a
bilayer of non-ionic surface active agents and hence
the name niosomes. The niosomes
are very small, and microscopic in size. Their size lies in the nanometric scale. Although structurally similar to liposomes, they offer several advantages over them. Niosomes have recently been shown to greatly increase transdermal drug delivery and also can be used in targeted drug
delivery, and thus increased study in these structures can provide new methods
for drug delivery. Niosomes are formed mostly by cholesterol incorporation
as an excipient. Other excipients can also be used. Niosomes have more penetrating capability than the previous
preparations of emulsions. They are structurally similar to liposomes
in having a bilayer, however, the materials used to
prepare niosomes make them more stable and thus niosomes offer many more advantages over liposomes
Niosomes are microscopic lamellar structures,
which are formed on the admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class
and cholesterol with subsequent hydration in aqueous media.
Structurally, niosomes are similar
to liposomes, in that they are also made up of a bilayer. However, the bilayer in
the case of niosomes is made up of non-ionic surface
active agents rather than phospholipids as seen in the case of liposomes. Most surface active agents when immersed in water
yield micellar structures,
however some surfactants can yield bilayer vesicles
which are niosomes.
Niosomes may be unilamellar
or multilamellar depending on the method used to
prepare them. The niosome is made of a surfactant bilayer with its hydrophilic ends exposed on the outside
and inside of the vesicle, while the hydrophobic chains face each other within
the bilayer. Hence, the vesicle holds hydrophilic
drugs within the space enclosed in the vesicle, while hydrophobic drugs are
embedded within the bilayer itself. The figure 1 will
give a better idea of what a niosome looks like and
where the drug is located within the vesicle.
A typical niosome vesicle would
consist of a vesicle forming ampiphile i.e. a
non-ionic surfactant such as Span-60, which is usually stabilized by the
addition of cholesterol and a small amount of anionic surfactant such as diacetyl phosphate, which also helps in stabilizing the
vesicle
2) Comparison of Niosome V/S Liposome:
Niosomes are different from liposomes in that they offer certain advantages over liposomes. Liposomes face
problems such as –they are expensive, their ingredients like phospholipids are
chemically unstable because of their predisposition to oxidative degradation,
they require special storage and handling and purity of natural phospholipids
is variable. Niosomes do not have any of these
problems. Also since niosomes are made of uncharged
single-chain surfactant molecules as compared to the liposomes
which are made from neutral or charged double chained phospholipids, the
structure of niosomes is different from that of liposomes.
However Niosomes are similar to liposomes
in functionality. Niosomes also increase the
bioavailability of the drug and reduce the clearance like liposomes.
Niosomes can also be used for targeted drug delivery,
similar to liposomes. As with liposomes,
the properties of the niosomes depend both- on the
composition of the bilayer, and the method of
production used.
The
niosomes are classified as a function of the number
of bilayer (e.g. MLV, SUV) or as a function of size.
(e.g. LUV, SUV) or as a function of the method of
preparation (e.g. REV, DRV). The various types of niosomes
(Weiner et al., 1989) are described
below.
3.1) Multi lamellar vesicles (MLV)
3.2) Large unilamellar
vesicles (LUV)
3.3) Small unilamellar
vesicles (SUV)
3.1)
Multi lamellar vesicles (MLV):
It
consists of a number of bilayer surrounding the
aqueous lipid compartment separately. The approximate size of these vesicles is
0.5-10 µm diameter. Multilamellar vesicles are the
most widely used niosomes (Bangham
et al., in 1974). It is simple to
make and are mechanically stable upon storage for long periods. These vesicles
are highly suited as drug carrier for lipophilic
compounds.
3.2) Large unilamellar
vesicles (LUV):
Niosomes of
this type have a high aqueous/lipid compartment ratio, so that larger volumes
of bio-active materials can be entrapped with a very economical use of membrane
lipids.
These
provide a number of advantages as compared to multilamellar
vesicles, including high encapsulation of water-soluble drugs, economy of lipid
and reproducible drug release rates.
The
term ‘large unilamellar’ usually means any unilamellar structure larger than 100 µcm. Because of the
large size of the vesicles, a high percentage drug capture can be achieved. A
number of techniques are used for the preparation of large unilamellar
vesicles including freeze-thaw cycling (Shew and Deamer, 1985), Reverse phase evaporation method, ether
injection method and calcium induced fusion method.
3.3) Small unilamellar
vesicles (SUV):
These
small unilamellar vesicles are mostly prepared from multilamellar vesicles by sonication method, French press extrusion method or, homogenization method. The approximate
sizes of small unilamellar vesicles are 0.025-0.05
µcm diameter. They are thermodynamically unstable and are susceptible to
aggregation and fusion. Their entrapped volume is small and percentage
entrapment of aqueous solute is correspondingly low.
The
methodology for niosome preparation has been evolved
rapidly during the last few years as a response to prepare well defined niosomes for specific applications.
Bangosomes
popularly known as multilamellar vesicles are prepared as per the
method described by Bangham et al., 1974. In this method the lipids are dissolved in an organic
solvent in a round bottom flask. A thin lipid layer is formed on the inside
wall of the flask after removal of the organic solvent by rotatory
evaporation at reduced pressure.
Multilamellar
vesicles are formed spontaneously when an excess volume of aqueous buffer is
added to the dry lipid. After shaking (by hand or vortex mixer), it results in
formation of dispersion of multilamellar vesicles.
Duration and intensity of shaking, the presence of charge inducing agents in
the bilayer, ionic strength of the aqueous medium and
lipid concentration are the important parameters influencing the size and the
encapsulating efficiency of multilamellar vesicles.
The lipids formed are quite heterogeneous both in size and in the number of
lamella.
4.2.1) Sonication:
In
this method, the preparation of small lamellar vesicles has been reviewed by Bangham (Bangham et al., 1974). The usual multilamellar vesicles and large unilamellar
vesicles are sonicated either with a bath type sonicator or a probe sonicator,
under an inert atmosphere (usually nitrogen or argon) to get the small unilamellar vesicles. During sonication, the multilamellar vesicles are broken down and small unilamellar vesicles with high radius of curvatures are
formed.
4.2.2) French press method:
Dispersions
of MLV’s can be converted to small unilamellar
vesicles by passage through a small orifice under high pressure (Berenholz et al.,
1977). A French pressure cell was used by Hamilton and Guo
in 1984. Multilamellar vesicles dispersion is placed
in the French press and extruded at about 20000 psi at 4oC(Hamilton
and Guo, 1984): On passing through the cell, a
heterogeneous population of vesicles are formed ranging from several
micrometers in diameter to small unilamellar vesicles
size. Multiple extrusions results in a progressive decrease
in the mean particle diameter (30-80nm) depending
upon the pressure used. These niosomes are
more stable than sonicated ones and can be used
advantageously as drug delivery carriers.
4.2.3) Ethanol injection method:
An
alternative method for producing small niosomes that
avoids both sonication and high pressure is the ethanol injection method, first
described by Batzri and Korn
in 1973. In this method, the lipid is dissolved in ethanol and is rapidly injected into an excess of
buffer solution or other aqueous medium though a needle. The force of the
injection is usually sufficient to achieve complete mixing, so that the ethanol
is diluted almost instantaneously in water and the phospholipids molecules are
dispersed evenly throughout the medium.
This
procedure can yield a high proportion of small unilamellar
vesicles. This method has the advantage of extreme simplicity and a very low
risk of bringing about degradative changes in
sensitive lipids. Its major short comings are the limitation of solubility of
lipids in ethanol and the volume of ethanol that is introduced into the medium
(7.5% V/V maximum). The percentage of encapsulation is low if the materials (to
be entrapped) are dissolved in the aqueous phase. Another drawback is the
difficulty of removing ethanol from phospholipid
membrane.
4.2.4) Ether injection method:
This
method is very similar to the ethanol injection method and was introduced by Deamer and Bangham in 1976. This
method provides a means of making small lamellar vesicles by slowly introducing
a solution of lipids dissolved in diethyl ether into a warm aqueous medium. The
lipid mixture is injected into an aqueous solution of the material to be
encapsulated (using a syringe-type infusion pump) at 55-65oC or
under reduced pressure. The subsequent removal of residual ether under vacuum
leads to the formation of single layer vesicles.
Ether
injection is a method which treats sensitive lipids very gently and has very
little risk of causing oxidative degradation. Since the solvent is removed at
the same rate as that of its introduction rate. There is no limit to the final
concentration of lipid which is achieved. The process can be run continuously
for a long period of time, giving rise to a high percentage of the aqueous
medium encapsulated within the vesicles. The disadvantages of this technique
include the long time taken to produce a batch of niosomes,
a careful control for the introduction of lipid solution and requirement of a
mechanically operated infusion pump.
4.2.5) Homogenization:
The
homogenization of multilamellar vesicles or other lipid
dispersions by commercially available high sheer homogenizer like micro
fluidizer produces unilamellar vesicles. The small unilamellar vesicles formed are longer than the minimal
size formed by sonication alongwith significant
amounts of large particles. The size of the vesicles produced by micro
fluidizer depends on the pressure used the number of passes of the preparation
through this device and the niosomal lipid
composition.
4.2.6) Dried reconstituted vesicles:
In
this method (Kirby and Gregoriadis, 1984, Tohsawa et al.,
1984) the solid lipid is dispersed into a finely divided form before contact
with the aqueous fluid, which forms the medium for the final suspension. Freeze
drying is used instead of drying the lipids from the organic solution and subsequently
the suspension of empty small unilamellar vesicles
are frozen and lyophilized. The small unilamellar
vesicles dried lipid is already very highly organized into membrane structures
which on addition of water can be rehydrated, fused and resealed to form
vesicles with high capture efficiency.
Large
unilamellar vesicles provide a number of important
advantages as compared to the multilamellar vesicles
including high encapsulation of water soluble drugs with economy of lipid and
reproducible drug release rates. However, large unilamellar
vesicles are perhaps the most difficult type of niosomes
to produce.
4.3.1) Reverse phase evaporation method:
Large
Unilamellar vesicles can be prepared by forming water
in oil emulsion of phospholipids and buffer in the excess organic phase
followed by removal of the organic phase under reduced pressure. The two phases
are usually emulsified by sonication. Removal of the organic solvent under
vacuum causes phospholipid coated water droplets to
cool and eventually form a viscous gel. The next step is to bring about the
collapse of certain proportion of water droplets.
In
these circumstances, the lipid monolayer which encloses the collapsed vesicle contributes to adjacent intact vesicles
to form the outer leaflet of the bilayer of a large unilamellar niosomes. The aqueous
content of the collapsed droplet provides the medium required for the
suspension of these newly formed niosomes. After
conversion of the gel to a homogeneous free flowing fluid, the suspension is
dialyzed in order to remove the last traces of solvent. This method has gained
widespread use for applications where high encapsulation of water soluble drug
is required (Szoka and Papahadjopoulos,
1978). Entrapment efficiency up to 65% can be obtained with this method and can
be used to encapsulate both small and large molecules. The biologically active
macromolecules such as RNA and various enzymes have been encapsulated without
loss of activity. The disadvantage of this method is the exposure of the
material (to be encapsulated) to organic solvents and mechanical agitation
which lead to the denaturation of some proteins or
breakage of DNA strands.
4.3.2) Calcium induced method:
This
method is used to produce unilamellar vesicles and it
is of high interest for the present investigation as it has the advantage of
aggregation of small vesicles in the presence of calcium followed by
subsequently fusion.
In
this method (Papahadjopoulos et al., 1975) the drug encapsulation depends on the lipid
concentration and approximately 30% of encapsulation of the drug is expected.
The vesicles are obtained in the size range of 0.2-1 µcm diameter.
The
flocculent precipitate is formed as a result of aggregation of the negatively
charged vesicles by calcium cations. After
incubation, the membranes are fused to give extended sheets of phospholipid lamella which are said to roll up into long cochleate cylinders with a swill-roll cross section,
presumably again with calcium ions as a driving force, in different parts of
the same membrane sheet, together being pulled upon itself.
On addition of EDTA these lamella get unravelled and
released subsequently forming large unilamellar
vesicles.
This
technique has the advantage that it does not expose lipids or entrapped
materials to the deleterious chemicals or physical condition.
4.3.3) Dehydration/rehydration
of small unilamellar vesicles:
In
this method (Shew and Deamer,1985)
sonicated vesicles are mixed in an aqueous solutions
with the solute desired to be encapsulated and the mixture is dried under a
stream of nitrogen. As the sample is dehydrated, the small vesicles fuse to
form a multilamellar film that effectively sandwich’s
the solute molecules between successive layers. Upon rehydration, large
vesicles are produced encapsulating a significant proportion of the solute. The
optimal mass ratio of lipid to solute is approximately 1:2 to 1:3. This method
has the potential application to large scale production, since it depends only
on controlled drying and rehydration processes and does not require extensive
use of organic solvents, detergents or dialysis system.
4.3.4) Detergent removal method:
Removal
of detergent from the mixed micelles formed by solubilization
of dried lipid mixtures or preformed niosomes with a
detergent containing aqueous phase results in the formation of unilamellar vesicles.
This
is a gentle method where no strong mechanical forces and no high temperature
are applied. The procedure should include a step to minimize the residual
detergent level after niosomes formation. The
techniques reported for the removal of detergents include dialysis (Kagawa and Racker, 1971), column chromatography (Enoch and Strittmatter, 1979), and biobeads
method (Gerristen et
al., 1978).
In vivo niosomes have been found equiactive
to liposomes in improving the therapeutic performance
of the drug (Hunter et al., 1988) and
their distribution in body follows the pattern of their colloidal drug delivery
systems. Although, tissues of extravasation: liver,
lung, spleen and bone marrow are responsible for disposition of a major part of
niosomes, yet their level in liver is always higher
due to the natural vectoring process (Hunter et al., 1988, Azmin et al., 1985). Variation in size also influences the pattern of niosomal disposal from the blood. The large size niosomes may reside in lung due to alveolar and effect of
alveolar phagocytic cells, whereas, the small sized
vesicles, can pass through fenestrations in liver sinusoidal epithelium and
thus, have better access to spleen (Carter et
al., 1989, Rogerson et al., 1988)
It
appears that, like liposomes, niosomes
are also taken up intact by the liver and substantial of the niosomes results in the release of the free drug which
eventually re-enters the circulation and maintains the plasma drug level (Azmin et al.,
1985). The effect of two doses of niosomal sodium stibogluconate given on successive days was additive,
indicating that liver might act as a depot of drugs.
Parthasarathi
et al., 1994 found that niosomes are stable in plasma. However, non-ionic
surfactants in higher concentration delipidize the
low density lipoproteins (Tucker and Florence, 1983).
The
success of liposomal system has stimulated the search for other vesicle forming
amphiphiles. Non-ionic surfactant vesicles (niosomes) are among the first alternative materials studied
for the drug delivery. Niosomes, the multilamellar vesicles made up of non-ionic surfactant with
or without cholesterol surrounding aqueous compartments are one of those
carriers.
Niosomes
are efficient carriers for controlled drug delivery, to entrap hydrophilic
drugs in the larger interior aqueous layer , whereas, lipophilic drugs in the outer lipid bilayer.
Since, the niosomes, are biodegradable and non toxic and hence, a good carrier
for targeting of therapeutic agents at the site of interest with reduced
systemic toxicity.
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Received on 01.07.2012
Accepted
on 29.07.2012
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Research Journal of Pharmaceutical Dosage Forms and
Technology. 4(4): July-Aug. 2012,
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