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Nisomes
Nisomes
ABSTRACT: Vesicles prepared from self-assembly of hydrated non-ionic surfactants molecules are called
niosomes. These types of vesicles were first reported in the cosmetic industries. Niosomes exhibit more
chemical stability than liposomes (a phospholipids vesicle) as non-ionic surfactants are more stable than
phospholipids. Non-ionic surfactants used in formation of niosomes are polyglyceryl alkyl ether, glucosyl
dialkyl ether, crown ether, polyoxyethylenealkyl ether, ester-linked surfactants, and steroid-linked surfactants
and a spans, and tweens series. Niosomes preparation is affected by processes variables, nature of
surfactants, and presence of membrane additives and nature of drug to be encapsulated. This review article
presents an overview of theoretical concept of factors affecting niosome formation, techniques of noisome
preparation, characterization of niosome, applications, limitations and market status of such delivery system.
KEY WORDS: Niosomes; Liposomes; Anticancer; Surfactant; Proniosomes; Cholesterol.
If ½ < CPP < 1 formation of bilayer micelles, Along with the above mentioned factors, volume of
hydration medium and time of hydration of niosomes are
If CPP > 1 formation inverted micelles.11 also critical factors. Improper selection of these factors
may result in formation of fragile niosomes or creation of
Membrane composition drug leakage problems.
The stable niosomes can be prepared with addition of
different additives along with surfactants and drugs. Characterization of niosome
Niosomes formed have a number of morphologies and
their permeability and stability properties can be altered by Size
manipulating membrane characteristics by different Shape of niosome vesicles assumed to be spherical, their
additives. In case of polyhedral niosomes formed from mean diameter can be determined by using laser light
C16G2, the shape of these polyhedral niosome remains scattering method (Almira I et al., 2001). Also, diameter
unaffected by adding low amount of solulan C24 can be determined by using electron microscopy,
molecular sieve chromatography, ultracentrifugation,
(cholesteryl poly-24-oxyethylene ether), which prevents
photon correlation microscopy and optical microscopy
aggregation due to development of steric hindrance
(Kreuter J, 1966; Azmin MN et al., 1985).
(Arunothayanun P et al., 2000). In contrast spherical
niosomes are formed by C16G2: cholesterol:solulan Bilayer formation
(49:49:2) (Arunothayanun P et al ., 2000).The mean size of Assembly of non-ionic surfactants to form bilayer vesicle
niosomes is influenced by membrane composition such as is characterized by X-cross formation under light
polyhedral niosomes formed by C16G2:solulan C24 in ratio polarization microscopy (Manosroi A et al., 20003).
(91:9) having bigger size (8.0 ± 0.03mm) than
spherical/tubular niosomes formed by C16G2: Number of lamellae
cholesterol:solulan C24 in ratio (49:49:2) (6.6±0.2mm) It is determined by using NMR spectroscopy, small angle
(Arunothayanun P et al., 2000). Addition of cholesterol X-ray scattering and electron microscopy (Kreuter J,
molecule to niosomal system provides rigidity to the 1966).
membrane and reduces the leakage of drug from niosome
(Rogerson A et al., 1987). Membrane rigidity
Membrane rigidity can be measured by means of mobility
Nature of encapsulated drug of fluorescence probe as function of temperature
The physico-chemical properties of encapsulated drug (Manosroi A et al., 2003).
influence charge and rigidity of the niosome bilayer. The
Entrapment efficiency (EE)
drug interacts with surfactant head groups and develops the
charge that creates mutual repulsion between surfactant The entrapment efficiency (EE) is expressed as
bilayers and hence increases vesicle size (Stafford S et al., EE = amount entrapped/total amount added ´ 100. 22
Biswal et al. : Vesicles of Non-ionic Surfactants (Niosomes) and Drug Delivery Potential 3
It is determined after separation of unentrapped drug, surfactant/lipid film is then hydrated with aqueous solution
on complete vesicle disruption by using about 1ml of 2.5% of drug at temperature slightly above the phase transition
sodium lauryl sulfate, briefly homogenized and centrifuged temperature of surfactants used, for specified period of
and supernatant assayed for drug after suitable dilution time (time of hydration) with constant mild shaking
(Balasubramanian A et al., 2002). Entrapment efficiency is (Naresh RAR et al., 1996; Nasseri B and Florence AT,
affected by following factors. 2003; Azmin MN et al., 1985 and Baillie AJ et al., 1985).
Surfactants Reverse phase evaporation
The chain length and hydrophilic head of non-ionic
The surfactants/lipids and cholesterol dissolve in a mixture
surfactants affect entrapment efficiency, such as stearyl
of ether and chloroform, followed by addition of aqueous
chain C18 non-ionic surfactant vesicles show higher
phase containing drug. The resulting two-phase system is
entrapment efficiency than lauryl chain C12 non-ionic
then homogenized using homogenizer (Baalasubramanian
surfactant vesicles (Manosroi A et al., 2003). The tween A et al., 2002). The organic phase is removed under
series surfactants bearing a long alkyl chain and a large
reduced pressure to form niosomes dispersed in aqueous
hydrophilic moiety in the combination with cholesterol at
phase. In some cases suspensions results a must be further
1:1 ratio have highest entrapment efficiency for water-
hydrated or homogenized to yield niosomes
soluble drugs (Manosroi A et al., 2003). HLB value of
surfactants affects entrapment efficiency, such as HLB (Balassubramanian A et al., 2002; Parthsarathi G et al.,
value of 14 to 17 is not suitable for niosomes but HLB 1994).
value of 8.6 has highest entrapment efficiency and
Ether injection
entrapment efficiency decreases with decrease in HLB
value from 8.6 to 1.7 (Shahiwala A and Misra AJ, 2002). In this method, surfactant or surfactant-cholesterol or
The entrapment efficiency is affected by phase transition surfactant cholesterol-diacetyl phosphate or surfactant-
temperature of surfactants, i.e. span 60 exhibits highest cholesterol-drug solution mixture dissolves in diethyl ether
entrapment efficiency in series having highest transition then it is injected slowly into aqueous solution of drug or
temperature (Tc) (Yoshida Hetal., 1992). aqueous phase which is heated above the boiling point of
the organic solvent.
Cholesterol contents
The incorporation of cholesterol into bilayer composition Bubbling of inert gas nitrogen
of niosome induces membrane-stabilizing activity and Niosomes are prepared by bubbling of nitrogen gas
decreases the leakiness of membrane (Rogerson A et al., through the homogenized mixture of surfactant/lipid
1988). Hence, incorporation of cholesterol into bilayer
(Talsma H et al., 1999). Uchegbu et al. reported that
increases entrapment efficiency. The permeability of
niosomes may also be formed from a mixed micellar
vesicle bilayer to 5, 6-carboxy flourescein (CF) is reduced
by 10 times due to incorporation of cholesterol (Baillie AJ solution by enzymatic process ( Uchegbu F et al., 1998).
et al., 1985). Sizing of niosomes
Techniques for preparation of niosome The size ranges of niosomes have a major effect on their
By using following general steps niosomes can be fate in-vivo and in-vitro. Hence, size reduction stage of
prepared: niosome is essential after hydration stage. The more
commonly used methods for niosome size reduction found
• Hydration of mixture of the surfactants/lipids at in literature are given below:
elevated temperature,
• Sizing of niosomes, Probe sonication
• Removal of the unentrapped material from the vesicles Niosomes prepared by reverse phase evaporation and
by different methods. hand-shaking method are usually in micron size range
(1.15 and 2.75mm) (Naresh RAR et al., 1996; Azmin MN
Hydration stage et al., 1985). By using probe sonication size of C16G3
Hydration of mixture of the surfactants / lipids at elevated niosomes formed by hand shaking method are reduced to
temperature can be done by using following method. 100-140 nm (Bhaskaran S and Panigrahi L, 2002).
Hand shaking/lipid layer hydration Nucleopore filters extrusion
Solution of surfactants/lipids is prepared by dissolving Size of niosome reduces to nano range (140 nm) by
both in organic solvent (chloroform). The organic solvent extrusion of niosome through nucleopore filters of pore
is removed by rotary flask evaporation/under reduced size 100 nm (Stafford S et al. 1988).
pressure leads formation of drug surfactant/lipid film. The
4 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 1 • Issue 1 • April - June 2008
Polyhedral niosomes The niosomal formulation was able to destroy the Dalton’s
ascitic lymphoma cells in the peritoneum within the third
Polyhedral niosomes can be obtained from mixture of
day of treatment, while free drug took around six days and
C16EO5 and solulan-C24 in low concentration of cholesterol
the process was incomplete. The hematological studies
(Nasseri B and Florence AT, 2003). A.T.Florence et al., also prove that the niosomal formulation was superior to
worked on extrusion of polyhedral niosomes by capillary free drug treatment. An enhanced mean survival time was
and studied some properties of extruded polyhedral achieved by the niosomal formulation that finally
niosomes(Nasseri B and Florence AT, 2003). When substantiates the overall efficacy of the niosomal
polyhedral niosomes extruded under certain condition into formulation (Balasubramanian A et al., 2002) .
aqueous media fuse to produce long continuous stable
tubules by controlling factor such pressure need to extrude Doxorubicin
niosomes and composition of vesicles(Nassseri B and
Florence AT, 2003). The applied shear stress on vesicle Rogerson et al., studied distribution of niosomal
affects its release pattern such as increasing sheer stress by doxorubicin prepared from C16 monoalkyl glycerol ether
narrowing size of micropipette aperture increases higher with or without cholesterol. Niosomal formulation
release pattern of entrapped materials(Arunothayanum P exhibited an increased level of doxorubicin in tumor cells,
et al., 1998) serum and lungs, but not in liver and spleen. Doxorubicin-
loaded cholesterol-free niosomes decreased the rate of
Vesicles in water and oil system (V/W/O)
proliferation of tumor and increased life span of tumor-
Yoshioka et al., reported that the emulsification of an bearing mice. The cardio toxicity effect of doxorubicin was
aqueous niosomes into an oil phase form vesicle in water reduced by niosomal formulation. Niosomal formulation
in oil emulsion (V/W/O)(Yoshioka T and Florence AT, changes the general metabolic pathway of doxorubicin
1994). On addition of niosomes suspension formed from
(Rogerson A et al., 1988).
mixture of sorbitol mono stearate, cholesterol and solulan
C24 to oil phase at 60oC(Murdan S et al., 1999). There is Methotrexate
formation of vesicle in water in oil emulsion but cooling to
Azmin et al., quoted in their research article that niosomal
room temperature forms vesicle in water in oil gel (V/W/O
gel)(Murdan S et al., 1999). The (V/W/O gel) can formulation of methotrexate exhibits higher AUC as
entrap protein and also protect it from enzymatic compared to methotrexate solution, administered either
degradation after oral administration and controlled intravenously or orally. Tumoricidal activity of
release. The release of entrap material is lowest in case of niosomally-formulated methotreaxate is higher as
V/W/O gel as compared to W/O gel and niosomal compared to plain drug solution (Azmin MN et al., 1985).
suspension (Murdan S et al., 1999). Florence et al., studied
on immugencity properties of V/W/O gel and (W/O) gel, Bleomycin
reported that both exhibit immunoadjuvant tendency. Niosomal formulation of bleomycin containing 47.5%
cholesterol exhibits higher level drug in the lever, spleen
Niosomes in hydroxypropyl methylcellulose and tumour as compared to plan drug solution in tumor-
Reddy et al., studied on anti-inflammatory effect of bearing mice (Naresh RAR et al., 1996). There is no
noisome after incorporating into hydroxypropyl methyl significant difference in drug concentration with niosomal
cellulose semi-solid base containing 10% glycerin (Reddy formulation in lung as compared to plan drug
DN and Udupa N, 1993). The bio availability and solution.10Also, there is less accumulation of drug in gut
reduction of carageenan induced higher rat paw edema in and kidney in case of niosomal formulation (Naresh RAR
case of noisome formulated in hydroxylpropyl methyl et al., 1996).
cellulose as compared to plain formulation of flurbiprofen
(R Reddy DN and Udupa N, 1993). Vincristine
reticuloendothelial system. Niosomal or liposomal skin than those proniosome prepared from tween20
formulation of sodium stibogluconate exhibits higher (Alsarra AI et al., 2005). It is also identified in literature
levels of antimony as compared to free drug solution in that the bioavailability and therapeutic efficacy of drug like
liver (Ballie AJ et al., 1986). Antimony level is same in diclofenac , flurbiprofen and nimesulide are increased
both formation i.e. niosome and liposome. with niosomal formulation (Naresh AR et al., 1993; Reddy
DN and Udupa N, 1993; Shahiwala A and Misra AJ,
Niosomal formulation of rifampicin exhibits better anti-
2002).
tubercular activity as compared to plain drug (Uchegbu F
et al., 1998). Niosomes in oral drug delivery
Anti-inflammatory agents An oral administration of niosomal formulation of
methotrexate exhibits higher concentration of drug in
Niosomal formulation of diclofenac sodium with 70%
serum with more uptakes by the liver as compared to plain
cholesterol exhibits greater anti-inflammation activity as
drug in mice (Azmin MN et al., 1985). So it concludes that
compared to free drug (Naresh AR et al., 1993). Niosomal
gastrointestinal tract absorption of drug increases in
formulation of nimesulide and flurbiprofen also exhibits
niosomal formulation. Niosomal formulation of insulin
greater anti-inflammation activity as compared to free drug
prepared from span 20, 40, 60, 80 shows lower in-vitro
(Shahiwala A and Misra AJ, 2002; Reddy DN et al., 1993).
release of insulin in simulated intestinal fluid from span 40
Diagnostic imaging with niosomes and 60 than span 20 and 80 (Varshosaz J et al., 2003).
Niosomes prepared from span 60 exhibits highest
Niosomal system can be used as diagnostic agents.
protection of insulin against proteolytic enzymes and good
Conjugated niosomal formulation of gadobenate
stability in presence of sodium deoxycholate and storage
dimeglcemine with [N-palmitoyl-glucosamine (NPG)],
temperature (Varshosaz J et al., 22003).
PEG 4400, and both PEG and NPG exhibit significantly
improved tumor targeting of an encapsulated paramagnetic Niosome formulation as a brain targeted delivery
agent assessed with MR imaging (Luciani A et al., 2004). system for the vasoactive intestinal peptide (VIP)
Ophthalmic drug delivery Radiolabelled (I125) VIP-loaded glucose-bearing niosomes
were injected intravenously to mice. Encapsulated VIP
It is difficulty to achieve excellent bioavailability of drug
within glucose-bearing niosomes exhibits higher VIP brain
from ocular dosage form like ophthalmic solution,
uptake as compared to control (Dufes C et al., 2004).
suspension and ointment due to the tear production,
impermeability of corneal epithelium, non-productive Conclusion
absorption and transient residence time. But to achieve
good bioavailability of drug various vesicular systems are It is obvious that niosome appears to be a well preferred
proposed to be use, in experimental level, like niosomes, drug delivery system over liposome as niosome being
liposomes. stable and economic. Also niosomes have great drug
Bioadhesive-coated niosomal formulation of delivery potential for targeted delivery of anti-cancer, anti-
acetazolamide prepared from span 60, cholesterol infective agents.Drug delivery potential of niosome can
stearylamine or dicetyl phosphate exhibits more tendency enhance by using novel concepts like proniosomes,
for reduction of intraocular pressure as compared to discomes and aspasome.Niosomes also serve better aid in
marketed formulation (Dorzolamide) (Aggardwal D et al., diagnostic imaging and as a vaccine adjuvant. Thus these
2004). The chitosan-coated niosomal formulation timolol areas need further exploration and research so as to bring
maleate (0.25%) exhibits more effect for reduction out commercially available niosomal preparation.
intraocular pressure as compared to a marketed
formulation with less chance of cardiovascular side effects Acknowledgement
(Aggarwal D et al., 2004). The authors wish to thank Dr A.K.Dorle (Emeritus
Transdermal drug delivery Professor, Department of Pharmaceutical Sciences Nagpur
University, Nagpur) for his constant encouragement and
Administration of drugs by the transdermal route has also UGC and AICTE, New Delhi for providing financial
advantages such as avoiding the first pass effect, but it has assistance.
one important drawback, the slow penetration rate of drugs
through the skin. Various approaches are made to References
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