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NIOSOMeS
SRAVANTHI.B
INDUSTRIAL PHARMACY
Contents
Introduction
Structure of niosomes
Materials used in the preparation of niosomes
Advantages & disadvantages of niosomes
Formation of niosomes from proniosomes
Methods of preparation
Size reduction methods & drug loading
Encapsulation of drugs & removal of unentrapped drug
Characterization of niosomes
Stability of niosomes
Applications
Recent advances in niosomes
Conclusion
References
INTRODUCTION
Niosomes definition

Niosomes are essentially non-ionic surfactant based
multilamellar or unilamellar vesicles in which an
aqueous solution of solute (s) is entirely enclosed by a
membrane resulted from the organization of surfactant
macromolecules as bilayers”

Niosomes made-up of self assembly of hydrated nonionic surfactant molecules (eg:
tweens and spans) with or with out cholesterol and dicetyl phosphate.

The assembly into closed bilayers is rarely spontaneous and
usually involves some input of energy such as physical agitation
or heat.
Niosomes also called as Nonionic surfactant vesicles or NSV s
Nios =
somes =
non ionic surfactant
vesicles
NSVS results from the self assembly of hydrated surfactant monomers results in
closed bilayer structures
Drug carriers
Biodegradable, biocompatible and non immunogenic
Large qty of material can be encapsulated
Very small ,microscopic in size.
Most surface active agents when immersed in water yield micellar structures,
how ever some surfactants can yield bilayered vesicles which are niosomes
STRUCTURE OF NIOSOMES
COMPARISION OF NIOSOMES VS LIPOSOMES
Niosomes behave in-vivo like liposomes, prolonging the circulation of entrapped drug And altering its
organ distribution and metabolic stability
In both basic unit of assembly is Amphiphiles, but they phospholipids in liposomes and nonionic
surfactants in niosomes.
Both can entrap hydrophilic and lipophilic drugs.
Both have same physical properties but differ in their chemical composition.
Niosomes has higher chemical stability than liposomes.
Niosomes
made of uncharged single chain surfactant molecules
Liposomes
made of neutral or charged double chain phospholipids.
Niosomes and liposomes are similar in




Function
Increase the bioavailability
Decrease the clearence
Used for targeted drug delivery
Properties depends on both composition of bilayer and method of preparation
ADVANTAGES OF NIOSOMES OVER LIPOSOMES


Ester bonds of phospholipids are easily hydrolyzed, this can lead to phosphoryl
migration at low PH
Peroxidation of unsaturated phospholipids.

This requires that purified phospholipids and liposomes have to be stored and
handled in an inert (N2) atmosphere this problem is not seen with niosomes because
these are made up of nonionic surfactants & these does require special storage
condition

Phospholipid raw materials are naturally occurring substances and as such require
extensive purification thus making them costly

Niosomes has high adjuvanticity when compared to liposomes
ADVANTAGES OF NIOSOMES
They are osmotically active and stable.
They increase the stability of the entrapped drug Handling and storage of surfactants do not
require any special conditions
Can increase the oral bioavailability of drugs
Can enhance the skin penetration of drugs
They can be used for oral, parenteral as well topical use
In cosmetics was first done by L’Oreal as they offered the following advantages:




The vesicle suspension being water based offers greater patient compliance over oil based
systems
Since the structure of the niosome offers place to accommodate hydrophilic, lipophilic as well as
amphiphilic drug moieties, they can be used for a variety of drugs.
The characteristics such as size, lamellarity etc. of the vesicle can be varied depending on the
requirement.
The vesicles can act as a depot to release the drug slowly and offer a controlled release.
The surfactants are biodegradable, biocompatible, and non-immunogenic
Improve the therapeutic performance of the drug by protecting it from the biological
environment and restricting effects to target cells, thereby reducing the clearance of the drug.
The Niosomal dispersions in an aqueous phase can be emulsified in a non-aqueous phase to
control the release rate of the drug and administer normal vesicles in external non-aqueous
phase.
USES OF NIOSOMES
Topical niosomes may serve as As solubilization matrix,
As a local depot for sustained release of dermally active compounds,
As penetration enhancers,
As rate-limiting membrane barrier for the modulation of systemic absorption of drugs
DISADVANTAGES/PROBLEMS ASSOCIATED WITH NIOSOMES
As high input of energy is required in the size reduction of niosomes, they aggregate and fuse
togeather on prolonged storage
Physicochemical instability remains the major problem in the development of Niosomal system
at industrial levels
DISTRIBUTION OF DRUGS IN NIOSOMES

Carriers for both lipophilic & hydrophilic drugs

Highly hydrophilic drugs are exclusively located in the aqueous domain

Highly lipophilic drugs are entrapped within the lipid bilayers of the niosomes

Drugs with intermediary partition coefficient equilibrate b/w lipid & aqueous domains
Different Niosomes
1. Bola-Surfactant containing Niosomes:
Niosomes made of alpha,omega-hexadecyl-bis-(1-aza-18-crown-6) (Bola-surfactant)-Span
80-cholesterol (2:3:1 molar ratio) are named as Bola-Surfactant containing Niosomes.
2. Proniosomes:
A dry product which may be hydrated immediately before use to yield aqueous Niosome
dispersions. These ‘proniosomes’ minimize problems of Niosome physical stability such as
aggregation, fusion and leaking, and provide additional convenience in transportation,
distribution, storage, and dosing.
In short;
1. Carrier + Surfactants = Proniosomes
2. Proniosomes + H2O = Niosomes
In case of Frusemide delivery in the body, it has been found that proniosomal formulations
have been found effective
MOLECULAR GEOMETRY & VESICLE FORMATION
Concept of Critical Packing Parameter (Israelachvili, 1985)
Prediction of vesicle forming ability is not a simply a matter of HLB
CPP = v/lca0
where
v - hydrophobic group volume,
lc - critical hydrophobic group length and
a0 - area of the hydrophilic head group
CPP between
0.5 and 1 likely to form vesicles.
<0.5 (indicating a large contribution from the hydrophilic head group area) is said to give spherical
micelles.
>1 (indicating a large contribution from the hydrophobic group volume) should produce inverted
micelles, the latter presumably only in an oil phase, or precipitation would occur.
Small
Unilamellar
Vesicle
(SUV)
Large
Unilamellar
Vesicle
(LUV)
Multilamellar
Vesicle
(MLV)
Typical Size Ranges: SLV: 20-50 nm – MLV:100-1000 nm
MATERIALS USED IN THE PREPARATION OF NIOSOMES
Non ionic surfactants – Amphiphiles
Sterols like cholesterol
Charge inducers
Non-ionic surfactant structure
Hydrophilic head groups found in vesicle forming surfactants
Glycerol head groups
Ethylene oxide head groups
Crown ether head groups
Polyhydroxy head groups
Sugar head groups + amino acids
Sugar head groups (galactose, mannose, glucose, lactose)
Hydrophobic moiety
One or two alkyl or perfluoroalkyl groups or in certain cases a single
steroidal group.
Alkyl group chain length is usually from C12–C18 (one, two or three
Perfluoroalkyl surfactants that form vesicles possess chain lengths as short as
C10
Additionally crown ether amphiphiles bearing a steroidal C14 alkyl or C16 alkyl
hydrophobic unit have been shown to form vesicles.
The water soluble detergent polysorbate 20 also forms niosomes in the presence
of cholesterol
two portions of the molecule are linked by ether, ester & amide linkages.
.
STEROIDS – Cholesterol
Improves the fluidity of the bilayer.

Minimizes leaching out of water soluble drug.

Systems resulting in less leaky vesicles.

Improves stability in biological fluids – reduce interaction
with plasma proteins
CHARGE INDUCERS – Dicetyl Phosphate, Sod. Cholate, Stearylamine
Prevents aggregation
 Increases drug loading of water soluble drugs in MLV

FACTORS GOVERNING THE SELF ASSEMBLY OF
NIOSOMES

Non ionic surfactant structure

Membrane additives

Nature of the encapsulated material/drug

Surfactant & lipid levels

Temperature of hydration
FACTORS INFLUENCING THE NIOSOMAL PHYSICAL CHEMISTRY
Formation of niosomes from proniosomes
Another method of producing niosomes is to coat a water-soluble carrier
such as sorbitol with surfactant.
The result of the coating process is a dry formulation. In which each watersoluble particle is covered with a thin film of dry surfactant.
This preparation is termed “Proniosomes”.
The niosomes are recognized by the addition of aqueous phase at T > Tm
and brief agitation.
T = Temperature.
Tm = mean phase transition temperature.
Method of preparation
A. Ether injection method
surfactant : cholesterol(150µmol)
ether(20ml)
14 gauge needle
(.25ml/min)

LUV
aqueous phase
(4ml at 60 0 c)
Mechanism of action:
Slow vapourization of solvent resulting into a ether gradient extending across the interfacial
lipid/surfactant monolayer at ether water interface results in the formation of bilayer sheet
which eventually folds on itself to form sealed vesicles.
B. HAND SHAKING METHOD (THIN FILM TECNIQUE)
Surfactant : cholesterol(150µmol)
Folds to form vesicles
diethyl ether(10ml)
Surfactant swells
evaporated
in rotary
evaporater
hydration
C. SONICATION
surfactant : cholesterol
(150µmol)


Probe sonication
Aqueous phase
(3min at 60 0 c)
in vial
(2ml)
Ultrasonic
ULV
MLV
vibration
Probe sonicator used when sample size is small volume
Bath sonicator used for larger volumes
D. REVERSE PHASE EVAPORATION
surfactant
Chloroform&
phosphate buffer
W/O emulsion
vesicles
Sonication & evaporation
hydration
E . MICROFLUIDIZATION

This method is based on submerged jet principle in which two fluidized streams
interact at ultra high velocities, in precisely defined micro channels within the
interaction chamber.

The impingement of thin liquid sheet along a common front is arranged such that
the energy supplied to the system remains within the area of niosomes formation.

The result is a greater uniformity, smaller size and better reproducibility of
niosomes formed
METHODS USED FOR NIOSOME PREPARATION IN INDUSTRIAL SCALE
ARE
Novasome
Handjani – Vila et al. - for larger qty i.e. Kg of dispersions
F. Multiple membrane extrusion method
Surfactant, cholesterol, diacetyl
phosphate in chloroform
Niosomes
(of controlled size)
Thin films by
evaporation
Upto 8 passages
forms vesicles
Hydrated with
aqc drug soln
Suspension extruded
through polycarbonate
membranes
G. Trans membrane pH gradient (inside acidic) Drug Uptake Process (Remote Loading)
Surfactant, cholesterol
in chloroform
Heating at 60 0 c
forms niosomes
evaporation
P H 7 -7.2 with
1M disodium
phosphate
Hydration with
300mM citric acid
Acq drug soln
(10mg/ml)
MLV
Frozen,thawed
& sonicated
(Niosomal
suspension)
H. BUBBLE METHOD
This method does uses organic solvents - adv

The bubbling unit consists of round-bottomed flask with three necks positioned in water bath to control the
temperature.
Water-cooled reflux and thermometer is positioned in the first and second neck and nitrogen supply through the
third neck
Surfactant, cholesterol
Dissolved in buffer
at p H 7.4 at 70 0 c
Homogenization
For 15 min
niosomes
Bubbled at 70 0 c
using N 2 gas
I.
MICELLAR SOLUTION METHODS
Mixed micellar solution
Esterases ,non ionic surfactant ,
Charged inducer
Esterases enzymes cleavage the micellar solution
NIOSOMES

SIZE REDUCTION METHODS

Probe sonication

Extrusion method

Sonication & filtration

Microfluidizer

High pressure homogenization

DRUG LOADING

Active loading / Remote loading

Passive loading
100 -140nm
in the range of 140nm
in the range of 200nm
<50nm
<100nm
ENCAPSULATION OF DRUGS IN NIOSOMES
Encapsulation volume/Trapped volume
Volume of aqueous solution entrapped in niosomes per mole
of surfactant (µL/µmol surfactant)
Encapsulation Efficiency
It is determined after separation of unentrapped drug, on complete vesicle disruption by using
about 1 ml of 2.5% sodium lauryl sulphate, briefly homogenized and centrifuged and
supernatant assayed for drug after suitable dilution.
% Encapsulation
Drug entrapped in niosomes
x 100
Total drug added
The effect of the choice of niosome forming surfactant on the properties of
the niosome dispersion
The effect of the nature of the encapsulated drug on the properties of the niosome dispersion.
DRUGS INCORPORATED INTO NIOSOMES BY VARIOUS METHODS
Method of preparation
Drug incorporated
Ether Injection
Sodium stibogluconate
Doxorubicin
Hand Shaking
Methotrexate
Doxorubicin
Sonication
9-desglycinamide
8-arginine
Vasopressin
Oestradiol
Reverse phase evaporation
Diclofenac sodium
. Characterization of niosomes
a) Entrapment efficiency
The drug remained entrapped in niosomes is determined by complete vesicle disruption using 50% npropanol or 0.1% Triton X-100 and analyzing the resultant solution by appropriate assay method for
the drug. Where,
Entrapment efficiency (EF) = ( amount entrapped / total amount) x 100
b) Vesicle diameter
Niosomes, similar to liposomes, assume spherical shape and so their diameter can be determined using –
light microscopy,
photon correlation microscopy
freeze fracture electron microscopy.
Freeze thawing (keeping vesicles suspension at –20°C for 24 hrs and then heating to ambient temperature) of
niosomes increases the vesicle diameter, which might be attributed to fusion of vesicles during the
cycle
(c) In-vitro release
dialysis tubing
A dialysis sac is washed and soaked in distilled water.
The vesicle suspension is pipetted into a bag made up of the tubing and sealed.
The bag containing the vesicles is placed in 200 ml of buffer solution in a 250 ml beaker with
constant shaking at 25°C or 37°C.
At various time intervals, the buffer is analyzed for the drug content by an appropriate assay method
Factors affecting vesicles size, entrapment efficiency and release characteristics
a) Drug
entrapment of drugs in niosomes increase the vesicle size by1.interaction of solute with surfactant head groups
2.increasing the charge
3.mutual repulsions of the surfactant bilayers
In PEG coated vesicles, some of the drug entrapped in long PEG chains there by reducing the
charge
b) Amount and type of surfactant
Hydrophilic Lipophilic Balance (HLB) is a good indicator of the vesicle forming ability of any
surfactant.
With the sorbitan monostearate (Span) surfactants, a HLB number of between 4 and 8 was found
to be compatible with vesicle formation
Bilayers of vesicles are in gel or liquid state depending on1. Temp
2. Type of liquid or surfactant
3. Cholesterol
Surfactants or lipids are characterized by gel - liquid phase transition temp (TC)
TC of surfactant also effect entrapment efficiency i.e., span 60 has higher TC so better entrapment
c) cholesterol content & charge
Cholesterol
increase the hydrodynamic diameter & entrapment efficiency
Action is two ways –
1.
2.
Increase the chain order of liquid state bilayers
Decrease the chain order of gel state bilayers
at high cholesterol conc -
gel state
less ordered liquid crystalline phase
Increase in cholesterol contentIncrease the rigidity of bilayers
Decrease the release rate of encapsulated material
charge - induced by stearylamine & Diacetyl phosphate
Increase the interlamellar distance b/w the successive bilayers in multilamellar
vesicles
Overall greater entrapped volume
d) Methods of preparation


Hand shaking method forms vesicles with greater diameter (0.35-13nm) compared to the
ether injection method (50-1000nm)
Small sized niosomes can be produced by Reverse Phase Evaporation (REV) method

Micro fluidization method gives greater uniformity and small size vesicles.

Niosomes also prepared by trans membrane pH gradient (inside acidic) drug uptake process
, showed greater entrapment efficiency and better retention of drug
e)
Resistance to osmotic stress

Addition of a hypertonic salt solution to a suspension of niosomes brings about reduction in
diameter.

In hypotonic salt solution, there is initial slow release with slight swelling of vesicles
probably due to inhibition of eluting fluid from vesicles, followed by faster release, which
may be due to mechanical loosening of vesicles structure under osmotic stress.
CHARACTERIZATION OF NIOSOMES

Mean Size & Size distribution

Surface Potential & Surface pH

No of lamellae

Structural & Motional behavior
of lipids
-


Surface Chemical Analysis
Bilayer formation
Membrane rigidity
-
Electron Microscopy
Dynamic Light Scattering (PCS)
molecular sieve chromatography
-
-
Micro electrophoresis
Small angle X ray Scattering,
NMR, Electron microscopy
DSC, ESR, NMR
-
NMR
X cross formation under light
polarization microscopy
mobility of fluorescence probe as a
function of temp
STABILITY OF NIOSOMES

Stability in buffer

Stability in hypertonic media

Stability in hypotonic media

Stability in – vivo

Stability is also influenced by –
Surfactant/lipid ratio
Encapsulated drug
Temperature of storage
Detergents
Applications
1)
Targeting of bioactive agents
a) To reticulo - endothelial system (RES)
b) To organs other than RES
2) Neoplasia
Doxorubicin
dose dependant irreversible cardio toxic effect.
Niosomal delivery of this drug to mice bearing S-180 tumor increased their life span and
decreased the rate of proliferation of sarcoma.
Niosomal entrapment increased the half-life of the drug, prolonged its circulation and
altered its metabolism.
Intravenous administration of methotrexate entrapped in niosomes to S-180 tumor bearing
mice resulted in total regression of tumor and also higher plasma level and slower
elimination.
3) Leishmaniasis
sodium stibogluconate
4) Niosomes in Oral & Opthalmic drug delivery
Oral
Ergot alkaloids
Opthalmic Cyclopentolate (polysorbate – 20 & cholesterol)
5) Diagnostic imaging with niosomes
Iopromide
6) Anti infective agents
Rifampicin
7) Anti cancer therapy
methotrexate
8) Niosomes as Vaccine Adjuvants
9) Delivery of peptide drugs
9-desglycinamide, 8-arginine, vasopressin
10) Immunological application
11) Carriers for haemoglobin
12) Transdermal delivery of drugs
Oestradiol
13) Other applecations
a) Sustained release
b) Localized drug action
c) Cosmetics
14) Niosomes also used as drug carrier
Ciprofloxacin & Norfloxacin
Indomethacin
Diclofenac Sodium
8 – Arginine
Propylthiouracil
Doxorubicin
Pentoxyphillin
9 – desglycinamide
Vasopressin
Suitable niosome sizes for particular routes of
administration
RECENT ADVANCES IN NIOSOMES

Combination of PEG and glucose conjugates on the surface of niosomes significantly
improved tumor targeting of an encapsulated paramagnetic agent assessed with MR
imaging in a human carcinoma xenograft model.

Phase I and phase II studies were conducted for Niosomal methotrexate gel in the
treatment of localized psoriasis. These studies suggest that niosomal methotrexate
gel is more efficacious than placebo and marketed methotrexate gel.

A research article was published that Acyclovir entrapped niosomes were prepared by
Hand shaking and Ether injection methods increases the oral bioavailability

Lancome has come out with a variety of anti-ageing products which are based on
niosome formulations
Conclusion


The concept of incorporating the drug into liposomes or niosomes for a better targeting of the drug at
appropriate tissue destination is widely accepted by researchers and academicians.
Niosomes represent a promising drug delivery module.

They presents a structure similar to liposome and hence they can represent alternative vesicular systems
with respect to liposomes, due to the niosome ability to encapsulate different type of drugs within their
multi environmental structure.

Niosomes are thoughts to be better candidates drug delivery as compared to liposomes due to various
factors like cost, stability etc
.

Various type of drug deliveries can be possible using niosomes like targeting, ophthalmic, topical,
parenteral, etc.

Niosomes can also serve better aid in diagnostic imaging and vaccine adjuvant in pharmaceutical
industry.

Niosomes are considered as promising controlled drug delivery carrier which increase the half life of
drugs and helps in formulating prolonged/controlled acting dosage forms

Niosomes have great drug delivery potential for targeted delivery of anti-cancer, anti infective agents.
REFERENCES
1) S.P.Vyas, R.K.Khar., Targetted and controlled drug delivery.
2) N.K.Jain., Advances in controlled and novel drug delivery.
3)James Swarbrick, Encyclopedia of pharmaceutical technology, third edition ,
vol-2
4) en.wikipedia.org
5) Informa Healthcare – Journal of Liposome Research
6) AAPS PharmaSciTec.com
7) Pharmainfo.net
8) I. F. Uchegbu, S.P. Vyas : International Journal of Pharmaceutics 172 (1998)
33–70
9)Journal of Pharmacy Research Vol.1.Issue 2. Oct-December 2008
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