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Niosome and Proniosome – Vesicular Structured Dosage Form for
Targeted Drug Delivery System
Yashavantsinh Chavda1*, Bhavin Bhimani1, Dr. Upendra Patel1,
Ghanshyam Patel2, Dhiren Daslaniya2
1.
Department of Pharmaceutics, Arihant School of Pharmacy & BRI, Adalaj, Gandhinagar.
2.
Department of Pharmacy, JJT University, Jhunjhunu, Rajsthan.
Corresponding authorYashavantsinh Chavda
Email ID- [email protected]
Ph. NO- 09924362838
INTRODUCTION
Drug targeting is a specific form of drug delivery where the pharmacological agent is directed
selectively to its site of action or absorption. The specific site may be a particular organ,
structure, cell or an intracellular region. Targeted drug delivery is a method of delivering
medication to a patient in a manner that increases the concentration of the medication in some
parts of the body relative to others. Targeted drug delivery seeks to concentrate the
medication in the tissues of interest while reducing the relative concentration of the
medication in the remaining tissues.1This improves efficacy of the while reducing side
effects. Drug targeting is the delivery of drugs to receptors or organs or any other specific
part of the body to which one wishes to deliver the drugs exclusively.2 The drug’s therapeutic
index, as measured by its pharmacological response and safety, relies in the access and
specific introduction of the drug with its candidate receptor, while minimizing its
introduction with non-target tissue. The desired differential distribution of drug its targeted
delivery would spare the rest of the body and thus significantly reduce the overall toxicity
while maintaining its therapeutic benefits. The targeted or site- specific delivery of drugs is
indeed a very attractive goal because this provides one of the most potential ways to improve
the therapeutic index of the drugs.3
Targeted drug delivery systems are drug carrier systems that deliver the drug to the target or
receptor site in a manner that provides maximum therapeutic activity, prevents degradation or
inactivation during transit to the target sites, and protects the body from adverse reactions
because of inappropriate disposition.4,5 Design of an effective delivery system requires a
thorough understanding of the drug, the disease, and the target site. Examples include
macromolecular drug carriers (protein drug carriers), particulate drug delivery systems (eg,
microspheres, nanospheres, and liposomes), monoclonal antibodies, and cells. Plasma
clearance kinetics, tissue distribution, metabolism, and cellular interactions of a drug can be
controlled by the use of a site-specific delivery system.6 Targeting of drugs to specific sites in
the body can be achieved by linking particulate systems or macromolecular carriers to
monoclonal antibodies or to cell specific ligands (eg, asialofetuin, glycoproteins, or
immunoglobulins), or by alterations in the surface characteristics so that they are not
recognized by the reticuloendothelial systems (RES).7
IMPORTANCE OF TARGETING
Site-specific carriers guide the drug to the intended target site in which the receptors is
located with exposing the drug to other tissues thereby avoiding adverse toxicity. The amount
of drug needed will be reduced.
APPROACHES TO DRUG TARGETING
Basically there are four approaches
 Physical targeting: Involves the use of biologically active agents that are both potent
& selective to a particular site in the body.
 Chemical targeting: Also known as prodrug approach. Preparation of
pharmacologically inert forms of active drugs when they reach the active site they
become activated by chemical or enzymatic reaction.
 Natural or passive targeting: Here a biologically inert micromolecular carrier system
is utilized which direct the drug to a specific site where it accumulates and effects its
response. Eg. Liposomes, nanoparticles etc…
 Active targeting: This is also known as ligand medicated targeting. Here the drug is
attached to appropriate ligands. Eg. Monoclonal antibodies.
RECENT APPROACHES
Quantam dots
A quantum dot is a semiconductor nanostructure that confines the motion of conduction band
electrons, valence band holes, or excitons (bound pairs of conduction band electrons and
valence band holes) in all three spatial directions. The confinement can be due to electrostatic
potentials (generated by external electrodes, doping, strain, impurities), the presence of an
interface between different semiconductor materials (e.g. in core-shell nanocrystal systems),
the presence of the semiconductor surface (e.g. semiconductor nanocrystal), or a combination
of these. Quantum dots are particularly significant for optical applications due to their
theoretically high quantum yield. The ability to tune the size of quantum dots is advantageous
for many applications and it is one of the most promising candidates for use in solid-state
quantum computation and diagnosis , drug delivery, Tissue engineering, catalysis, filtration
and also textiles technologies.7
Transdermal Approach
Transdermal drug delivery system is topically administered medicaments in the form of
patches that deliver drugs for systemic effects at a predetermined and controlled rate. A
transdermal drug delivery device, which may be of an active or a passive design, is a device
which provides an alternative route for administering medication. These devices allow for
pharmaceuticals to be delivered across the skin barrier. In theory, transdermal patches work
very simply. A drug is applied in a relatively high dosage to the inside of a patch, which is
worn on the skin for an extended period of time. Through a diffusion process, the drug enters
the bloodstream directly through the skin. Since there is high concentration on the patch and
low concentration in the blood, the drug will keep diffusing into the blood for a long period
of time, maintaining the constant concentration of drug in the blood flow.8
Folate Targeting
Folate targeting is a method utilized in biotechnology for drug delivery purposes. It involves
the attachment of the vitamin, folate (folic acid), to a molecule/drug to form a "folate
conjugate". Based on the natural high affinity of folate for the folate receptor protein (FR),
which is commonly expressed on the surface of many human cancers, folate-drug conjugates
also bind tightly to the FR and trigger cellular uptake via endocytosis. Molecules as diverse
as small radiodiagnostic imaging agents to large DNA plasmid formulations have
successfully been delivered inside FR-positive cells and tissues. FA also displays high
affinity for the folate receptor (FR), a glycosylphosphatidyinositol-linked protein that
captures its ligands from the extracellular milieu and transports them inside the cell via a nondestructive, recycling endosomal pathway. The FR is also a recognized tumor
antigen/biomarker. Because of this, diagnostic and therapeutic methods which exploit the
FR’s function are being developed for cancer.8
Brain targeted drug delivery system
The brain is a delicate organ, and evolution built very efficient ways to protect it. The
delivery of drugs to central nervous system (CNS) is a challenge in the treatment of
neurological disorders. Drugs may be administered directly into the CNS or systematically
(e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS
drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain
substance. Advances in understanding of the cell biology of the BBB have opened new
avenues and possibilities for improved drug delivery to the CNS. Various strategies that have
been used for manipulating the blood-brain barrier for drug delivery to the brain include
osmotic and chemical opening of the blood-brain barrier as well as the use of transport/carrier
systems. Other strategies for drug delivery to the brain involve bypassing the BBB. Various
pharmacological agents have been used to open the BBB and direct invasive methods can
introduce therapeutic agents into the brain substance. It is important to consider not only the
net delivery of the agent to the CNS, but also the ability of the agent to access the relevant
target site within the CNS. Various routes of administration as well as conjugations of drugs,
e.g., with liposomes and nanoparticles, are considered.8
Liposomes
These are vesicular concentric structures, range in size from a nanometer to several
micrometers, containing a phospholipids bilayer and are biocompatible, biodegradable and
non immunogenic. Liposomes have generated a great interest because of their versatility and
have played a significant role in formulation of potent drugs to improve therapeutics.
Enhanced safety and efficacy have been achieved for a wide range of drug classes, including
antitumor agents, antiviral, antimicrobials, vaccines, gene therapeutics etc…Recently
pharmaceutical science is using liposomes to reduce toxicity and side effect of drugs. The
various problems like poor solubility, short half life and poor bioavailability & strong side
effect of various drugs can be overcome by employing the concept of liposomes especially in
various diseases like cancer etc. Liposomes offer ample opportunities for the investigators to
explore the unidentified breakthrough in the field of pharmaceutical technology.9
Niosomes
Niosomes are non-ionic surfactant vesicles that can entrap a solute in a manner analogous to
liposomes.They are osmotically active, and are stable on their own, while also increasing the
stability of the entrapped drugs.10,11
1. Handling and storage of surfactants require no special conditions. Niosomes possess an
infrastructure consisting of hydrophilic and hydrophobic moieties together, and as a result,
can accommodate drug molecules with a wide range of solubilities.12
2. Although niosomes as drug carriers have shown advantages such as being cheap and
chemically stable, they are associated with problems related to physical stability such as
fusion, aggregation, sedimentation and leakage on storage.13
3. All methods traditionally used for preparation of niosomes are time consuming and many
involve specialized equipments. Most of these methods allow only for a predetermined lot
size so material is often wasted if smaller quantities are required for particular dose
application.14
4. The size of niosomes are microscopic and lies in nanometric scale. The particle size ranges
from 10nm-100nm.15,16
Niosomes as drug carriers
Several studies have described the properties of niosomes as drug carriers. Niosomes behave
similarly to liposomes in vivo by prolonging circulation time of the encapsulated drug and
altering chemical distribution within the body.17,18 However, niosomes have advantages over
liposomes as drug carriers, including greater chemical stability, lower cost, easier storage and
handling, and are less likely than liposomes to become toxic.19,20 Niosomal encapsulation
reduces toxicity of drugs in many different applications and therapies. Niosomal drug
delivery has been studied using various methods of administration,21 including
intramuscular,22 intravenous23 peroral24 and transdermal25,26,27,28 Nebulized surfactants
entrapping all-trans-retinoic acid (ATRA) were delivered as an inhaled aerosol reducing the
drug toxicity and altering the pharmacokinetics. In addition, as drug delivery vesicles,
niosomes have been shown to enhance absorption of some drugs across cell membranes to
localize in targeted organs, tissues and to elude the reticulo endothelial system (RES).29
Cellular uptake of niosomes can be via endocytosis;12 however they have been shown to bind
and fuse with cell plasma membranes via cellular receptors when vesicle surface charge is
sufficiently negative.30
Method of Preparation of Niosomes
Ether injection method
In this method, a solution of the surfactant is made by dissolving it in diethyl ether. This
solution is then introduced using an injection (14 gauge needle) into warm water or aqueous
media containing the drug maintained at 60°C. Vaporization of the ether leads to the
formation of single layered vesicles. The particle size of the Niosomes formed depend on the
conditions used, and can range anywhere between 50-1000μm.31
Hand shaking method (Thin Film Hydration Technique)
In this method a mixture of the vesicle forming agents such as the surfactant and cholesterol
are dissolved in a volatile organic solvent such as diethyl ether or chloroform in a round
bottom flask. The organic solvent is removed at room temperature using a rotary evaporator,
which leaves a thin film of solid mixturedeposited on the walls of the flask. This dried
surfactant film can then be rehydrated with the aqueous phase, with gentle agitation to yield
multilamellar Niosomes. The multilamellar vesicles thus formed can further be processed to
yield unilamellar Niosomes or smaller Niosomes using sonication, micro fluidization or
membrane extrusion techniques.32
Reverse phase evaporation technique
This method involves the creation of a solution of cholesterol and surfactant (1:1 ratio) in a
mixture of ether and chloroform. An aqueous phase containing the drug to be loaded is added
to this, and the resulting two phases are sonicated at 4-5°C. A clear gel is formed which is
further sonicated after the addition of phosphate buffered saline (PBS). After this the
temperature is raised to 40°C and pressure is reduced to remove the organic phase. This
results in a viscous Niosome suspension which can be diluted with PBS and heated on a
water bath at 60°C for 10 min to yield Niosomes.32
Trans membrane pH gradient (inside acidic) Drug Uptake Process (remote loading)
In this method, a solution of surfactant and cholesterol is made in chloroform. The solvent is
then evaporated under reduced pressure to get a thin film on the wall of the round bottom
flask, similar to the hand shaking method. This film is then hydrated using citric acid solution
(300mM, pH 4.0) by vortex mixing. The resulting multilamellar vesicles are then treated to
three freeze thaw cycles and sonicated. To the niosomal suspension, aqueous solution
containing 10mg/ml of drug is added and vortexed. The pH of the sample is then raised to
7.0-7.2 using 1M disodium phosphate (this causes the drug which is outside the vesicle to
become non-ionic and can then cross the niosomal membrane, and once inside it is again
ionized thus not allowing it to exit the vesicle). The mixture is later heated at 60°C for 10
minutes to give Niosomes.32
The Bubble Method
It is a technique which has only recently been developed and which allows the preparation of
Niosomes without the use of organic solvents. The bubbling unit consists of a round bottom
flask with three necks, and this is positioned in a waterbath to control the temperature. Watercooled reflux and thermometer is positioned in the first and second neck, while the third neck
is used to supply nitrogen. Cholesterol and surfactant are dispersed together in a buffer (pH
7.4) at 70°C. This dispersion is mixed for a period of 15 seconds with high shear
homogenizer and immediately afterwards, it is bubbled at 70°C using the nitrogen gas to
yield Niosomes.32
Formation of Proniosomes and Niosomes from Proniosomes
To create Proniosomes, a water soluble carrier such as Sorbitol is first coated with the
surfactant. The coating is done by preparing a solution of the surfactant with cholesterol in a
volatile organic solvent, which is sprayed onto the powder of Sorbitol kept in a rotary
evaporator. The evaporation of the organic solvent yields a thin coat on the Sorbitol particles.
The resulting coating is a dry formulation in which a water soluble particle is coated with a
thin film of dry surfactant. This preparation is termed Proniosome.33
Film Method
The mixture of surfactant and cholesterol is dissolved in an organic solvent (e.g. diethylether, chloroform, etc.) in a round-bottomed flask. Subsequently, the organic solvent is
removed by low pressure/vacuum at room temperature, for example using a rotary
evaporator. The resultant dry surfactant film is hydrated by agitation at 50–60°C and
multilamellar vesicles (MLV) are formed.33
Sonication
Typically the aqueous phase is added into the mixture of surfactant and cholesterol in a
scintillation vial. Then, it is homogenized using a sonic probe. The resultant vesicles are of
small unilamellar (SUV) type Niosomes. The SUV type Niosomes are larger than SUV
liposomes (i.e. SUV Niosomes are >100 nm in diameter while SUV liposomes are <100 nm
in diameter). It is possible to obtain SUV Niosomes by sonication of MLV type vesicles,
obtained for example through the film method explained above. For small volume samples
probe type sonicator is used while for larger volume samples bath type sonicator is more
appropriate.33
Method of Handjani–Vila
Equivalent amounts of synthetic non-ionic lipids are mixed with the aqueous solution of the
active substance to be encapsulated and a homogenous lamellar film is formed by shaking.
The resultant mixture is homogenized employing ultracentrifugation and agitation at a
controlled temperature. The Niosomes can be prepared from the Proniosome by adding the
aqueous phase with the drug to the Proniosomes with brief agitation at a temperature greater
than the mean transition phase temperature of the surfactant.33
Marketed Products
Lancôme has come out with a variety of antiageing products which are based on noisome
formulations. L’Oreal is also conducting research on anti-ageing cosmetic products.
Niosomal Preparation in the Market is – Lancôme (www.lancome.com)34
Disadvantages of Niosomes
1. Physical instability
2. Aggregation
3. Fusion
4. Leaking of entrapped drug
5. Hydrolysis of encapsulated drugs which limiting the shelf life of the dispersion
Proniosomes:
To overcome all above Disadvantages of Niosomes, Proniosomes are prepared and
reconstituted into Niosomes.
Hu and Rhodes et al reported that Proniosomes are dry formulations of surfactant-coated
carrier, which can be measured out as needed and rehydrated by brief agitation in hot water.
These “proniosomes” minimize problems of niosomes physical stability such as aggregation,
fusion and leaking and provided additional convenience in transportation, distribution,
storage and dosing.
Proniosome-derived niosomes are superior to conventional niosomes in convenience of
storage, transport and dosing. Stability of dry proniosomes is expected to be more stable than
a pre-manufactured niosomal formulation. In release studies proniosomes appear to be
equivalent to conventional niosomes. Size distributions of proniosome-derived niosomes are
somewhat better that those of conventional niosomes so the release performance in more
critical cases turns out to be superior.35
Proniosomes are dry powder, which makes further processing and packaging possible. The
powder form provides optimal flexibility, unit dosing, in which the proniosome powder is
provided in capsule could be beneficial.
A proniosome formulation based on maltodextrin was recently developed that has potential
applications in deliver of hydrophobic or amphiphilic drugs. The better of these formulations
used a hollow particle with exceptionally high surface area. The principal advantage with this
formulation was the amount of carrier required to support the surfactant could be easily
adjusted and proniosomes with very high mass ratios of surfactant to carrier could be
prepared. Because of the by slurry method, hydration of surfactant from proniosomes of a
wide range of compositions can be studied.36
Advantages of proniosomes over the niosomes
 Avoiding problem of physical stability like aggregation, fusion, leaking.
 Avoiding hydrolysis of encapsulated drugs which limiting the shelf life of the
dispersion.
Commonly used materials for proniosomes preparation36



Surfactants: Span20, Span40, Span60, Span80, Span85, Tween20, Tween40,
Tween80
Stabilizers: Cholesterol, lecithin
Carriers: Maltodextrin, sorbitol, mannitol, magnesium aluminum silicate,
microcrystalline cellulose, spray dried lactose, glucose monohydrate and sucrose
Stearates Selection of the carrier in the proniosomal formulation requires more
attention as it affects some factors like flexibility in surfactant and other component
ratio, surface area, efficient loading, etc…
Method of Preparation of proniosomes
The proniosomes can be prepared by
1. Spraying method.
2. Slurry method.
Spraying method
(Hu and Rhodes et al in 1999) prepared proniosomes by spraying the surfactant in organic
solvent onto sorbitol powder and then evaporating the solvent. Because the sorbitol carrier is
soluble in the organic solvent, it is necessary to repeat the process until the desired surfactant
load has been achieved. The surfactant coating on the carrier comes out to be very thin and
hydration of this coating allows multilamellar vesicles to form.37
Slurry method
(A lmir.I and Blazek - Walsh et al in 2001) developed slurry method to produce proniosomes
using maltodextrin as a carrier. The time required to produce proniosome by this is
independent of the ration of surfactant solution to carrier material. In slurry method, the entire
volume of surfactant solution is added to maltodextrin powder in a rotary evaporator and
vacuum applied until the powder appears to be dry and free flowing.
Drug containing proniosome-derived niosomes can be prepared in manner analogous to that
used for the conventional niosomes, by adding drug to the surfactant mixture prior to
spraying the solution onto the carrier (sorbitol, maltodextrin) or by addition of drug to the
aqueous solution used to dissolve hydrate the proniosomes.37
Formation of Niosomes from Proniosomes
The niosomes can be prepared from the proniosomes by adding the aqueous phase with the
drug to the proniosomes with brief agitation at a temperature greater than the mean transition
phase temperature of the surfactant.
Fig:1 Formation of Niosomes from Proniosomes.
T > Tm
Where,
T = Temperature
Tm = mean phase transition temp
Blazek-Walsh A.I. et al has reported the formulation of niosomes from maltodextrin based
proniosomes. This provides rapid reconstitution of niosomes with minimal residual carrier.
Slurry of maltodextrin and surfactant was dried to form a free flowing powder, which could
be rehydrated by addition of warm water.37,38
Characterization of proniosomes
Measurement of Angle of repose
The angle of repose of dry proniosomes powder was measured by a funnel method
(Lieberman et al 1990). The proniosomes powder was poured into a funnel which was fixed
at a position so that the 13mm outlet orifice of the funnel is 5cm above a level black surface.
The powder flows down from the funnel to form a cone on the surface and the angle of
repose was then calculated by measuring the height of the cone and the diameter of its base.39
Scanning electron microscopy
Particle size of proniosomes is very important characteristic. The surface morphology
(roundness, smoothness, and formation of aggregates) and the size distribution of
proniosomes were studied by Scanning Electron Microscopy (SEM).Proniosomes were
sprinkled on to the double- sided tape that was affixed on aluminum stubs. The aluminum
stub was placed in the vacuum chamber of a scanning electron microscope (XL 30 ESEM
with EDAX, Philips, Netherlands). The samples were observed for morphological
characterization using a gaseous secondary electron detector (working pressure: 0.8 torr,
acceleration voltage: 30.00 KV) XL 30, (Philips, Netherlands).39
Optical Microscopy
The niosomes were mounted on glass slides and viewed under a microscope (Medilux207RII, Kyowa-Getner, Ambala, India) with a magnification of 1200X for morphological
observation after suitable dilution. The photomicrograph of the preparation also obtained
from the microscope by using a digital SLR camera.39
Measurement of vesicle size
The vesicle dispersions were diluted about 100 times in the same medium used for their
preparation. Vesicle size was measured on a particle size analyzer (Laser diffraction particle
size analyzer, Sympatec, Germany). The apparatus consists of a He-Ne laser beam of 632.8
nm focused with a minimum power of 5mW using a Fourier lens [R-5] to a point at the center
of multielement detector and a small volume sample holding cell (Su cell). The sample was
stirred using a stirrer before determining the vesicle size. Hu C. and Rhodes in 1999 reported
that the average particle size of proniosomes derived niosomes is approximately 6μm while
that of conventional niosomes is about 14μm.39,40
Entrapment efficiency
Entrapment efficiency of the niosomal dispersion in can be done by separating the
unentrapped drug by dialysis, centrifugation or gel filtration as described above and 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.39,40
In vitro drug release can be done by (Chen DB et al., 2001)
 Dialysis tubing
 Reverse dialysis
 Franz diffusion cell
Dialysis tubing
Muller et al in 2002 studied in vitro drug release could be achieved by using dialysis tubing.
The proniosomes is placed in prewashed dialysis tubing which can be hermetically sealed.
The dialysis sac is then dialyzed against a suitable dissolution medium at room temperature;
the samples are withdrawn from the medium at suitable intervals, centrifuged and analysed
for drug content using suitable method (U.V. spectroscopy, HPLC etc). The maintenance of
sink condition is essential.41,42
Reverse dialysis
In this technique a number of small dialysis as containing 1ml of dissolution medium are
placed in proniosomes. The proniosomes are then displaced into the dissolution medium. The
direct dilution of the proniosomes is possible with this method; however the rapid release
cannot be quantified using this method.42
Franz diffusion cell
The in vitro diffusion studies can be performed by using Franz diffusion cell. Proniosomes is
placed in the donor chamber of a Franz diffusion cell fitted with a cellophane membrane. The
proniosomes is then dialyzed against a suitable dissolution medium at room temperature; the
samples are withdrawn from the medium at suitable intervals, and analysed for drug content
using suitable method (U.V spectroscopy, HPLC, etc) .the maintenance of sink condition is
essential.41,43
Drug Release Kinetic Data Analysis
The release data obtained from various formulations were studied further for their fitness of
data in different kinetic models like Zero order, Higuchi’s and peppa’s. In order to understand
the kinetic and mechanism of drug release, the result of in-vitro drug release study of
Niosome were fitted with various kinetic equation like zero order (Equation 1) as cumulative
% release vs. time, higuchi’s model (Equation 2) as cumulative % drug release vs. square root
of time. r2 and k values were calculated for the linear curve obtained by regression analysis
of the above plots
C = k0t …..(1)
Where k0 is the zero order rate constant expressed in units of concentration / time and t is
time in hours.
Q = kHt1/2 …..(2)
Where kH is higuchi’s square root of time kinetic drug release constant. To understand the
release mechanism in-vitro data was analyzed by peppa’s model (Equation 3) as log
cumulative % drug release vs. log time and the exponent n was calculated through the slope
of the straight line.
Mt / M∞ = btn …..(3)
Where Mt is amount of drug release at time t, M∞ is the overall amount of the drug, b is
constant, and n is the release exponent indicative of the drug release mechanism. If the
exponent n = 0.5 or near, then the drug release mechanism is Fickian diffusion, and if n have
value near 1.0 then it is non-Fickian diffusion.44
Osmotic shock
The change in the vesicle size can be determined by osmotic studies. Niosomal formulations
are incubated with hypotonic, isotonic, hypertonic solutions for 3 hours. Then the changes in
the size of vesicles in the formulations are viewed under optical microscopy.45
Stability studies
To determine the stability of proniosomes, the optimized batch was stored in airtight sealed
vials at different temperatures. Surface characteristics and percentage drug retained in
proniosomes and proniosomes derived niosomes were selected as parameters for evaluation
of the stability, since instability of the formulation would reflect in drug leakage and a
decrease. in the percentage drug retained.45 the proniosomes were sample at regular intervals
of time (0,1,2,and 3months ),observed for color change, surface characteristics and tested for
the percentage drug retained after being hydrated to form niosomes and analysed by suitable
analytical methods(UV spectroscopy, HPLC methods etc).46
Zeta potential analysis
Zeta potential analysis is done for determining the colloidal properties of the prepared
formulations. The suitably diluted proniosome derived noisome dispersion was determined
using zeta potential analyzer based on electrophoretic light scattering and laser Doppler
velocimetry method (Zetaplus™, Brookhaven Instrument Corporation, New York, USA).46
The temperature was set at 25°C. Charge on vesicles and their mean zeta potential values
with standard deviation of 5 measurements were obtained directly from the measurement.47
Applications of Proniosomes:
Drug Targeting:
One of the most useful aspects of proniosomes is their ability to target drugs. Proniosomes
can be used to target drugs to the reticulo-endothelial system. The reticulo-endothelial system
(RES) preferentially takes up proniosome vesicles. The uptake of proniosomes is controlled
by circulating serum factors called opsonins. These opsonins mark the proniosome for
clearance. Such localization of drugs is utilized to treat tumors in animals known to
metastasize to the liver and spleen. This localization of drugs can also be used for treating
parasitic infections of the liver. Proiosomes can also be utilized for targeting drugs to organs
other than the RES. A carrier system (such as antibodies) can be attached to proniosomes (as
immunoglobulin bind readily to the lipid surface of the niosome) to target them to specific
organs.47
Many cells also possess the intrinsic ability recognize and bind specific carbohydrate
determinants, and this can be exploited by proniosomes to direct carrier system to particular
cells.48,49
1. Anti-neoplastic Treatment:
Most antineoplastic drugs cause severe side effects. Niosomes can alter the metabolism;
prolong circulation and half life of the drug, thus decreasing the side effects of the drugs.
Niosomal entrapment of Doxorubicin and Methotrexate50,51,52 (in two separate studies)
showed beneficial effects over the unentrapped drugs, such as decreased rate of proliferation
of the tumor and higher plasma levels accompanied by slower elimination.49
Podophyllotoxin-dipalmitoylphosphatidylcholine (PPT-DPPC) proliposomes (PPT-DPPCPL)
for improvement of the stability of PPT-DPPC liposome. Methods Freeze-drying method was
used to prepare PPT-DPPC-PL, and the particle morphology, size range, encapsulation
efficiency and stability of PPT-DPPC lip osome were investigated. Results After hydration
of PPTDPPC-PL, PPT-DPPC liposome appeared multivesicular under electron microscope
and the particles were distributed homogenously with an average particle size of 1.45±0.38
μm. The encapsulation efficiency of PPT was 72.3%, and alters storage at 4 to 40 for 4 to 6
months, the proliposome remained stable. Conclusion the prepared PPT-DPPC-PL particles
by freeze-drying method are evenly distributed. The preparation method is relatively simple
with higher embedding ratio and better stability.53
2. Leishmaniasis:
Leishmaniasis is a disease in which a parasite of the genus Leishmania invades the cells of
the liver and spleen. Commonly prescribed drugs for the treatment are derivatives of
antimony (antimonials), which in higher concentrations can cause cardiac, liver and kidney
damage. Use of pronoisome in tests conducted showed that it was possible to administer
higher levels of the drug without the triggering of the side effects, and thus allowed greater
efficacy in treatment.54,55
3. Delivery of Peptide Drugs:
Oral peptide drug delivery has long been faced with a challenge of bypassing the enzymes
which would breakdown the peptide. Use of niosomes to successfully protect the peptides
from gastrointestinal peptide breakdown is being investigated.55 In an invitro study conducted
by Yoshida et al, oral delivery of a vasopressin derivative entrapped in niosomes showed that
entrapment of the drug significantly increased the stability of the peptide.56
4. Uses in Studying Immune Response:
Proniosomes are used in studying immune response due to their immunological selectivity,
low toxicity and greater stability. Niosomes are being used to study the nature of the immune
response provoked by antigens.56
5. Proniosomes as Carriers for Haemoglobin:
(Moser P. and Marchand Arvier M. in 1989) reported that niosomes can be used as carriers
for haemoglobin within the blood.56 The niosomal vesicle is permeable to oxygen and hence
can act as a carrier for hemoglobin in anemic patients.57
6. Proniosomes used in Cardiac Disorders:
Proniosomal carrier system for captopril for the treatment of hypertension that is capable of
efficiently delivering entrapped drug over an extended period of time. The potential of
proniosomes as a transdermal drug delivery system for captopril was nvestigated by
encapsulating the drug in various formulations of proniosomal gel composed of various ratios
of sorbitan fatty acid esters, cholesterol, lecithin prepared by coacervation-phase separation
method.57,58
7. Sustained Release:
Azmin et al suggested the role of liver as a depot for methotrexate after niosomes are taken
up by the liver cells.59 Sustained release action of niosomes can be applied to drugs with
therapeutic index and low water solubility since those could be maintained in the circulation
via niosomal encapsulation.60
8. Localized Drug Action:
Drug delivery through niosomes is one of the approaches to achieve localized drug action,
since their size and low penetrability through epithelium and connective tissue keeps the drug
localized at the site of administration.61 Localized drug action results in enhancement of
efficacy of potency of the drug and at the same time reduces its systemic toxic effects e.g.
Antimonials encapsulated within niosome are taken up by mononuclear cells resulting in
localization of drug, increase in potency and hence decrease both in dose and toxicity. The
evolution of niosomal drug delivery technology is still at an infancy stage, but this type of
drug delivery system has shown promise in cancer chemotherapy and antileishmanial
therapy.61,62
9. Antibacterial treapy:
Amphotericin-b proliposomes could be stored for 9 months without significant changes in
distribution of vesicle size and for 6 months without loss of pharmacological activity. Even
though physical stability of the preparation can be increased, a vacuum or nitrogen
atmosphere is still required during preparation and storage to prevent oxidation of
phospholipid.62,63
10. Hormonal Therapy:
A proniosome based transdermal drug delivery system of levonorgestrel (LN) was developed
and extensively characterized both in vitro and in vivo. The proniosomal structure was liquid
crystallinecompact niosomes hybrid which could be converted into niosomes upon hydration.
The system was evaluated in vitro for drug loading, rate of hydration (spontaneity), vesicle
size, polydispersity, entrapment efficiency and drug diffusion across rat skin. The effect of
composition of formulation, amount of drug, type of Spans, alcohols and sonication time on
transdermal permeation profile was observed. The stability studies were performed at 4°C
and at room temperature.61,62 The biological assay for progestational activity included
endometrial assay and inhibition with the formation of corpora lutea. The study demonstrated
the utility of proniosomal transdermal patch bearing levonorgestrel for effective
contraception.63
11. Cosmetics/Cosmeceuticals:
Proniosomal gels are generally present in transparent, translucent or white semisolid gel
texture, which makes them physically stable during storage and transport. Due to the limited
solvent system present, the proniosomes formed were the mixture of many phases of liquid
crystal, viz. lamellar, hexagonal and cubic phase liquid crystals. Dissolution of most
surfactants in water, leads to the formation of lyotropic liquid crystals rather than micellar
solution. Lamellar phase shows sheets of surfactants arranged in bilayer form, whereas in
hexagonal phase cylindrical units are packed in hexagonal fashion. Cubic phase consists of
curved bio-continuous lipid bilayer extending in three dimensions, separating two congruent
networks of water channels. These liquid crystals present an attractive appearance because of
their, transparency and high viscosity, although in the beginning of its formation, a short
range of less viscous compositions (so called liquid/gel compositions) appear in some cases.
Addition of water leads to interaction between water and polar groups of the surfactant results
in swelling of bilayer. Proniosomes exists in two forms, i.e. semisolid liquid crystal gel and
dry granular powder, depending on their method of preparation.64,65,66
12. NSAID appllication:
Ketorolac tromethamine (KT) is a nonsteroidal agent with potent analgesic and moderate
anti-inflammatory activity. The drug is currently administered intramuscularly and orally in
divided multiple doses for short-term management of postoperative pain (30 mg q.i.d. by IM
injection and 10 mg q.i.d. as oral tablets).66 This frequent dosing, which results in
unacceptable patient compliance, is required due to the short half-life of the drug (4–6 h).
Therefore, an alternative noninvasive mode of delivery of the drug is needed. Transdermal
delivery certainly appears to be an attractive route of administration to maintain the drug
blood levels of KT for an extended period of time.67
13. As Antiallergic:
Investigate the preparation and safety of carboplatin proliposomes Methods: Carboplatin
liposomes were prepared by film extrusion. Mannitol was incorporated into the liposome to
prevent the liposome vesicles from aggregation. The carboplatin proliposomes were obtained
by lyophilization.Allergic reactions to carboplatin proliposomes were evaluated in Guinea
pigs. The vein irritation and hemolysis post the administration of liposomes in rabbits were
characterized.68
14. Preparation of Vitamins:
To prepare vitamin A proliposomes and to enhance stability of vitamin A. Methods: Freeze
drying method was used to prepare vitamin A proliposomes. The particle morphology, the
size range, encapsulation efficiency and stability of vitamin A liposomes were studied.69
15. Co-Enzyme preparation of Proliposome:
To enhance the stability of coenzyme Q10 liposomes, freeze-drying method was used to
prepare coenzyme Q10 proliposomes. Sucrose, trehalose, mannitol and lactose were selected
as cryoprotectant. The particle morphology, the size range and encapsulation efficiency of
coenzyme Q10 liposomes before freeze-drying and after hydrated were studied. The weight
ratios of the optimized formulation were trehalose egg lecithin 4 to1. After coenzyme Q10
proliposomes was hydrated, the average diameter of rehydration liposomes was 508nm,and
the encapsulation efficiency was about 75%.The analysis of FT-IR spectrum showed that the
hydrogen bond between trehalose and lipid head groups formed in the dry state.70
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MARKETED PRODUCTS
Name of
therapeutic agent
Therapeutic category
Route of delivery
Delivery system
Captopril
Antihypertensive
Transdermal
Proniosomal gel
Flurbiprofen
NSAIDs
Transdermal
Proniosomal gel
Furesemide
Antihypertensive
Transdermal
Proniosomal gel
Lasartan
Antihypertensive
Transdermal
Proniosomal gel