INTRODUCTION:

Paul Ehrlich, in 1909, initiated the era of development for targeted delivery when he envisaged a drug delivery mechanism that would target directly to diseased cell. Since then, numbers of carriers were utilized to carry drug at the target organ/tissues, which include immunoglobulins, serum proteins, synthetic polymers, liposomes, microspheres, erythrocytes, niosomes etc¹.

In niosomes, the vesicles forming amphiphileis a non-ionic surfactant such as Span – 60 which is usually stabilized by addition of cholesterol and small amount of anionic surfactant such as dicetyl phosphate ².

Niosomes and liposomes are equiactive in drug delivery potential and both increase drug efficacy as compared with that of free drug. Niosomes are preferred over liposomes because the former exhibit high chemical stability and economy³.

Surfactant forming niosomes are biodegradable, non-immunogenic and biocompatible. Incorporating them into niosomes enhances the efficacy of drug, such as nimesulide, flurbiprofen, piroxicam, ketoconazole and bleomycin exhibit more bioavailability than the free drug^4,5.

STRUCTURE OF NIOSOME:

A typical niosome vesicle would consist of a vesicle forming amphiphile 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 dicetyl phosphate, which also helps in stabilizing the vesicle^{.6, 7}

Advantages ^[8]

1. The vesicles may act as a depot, releasing the drug in a controlled manner.

2. They are osmotically active and stable, and also they increase the stability of entrapped drug.

3. They improve the therapeutic performance of the drug molecules by delayed clearance from the circulation, protecting the drug from biological environment and restricting effects to target cells.

4. The surfactants used are biodegradable, biocompatible and non-immunogenic.

5. They improve oral bioavailability of poorly absorbed drugs and enhance skin penetration of drugs.

6. They can be made to reach the site of action by oral, parenteral as well as topical routes.

7. The vesicles may act as a depot, releasing the drug in a controlled manner.

8. Handling and storage of surfactants requires no special conditions.

9. Due to the unique infrastructure consisting of hydrophilic, amphiphilic and lipophilic moieties together they, as a result can accommodate drug molecules with a wide range of solubilities.

Disadvantages

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.

COMPOSITIONS OF NIOSOMES:^9-11

The two major components used for the preparation of niosomes are,

1. Cholesterol

2. Nonionic surfactants

1. Cholesterol

Cholesterol is used to provide rigidity and proper shape, conformation to the niosomespreparations.

2. Nonionic surfactants

The role surfactants play a major role in the formation of niosomes. The following non ionic surfactants are generally used for the preparation of niosomes.

E.g.

· Spans (span 60, 40, 20, 85, 80)

· Tweens (tween 20, 40, 60, 80) and

· Brijs (brij 30, 35, 52, 58, 72, 76).

The non ionic surfactants possess a hydrophilic head and a hydrophobic tail.12

PREPARATION METHODS OF NIOSOMES:^12-18

The preparation methods should be chosen according to the use of the niososmes, following methods for preparation of niosomes.

A. Ether injection method

This method provides a means of making niosomes by slowly introducing a solution of surfactant dissolved in diethyl ether into warm water maintained at 60°C. The surfactant mixture in ether is injected through 14-gauge needle into an aqueous solution of material. Vaporization of ether leads to formation of single layered vesicles. Depending upon the conditions used the diameter of the vesicle range from 50 to 1000 nm.

Preparation steps

Surfactant is dissolved in diethyl ether

Then injected in warm water maintained at 60⁰c through a 14 gauze needle

Ether is vaporized to form single layered niosomes

B. Hand shaking method:

The mixture of vesicles forming ingredient like surfactant like surfactant and cholesterol are dissolved in a volatile oeganic solvent (diethyl ether, methanol) in a round bottom flask. Organic solvent is removed at room temperature (20^oC) using rotary evaporator leaving a thin layer of solid mixture deposited on the wall of the flask. The dried surfactant film can be rehydrated with aqueous phase at 0- 60°C with gentle agitation. This process forms typical multilamellar niosomes.

Preparation steps

Surfactant + Cholesterol + Solvent

Film can be rehydrated to form multilamellar niosomes

Sonication method:

A typical method of production of the vesicles is by sonication of solution as described by Cable. In this method analiquot of drug solution in buffer is added to the surfactant/cholesterol mixture in a 10-ml glass vial. The mixture is probe sonicated at 60°C for 3 minutes using a sonicator with a titanium probe to yield niosomes.

Preparationm steps

Drug in buffer + Surfactant/Cholesterolin 10 ml

Above mixture is sonicated for 3 mints at 60^oC using titanium probe yielding niosomes

C. Micro fluidization Method:

Micro fluidization is a recent technique used to prepare unilamellar vesicles of defined size distribution. 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.²¹

Preparation steps:

Two ultra high speed jets inside interaction chamber

Impingement of thin layer of liquid in micro channles

Formation of uniform niosomes

E. Multiple membrane extrusion method:

Mixture of surfactant, cholesterol and dicetyl phosphate in chloroform is made into thin film by evaporation. The film is hydrated with aqueous drug polycarbonate membranes, solution and the resultant suspension extruded through which are placed in series for up to 8 passages. It is a good method for controlling

noisome size. ²¹

F. Reverse Phase Evaporation Technique (REV):

Cholesterol and surfactant (1:1) are dissolved in a mixture of ether and chloroform. An aqueous phase containing drug is added to this and the resulting two phases are sonicated at 4-5°C. The clear gel formed is further sonicated after the addition of a small amount of phosphate buffered saline (PBS). The organic phase is removed at 40°C under low pressure. The resulting viscous noisome suspension is diluted with PBS and heated on a water bath at 60°C for 10 min to yield niosomes. ²²

Preparation steps

Cholesterol + Surfactant dissolved in ether + Chloroform

Sonicated at 5^oC and again sonicated after adding PBS

Drug in aqueous phase is added to above mixture

Heated on a water bath for 60^oC for 10 mints to yield niosomes.

G. Trans membranes PH gradient (inside acidic) Drug Uptake

Process: or Remote Loading Technique

Surfactant and cholesterol are dissolved in chloroform. The solvent is then evaporated under reduced pressure to get a thin film on the wall of the round bottom flask. The firm is hydrated with 300mM citric acid (PH 4.00 by vertex mixing. The multilamellar vesicles are frozen and shared 3 times and later sonicated. To this niosomal suspension. Aqueous solution containing 10 mg ml of drug is added and vortexes. The PH of the sample is then raised to 7.0-7.2 with 1M disodium phosphate. This mixture is later heated at 60°C for 10 minutes so give niosomes.23

Preparation Steps:

Surfactant +Cholesterol in chloroform

Solventis evaporated under reduced pressure

Thin film is deposited on the walls of RBF

Hydrated with citric acid by vortex mixing

3 cycles of freezing and thawing then sonication

RBF as bubbling unit with three necks in water bath

Reflux, thermometer and nitrogen supply by three necks

Cholesterol + Surfactant dispersed in buffer pH 7.4 at 70^oC

Above dispersion is homogenized for 15 sec and then bubbled with nitrogen gas at 70^oC

To get niosomes

H. The Bubble Method:

It is the novel technique for the one step preparation of liposomes and niosomes without use of organic solvents. 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. Cholesterol and surfactant are dispersed together in this buffer (PH 7.4) at 70°C, the dispersion mixed for 15 seconds with high shear homogenizer and immediately afterwards “bubbled” at 70°C using nitrogen gas.

Separation of Unentrapped Drug:

The removal of unentrapped solute from the vesicles by various techniques, which include: -

1. Dialysis:

The aqueous niosomal dispersion is dialyzed in dialysis tubing against suitable dissolution medium at room temperature. The samples are withdrawn from the medium at suitable time\ intervals, centrifuged and analyzed for drug content using suitable method (U.V. spectroscopy, HPLC etc).

2. Gel Filtration:

The unentrapped drug is removed by gel filtration of niosomal dispersion through a Sephadex-G-50 column and eluted with suitable mobile phase and analyzed with suitable analytical techniques.

3. Centrifugation:

The proniosome derived niosomal suspension is centrifuged and the supernatant is separated. The pellet is washed and then resuspended to obtain a niosomal suspension free from unentrapped drug.

Factors affecting formation of niosomes:

1. Drug:

Entrapment of the drug in niosomes to increases vesicle size, probably by interaction of solute with surfactant head groups, increasing the charge and mutual repulsion of the surfactant bilayers, for increasing vesicle size. In polyoxyethylene glycol (PEG) coated vesicles, some drug is entrapped in the long PEGchains, thus reducing the tendency to increase the size. The hydrophilic lipophilic balance[HLB] of the drug affects degree of entrapment.

2. Nature of surfactants:

Surfactant used for preparation of niosomesmust have a hydrophilic head and hydrophobic tail. The hydrophobic tail may consist of one or two alkyl or perfluoroalkyl groups or in some cases a single steroidal group¹⁹.

The ether type surfactants with single chainalkyl as hydrophobic tail is more toxic than corresponding dialkyl ether chain .The ester type surfactants are chemically less stable than ether type surfactants and the former is less toxic than the latter due to ester-linked surfactant degraded by esterases to triglycerides and fatty acid in vivo²⁰.

3. Cholesterol content and charge:

Inclusion of cholesterol in niosomes increased its hydrodynamic diameter and entrapment efficiency. In general, the action of cholesterol is two folds; on one hand, cholesterol increases the chain order of liquid-state bilayers and on the other, cholesterol decreases the chain order of gel state bilayers. At a high cholesterol concentration, the gel state is transformed to a liquid-ordered phase.

An increase in cholesterol content of the bilayers resulted in a decrease in the release rate of encapsulated material and therefore an increase of the rigidity of the bilayers obtained. Presence of charge tends to increase the interlamellar distance between successive bilayers in multilamellar vesicle structure and leads to greater overall entrapped volume.

4. Membrane composition:

The stable niosomes can be prepared with addition of different additives along with surfactants and drugs. Niosomes formed have a number of morphologies and permeability and stability properties can be altered by manipulating membrane characteristics by different additives. In case of polyhedral niosomes formed from C16G2, the shape of these polyhedral niosome remains unaffected by adding low amount of solulanC24 (cholesteryl poly-24-oxyethylene ether),which prevents aggregation due to development of steric hindrance²¹.

5. 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^27-31:

a. Measurement of Angle of repose:

The angle of repose of dry niosomes powder wasmeasured by a funnel method. The niosomes 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.

b. Scanning electron microscopy:

Particle size of niosomes is very important characteristic. The surface morphology (roundness, smoothness, and formation of aggregates) and the size distribution of niosomes were studied by Scanning Electron Microscopy (SEM). Niosomes were sprinkle don 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).

c. Bilayer formation

Assembly of non-ionic surfactants to form bilayer vesicle is characterized by X-cross formation under light polarization microscopy^25.

d. Number of lamellae:

It is determined by using NMR spectroscopy, small angle X-ray scattering and electronmicroscopy²⁶.

e. Membrane rigidity:

Membrane rigidity can be measured by means of mobility of fluorescence probe as function of temperature²⁵.

f. Optical Microscopy:

The niosomes were mounted on glass slides and viewed under a microscope (Medilux-207RII, 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.

g. 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-Nelaser beam of 632.8 nm focused with a minimum power of 5 mW 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 7 in 1999 reported that the average particle size of niosomes derived niosomes is approximately 6μm while that of conventional niosomes is about 14μm.

h. 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% n-propanol or 0.1% Triton X-100 and analyzing the resultant solution by appropriate assay method for the drug. Where,

Total drug – Diffused drug

Percentage entrapment = _______________________ × 100

Total drug

i. Zeta potential analysis:

Zeta potential analysis is done for determining the colloidal properties of the prepared formulations. The suitably diluted niosomes derived from pronoisome dispersion was determined using zeta potential analyzer based on electrophoretic light scattering and laser Doppler velocimetry method (Zeta plus™, Brookhaven Instrument Corporation, New York, USA). The temperature was set at 25°C. Charge on vesicles and their meanzeta potential values with standard deviation of measurements were obtained directly from the measurement.

Table 1.Method for evaluation of niosomes

Evaluation parameter	Method
Morphology	SEM, TEM, freeze fracture technique
Size distribution	Dynamic light scattering particle
Polydispersity index	Size analyzer
Viscosity	Ostwald viscometer
Membrane thickness	X-ray scattering analysis
Thermal analysis	DSC
Turbidity	UV-Visible diode array spectrophotometer
Entrapment efficacy	Centrifugation, dialysis, gel
In-vitro release study	Dialysis membrane
Permeation study	Franz diffusion cell

In-vitro methods for niosomes:

In vitro drug release can be done by

_ 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 niosomes 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 analyzed for drug content using suitable method (U.V. spectroscopy, HPLC etc). The maintenance of sink condition is essential.

Reverse dialysis:

In this technique a number of small dialysis as containing1ml 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.

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 analyzed for drug content using suitable method (U.V spectroscopy, HPLC, etc). The maintenance of sink condition is essential.

Applications of niosomes:

Application of niosomal drug delivery can be used to many pharmacological agents for there to treat a number of diseases. The following few of their therapeutic uses are as follows:

Targeting of bioactive agents:

1. To reticulo-endothelial system (RES)15. The vesicles occupy preferentially to the cells of RES. It is due to circulating serum factors known as opsonins, which mark them for clearance. Such localized drug accumulation has, however, been exploited in treatment of animal tumors known to metastasize to the liver and spleen and in parasitic infestation of liver.1

To organs other than reticulo-endothelial system(RES)^32-33

By use of antibodies, carrier system can be directed to specific sites in the body. Immunoglobulins seem to have affection to the lipid surface, thus providing a convenient means for targeting of drug carrier. Many cells have the intrinsic ability to recognize and bind particular carbohydrate determinants and this property can be used todirect carriers system to particular cells.

Delivery of peptide drugs:

Niosomal entrapped oral delivery of 9-desglycinamide, 8-arginine vasopressin was examined in an in-vitro intestinal loop model and reported that stability of peptideIncreasedsignificantly³⁴. Immunological applications of niosomes for studying the nature of the immune response provoked by antigens niosomes have been used. Niosomes have been reported as potent adjuvant in terms of immunological selectivity, low toxicity and stability³⁵.

Niosome as a carrier for Hemoglobin:

Niosomal suspension shows a visible spectrum superimposable onto that of free hemoglobin so can be used as a carrier for hemoglobin. Vesicles are also permeable to oxygen and hemoglobin dissociation curvecan be modified similarly to non-encapsulated haemoglobin ³⁶.

Transdermal delivery of drugs by niosomes:

An increase in the penetration rate has been achieved by transdermal delivery of drug incorporated in niosomes as slow penetration of drug through skin is the major drawback of transdermal route of delivery for other dosage forms. The topical delivery of erythromycin from various formulations including niosomes has studied on hair less mouse and from the studies, and confocal microscopy, it was found that non-ionic vesicles could be formulated to target pilosebaceous glands³⁷.

Diagnostic imaging with niosomes:

Niosomal system can be used as diagnostic agents. Conjugated niosomal formulation of gadobenate dimeglcemine with [N-palmitoylglucosamine(NPG)], PEG4400, and both PEG and NPG exhibit significantly improved tumor targeting of an encapsulated paramagnetic agent assessed with MR imaging³⁸.

Ophthalmic drug delivery:

From ocular dosage form like ophthalmic solution, suspension and ointment it is difficult to achieve excellent bioavailability of drug due to the tear production, impermeability of corneal epithelium, non-productive absorption and transient residence time. But niosomal and liposomal delivery systems can be used to achieve good bioavailability of drug. Bio adhesive-coated niosomal formulation of acetazolamide prepared from span 60, cholesterol stearylamine or dicetylphosphate exhibits more tendencies for reduction of intraocular pressure as compared to marketed formulation (Dorzolamide)³⁹.

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. 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 niosomes are taken up by mononuclear cells resulting in localization of drug, increase in potency and hence decrease both in dose

and toxicity⁴⁰.

Conclusion- Future Prospects:

There is lot of scope to encapsulate toxic anti-cancer drugs, anti-infective drugs, anti-AIDS drugs, anti-viral drugs, etc. In niosomes and to use the mas promosing drug carriers to achieve better bioavailability and targeting properties and for reducing the toxicity and side effects of the drugs. Niosomes also serve better aid in diagnostic imaging and as avaccine adjuvant. Thus these areas need further exploration and research so as to bring out commercially available niosomal preparation. 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. The present a structure similar to liposomes. Various type of drug deliveries can be possible using niosomes like targeting, ophthalmic, topical, parentral.

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Received on 12.04.2016 Modified on 20.04.2016

Res. J. Pharm. Dosage Form. & Tech. 2016; 8(3): 211-217.

DOI: 10.5958/0975-4377.2016.00029.X