Niosomes: A Vesicular Drug Delivery System

 

N. Narasimha Rao*, P. Srinivasa Babu. A Dihitha Chowdary, Y. Divya, T. Sri Laksmi, K. Sai Sneha Latha, P. Sirisha.

Department of Pharmaceutics, Vignan Pharmacy College, Vadlamudi, Guntur, Andhra Pradesh, India.

 

ABSTRACT:

Niosomes or  Non ionic surfactant vesicles are microscopic lamellar structures formed on admixture of non ionic surfactant of the alkyl or dialkylpolyglycerol ether class and cholesterol with subsequent hydration in aqueous media. Niosomes are unilamellar or multi lamellar structures that are microscopic in size. They are vesicular systems similar to liposomes that can be used as carriers of amphiphilic and lipophilic drugs ^[1]. The basic process of preparation is hydration by aqueous phase of the lipid phase which may be either a pure surfactant or a mixture of surfactant with cholesterol. Later preparing niosomal dispersion, by dialysis centrifugation or gel filtration the un entrapped drug is separated. The use of dialysis tubing is also included in Invitro rate release. Niosomes have been widely evaluated for controlled release and targeted delivery for treatment of cancer, viral infections and other microbial diseases. Circulation of the entrapped drug in body prolong as niosomes can entrap both hydrophilic and lipophilic drugs. Stable noisome dispersion must exhibit a constant particle size and a constant level of entrapped drug. Niosomes also serve better aid in diagnostic imaging and as a vaccine adjuvant. Niosomes are promising vehicle for drug delivery and being non ionic, it is less toxic and improves the therapeutic index of drug by restricting its action to target cells. They have all the advantages of liposomes but their low cost, greater stability and resultant ease of storage has lead to the exploitation of non ionic surfactants as alternative to phospholipids. This article gives information about the advantages, disadvantages, preparation methods, factors affecting, characterization, Invitro methods, and niosomal applications.^[2]

 

 

 

 

 

 

 

 

HISTORY:^[3]

In 1909, Paulehrlich started the devolopment of targeted delivary when he envisaged a drug delivary mechanism that would target directly to diseased cell. Since then, numbers of carriers were utilized to carry drug at target organ/tissue which includes liposomes and niosomes etc. Niosomes were first introduced in the future of cosmetic industry. Non ionic surfactants such as span-60 are preferred due to their less irritation power which decreases in order of cationic>anionic>ampholytic>non ionic surfactants which contains polar and non polar segments are posses high interfacial activity upon hydration bilayer in and entrap both hydrophilic and lipophilic drugs.

 

DEFINITION:

A Niosome is defined as a nonionic surfactant based liposome. Niosomes are formed mostly by with or without incorporation of cholesterol as an excipient and their lipids as an excipient. Niosomes are biodegradable and biocompatible immunogenic vesicles.

 

INTRODUCTION:^[4-6]

At present all offered drug delivery system achieves the positioning specific delivery solely with the controlled unhardness dynamics of drug in foreseeable manner. The selective drug delivery to the target tissues will increase the therapeutic effectivity of the drug and reduces its undesirable impact to non target tissues to extend the property and drug therapeutic index, however additionally to cut back the toxicity of the drug. Niosomes are unit shaped principally by non-ionic chemical agent associated steroid alcohol incorporation as an excipient is that the main goal of a web site specific drug delivery system. Alternative excipients may also be used. Niosomes have a lot of penetrating capability than the previous preparations of emulsions. The materials accustomed prepare niosomes build them a lot of stable however they're structurally like liposomes in having a bilayer. sac systems area unit a unique means that of drug delivery which will enhance bioavailability of encapsulated drug and supply therapeutic activity during a controlled manner for a chronic amount of your time. The conception of incorporating the drug into noisome for a more robust targeting of the drug at applicable tissue destination is wide accepted by researchers and academicians. Varied kinds of drug deliveries are potential exploitation niosomes like targeting, ophthalmic, topical, parenteral etc.

 

Advantages of Niosomes:^[7]

·      Niosomes enhance oral bioavailability of poorly absorbed drugs and improve skin penetration of drugs.

·      They surfactants are biodegradable, biocompatible and non-immunogenic.

·      Enhance the skin permeability of drugs when applied topically.

·      Handling and storage of surfactants do not require any special conditions.

·      The vesicle suspension being water based offers greater patient compliance over oily dosage forms.

·      Niosomes can act as depot to release the drug slowly and offer a controlled release.

·      They can increase the oral bioavailability of drugs.

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

·      Altering vesicle composition, size, lamellarity, tapped volume, surface charge and concentration can control the vesicle characteristics.

·      They can entrap both hydrophilic and hydrophobic drugs.

·      They are chemically stable as compare to liposomes.

·      Flexible in their structure characterization.

·      They prevent the metabolism of drugs from the enzymes present at tear/corneal epithelium interface.

·      Provide a prolonged and sustained release of drug.

·      Non-ionic surfactants vesicles.

·      No tissue irritation and damage was caused by penetration enchancers.

·      Relatively low cost of materials makes it suitable for industrial manufacture.

 

Disadvantages of niosomes: ^[8]

·      In rare cases, non-ionic surfactant interacts with other components of the system rendering the formulation homogenous or from precipitates.

·      Physical instability

·      Aggregation

·      Fusion

·      Leaking of entrapped drugs

·      Hydrolysis of encapsulated drugs which limiting shelf life of the dispersion.

 

Composition of niosomes: ^{[7, 8]}

The noisome structure was clearly shown in fig1.0. Cholesterol and non- surfactants are the two major components used for the preparation of niosomes. Cholesterol provides rigidity and proper shape. Few other surfactants that are reported to from niosomes are as follows.

Ÿ  Cholesterol

Ÿ  Non-ionic surfactants

 

a. Alkyl esters

b. Alkyl amides

c. Fatty acid and amino acid compounds

 

1.    Ether linked surfactant

2.    Di-alkyl chain surfactant

 

Cholesterol:                                                                      

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

 

Non-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.

 

Eg: Span (span 60, 40, 20, 85, and 80)

Tween (tween 20, 40, 60, 80)

 

a.    Alkyl esters:

Sorbitan esters are most preferred surfactant used for the preparation of niosomes amongst this category of surfactants.

Ex: polysorbate 60 has been utilized for encapsulation of dioclofenac sodium.

 

b.    Alkyl amides:

 Alkylamide (eg: galactosides and glycosides) have been utilized to produce niosomal vesicles.

 

c.    Fatty acid and amino acid compounds:

 Long chain fatty acids and amino acid moieties have also been used in some noisome preparation.

 

1.    Ether linked surfactant:

These are surfactants in which the hydrophilic hydrophobic moieties are ether linked, polyoxyethylene alkyl ethers with the general formula (CEOm), where n; i.e. Number of carbon atoms varies between 12 and 18 and; i.e. number of oxyethylene unit varies between 3 and 7

 

2.    Di- alkyl chain surfactant:

Surfactant was used as a principal component of niosomal preparation of sitbogluconate.

 

3.    Ester linked:

These are the surfactants in which hydrophilic and hydrophobic moieties are ester linked

 

 

Figure(1.0) shows the structure of liposome.

 

Preparation of semi uni lamellar vesicles:^[1,2]

This is a recent technique which is used to prepare small unilamellar vesicles. This method done based on submerged jet principle. In this process two fluidized streams interact at ultra high velocities and move forward through precisely defined micro channels with in the interaction chamber. The impingement of a thin liquid sheet along a common front is arranged such that the energy supplied to the system remains within the area of niosomes formation. Which results in a greater uniformity, smaller size and better reproducibility of niosomes found.

 

Sonication technique:

This is an one of the technique used for the preparation of niosomes. In this method drug is added to buffer solution and then drug-buffer solution is added to surfactant -cholesterol mixture in 10ml glass vial. Then the whole mixture is probe sonicated for 3minutes at 60°c by using a sonicator with a titanium probe to give niosomes. The resulted vesicles are small and unilamellar. This method was clearly shown in figure (1.1).

 

Fig(1.1) showing method of preparation of niosomes by sonication method.

 

Preparation of multilamellar vesicles:- ^[9,10] Thin film hydration technique: This is one of the technique used for preparation of niosomes. This method is also termed as hand shaking method. This technique typically used for multilamellar niosomes. This mixture of vesicles forming elements like surfactant and cholesterol are dissolved in volatile organic solvents like diethyl ether, chloroform or methanol in a round bottom flask. By using rotary evaporates the organic solvent removed at room temperature (20°c) and it leaves a thin layer of solid mixture deposited on the wall of the flask. The dried surfactant layer should be rehydrated. Rehydration is done with aqueous phase at 0-60°c with gentle agitation. This method was clearly shown in figure (1.2)

 

 

Figure (1.2).shows method of preparation of niosomes by thin film hydration method.

 

Preparation of unilamellar vesicles:^[11,12]

Ether injection method:

This is an one of the technique used for the preparation of niosomes. This method gives a mean of niosomes by slowly adding a mixture of surfactant dissolved in diethyl ether into water which should be maintained at 60°c. The solution of surfactant in ether is through 14-guage needle into an aqueous solution of material. Vaporization of ether leads to formation of single thin film layer vesicles. Based upon the conditions used the diameter of the vesicle ranging from 50nm to 1000nm.This method was clearly in figure (1.3).

 

Figure (1.3).shows method of preparation of niosomes by ether injection method.

 

Reverse phase evaporation technique:

This is one of the techniques used for preparation of niosomes. In this process cholesterol and surfactant (1:1) are dissolved in a mixture of ether and chloroform. 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 buffeted saline (PBS). The organic phase is removed at 40°c under low pressure. The resulting viscous niosomes suspension is diluted with PBS and heated on a water bath at 60°c for 10minutes to yield niosomes. It was reported that the preparation of dioclofenac sodium niosomes using tween85 by this method. This method show was in figure (1.4).

 

 

Figure (1.4).shows method of preparation of niosomes by reverse phase evaporation technique.

Miscellaneous techniques:^[13]

Multiple membrane extrusion technique:

This is an one of the technique used for preparation of niosomes. In this method mixture of surfactant, cholesterol and diacetyl phosphate in chloroform is made into thin film by evaporation. The film is hydrated with aqueous drug poly carbonate 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. This method was shown clearly in figure (1.5).

 

 

Figure(1.5).Shows the method of preparation of niosomes by multiple membrane extrusion technique.

 

Emulsion technique:

In this process an organic solution of surfactant, cholesterol and aqueous solution of drug, oil in water (o/w) emulsion is prepared. Then evaporated leaving niosomes dispersed in the aqueous phase. Liquid

 

injection technique:

This is one type of technique used for the preparation of niosomes. In this method either mixture of lipids and surfactant is first melted and then injected into a highly agitated heated aqueous phase containing dissolved drug or the drug can be dissolved in molten lipid and the mixture will be injected into agitated, heated aqueous phase containing surfactant. This method doesn’t require expensive organic phase. This method was clearly shown in figure (1.6).

 

Figure (1.6).show the method of preparation of niosomes by lipid injection method.

The bubble method:

This is one type of technique used for preparation of niosomes. It is a novel technique. It is also used for preparation of niosomes. In this process no organic solvents are used. Round bottomed flask is used as bubbling unit with its 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. At 70°c cholesterol and surfactant are dispersed together in the buffer (PH-7.4) and mixed with high shear homogenizer for 15 seconds and immediately afterwards bubbled at 70°c using nitrogen gas.

 

Evaluation of formulations:^[14-16]

1. Scanning electron microscopy method:

The shape and surface characteristics of niosomes were evaluated by Scanning electron microscopy(SEM).In this method lyophilized sample was taken in sample holder using double –sided sticking tape and after gold coating images were recorded at the required magnification.

 

2. Particle size:

 Particle size was determined by using an optical microscopy with a calibrated eye piece micrometer. About 200 niosomes were measured individually, average was taken, mean diameter was calculated.

 

3. Entrapment efficiency:

The % entrapment efficiency of vesicles was determined by freeze thawing centrifugation technique. Niosomal suspension was filled in drop tubes and stored at -20^o c in a refrigerator for 24 hours. After 24 hour’s niosomal suspension and stored temperature. This suspension was centrifuged at 1500 *G rpm for 30 minutes with water methanol mixture (80:20), then measured UV spectrophotometrically at 244nm against water methanol mixture as standard.

 

Entrapment efficiency was calculated by using following equation:

%EE= (Total amount of drug in suspension-drug in supernant) / (Total Amount of Drug in suspension))*100

 

4. Angle of repose method:

The angle of repose of dry niosomes powder was measured by a funnel method. The niosomes flows from the funnel to form a cone surface and the angle of repose was then calculated by measuring the height of cone and the diameter of its base.

 

Vesicle size change can be determined by these studies. In this method niosomes are incubated with hypotonic, isotonic, hypertonic solutions for 3 hours. These changes viewed under optical microscopy.

5. Stability Analysis:

Stability of niosomal dispersion was carried out for 30days at 2-80^oc and room temperature. Surface characteristics and percentage drug retained in niosomes, in this studies observed for colour change, surface characteristics and analyzed under suitable analytical methods like UV spectroscopy, HPLC methods etc.

 

6. Zeta potential method:

Zeta potential method used to determine the colloidal properties of the prepared formulations. Zeta potential analyzer based on electrophoretic light scattering and laser Doppler velocimetry method. Zeta potential values obtained directly from the measurement.

 

Invitro Methods:^[17-18]

In vitro drug release can be done by

 

1. Dialysis tubing:

In this method niosomes is placed in prewashed dialysis tubing which can be hermetically sealed. and then placed in 200ml buffer solution in a 250 ml beaker with constant shaking at 25^oc or body temperature .The buffer was analyzed at various time intervals .

 

2. Reverse dialysis:

Niosomes are placed in small dialysis tubes containing 1 ml of dissolution medium and niosomes are placed in dissolution medium.

 

3. Franz diffusion cell:

In this method cellophane membrane is used as the dialysis membrane and suitable dissolution medium taken at room temperature, the sample withdrawn at suitable time intervals.

 

Applications:^[19-22]

1.      Niosomes as drug carriers

2.      Diagnostic purpose:

Niosomes are used as diagnostic agents.PEG 4400 and N-Palmitoyl glucosamine improved targeting tumor of an encapsulated paramagnetic agent assessed with MR imaging.

 

3. Delivary of peptide drugs:

Niosomal entrapped oral delivary of 9-desglycinamide,8-arginine vasopressin was tested in an Invitro intestinal loop model and reported that the stability of peptide increased significantly.

 

4. Neoplasia:

Doxorubicin which has broad spectrum antibiotic activity shows a dose dependant irreversible cardio toxic effect. The half life of drug is increased by its niosomal entrapment of drug and its circulation is prolonged and alteration of metabolism. If a mice bearing S-180 tumor is treated with niosomal delivary of this drug it was observed that their life span increased.

 

5. Immunological applications:

Niosomes are used for studying the nature of the immune response provoked by antigens. Brewer and Alexander60 have reported niosomes as potent adjuvant in terms of immunological selectivity and low toxicity and stability.

 

6. Transdermal delivery of drugs by niosomes:

 Slow penetration of drug through skin is a disadvantage of transdermal drug delivery. An increase in penetration rate has been achieved by transdermal delivery of drug incorporated in niosomes. Jayraman et al61 has studied the topical delivery of erythromycin from various formulations including niosomes or hairless mouse. From these studies, and confocal microscopy, it was seen that non-ionic vesicles could be formulated to target pilosebaceous glands.

 

7. Niosomes as Hemoglobin carriers:

 Niosomes can be used as a carrier for hemoglobin. Niosomal suspension shows a visible spectrum super imposable onto that of free hemoglobin. Vesicles are permeable to oxygen and hemoglobin.

 

8. Niosomal formulation as a brain targeted delivery system for the vasoactive intestinal peptide:

Radiolabel led (I125) VIP-loaded with glucose bearing niosomes and injected intravenously to mice. Encapsulated VIP within the glucose bearing niosomes exhibits higher VIP brain uptake as compared to control drug delivary system.

 

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Accepted on 26.06.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(8): 3731-3736.