Drug Delivery System Vesicular Delivery Of Drug Niosomes Biology Essay

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Non-ionic surfactant vesicles (or niosomes) are now widely studied as alternates to liposomes. An increasing number of non-ionic surfactant has been found to form vesicles, capable of entrapping hydrophilic and hydrophobic molecules. Drug delivery system using colloidal particulate carrier such as liposomes or niosomes has distinct advantages over conventional dosage forms because the particles can act as drug containing reservoirs. Modification of the particle composition or surface can adjust the affinity for the target site and/or the drug release rate. Niosomes proved to be a promising drug carrier and has potential to reduce the side effects of drugs and increased therapeutic effectiveness in various diseases.


Niosomes, Surfactants, Cholesterol, Entrapment efficiency.

1. Introduction

Controlled release formulations are often prepared to permit the establishment and maintenance of any concentration at target site for longer period of time. One such technique of drug targeting is niosomes. Niosomes are microscopic lamellar structures formed on admixture of a nonionic surfactant, cholesterol and diethyl ether with subsequent hydration in aqueous media. They behave in vivo like liposomes prolonging the circulation of entrapped drug and altering its organ distribution [1]. Niosomal drug delivery has been studied using various methods of administration [2] including intramuscular [3], intravenous [4], peroral and transdermal [5,6]. In addition, as drug delivery vesicles, niosomes have been shown to enhance absorption of some drugs across cell membranes [7], to localize in targeted organs [8] and tissues and to elude the reticuloendothelial system. Niosomes has been used to encapsulate colchicines [9], estradiol [10], tretinoin [11,12], dithranol [13,14], enoxacin [15] and for application such as anticancer, anti-tubercular, anti-leishmanial, anti-inflammatory, hormonal drugs and oral vaccine [3,4,7,16-22]. Niosomes are preferred over other vesicular systems as they offer the following advantages [23,24] such as: The vesicle suspension is water based vehicle. This offers high patient compliance in comparison with oily dosage forms. They possess an infrastructure consisting of hydrophilic, amphiphilic and lipophilic moieties together and as a result can accommodate drug molecules with a wide range of solubilities. The characteristics of the vesicle formulation are variable and controllable. Altering vesicle composition, size, lamellarity, tapped volume, surface charge and concentration can control the vesicle characteristics. The vesicles may act as a depot, releasing the drug in a controlled manner. Other advantage of niosomes includes: They are osmotically active and stable, as well as they increase the stability of entrapped drug. Handling and storage of surfactants requires no special conditions. They improve oral bioavailability of poorly absorbed drugs and enhance skin penetration of drugs. They can be made to reach the site of action by oral, parenteral as well as topical routes. The surfactants are biodegradable, biocompatible and non-immunogenic. 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. Niosomal dispersion in an aqueous phase can be emulsified in a non-aqueous phase to regulate the delivery rate of drug and administer normal vesicle in external non-aqueous phase.

2. Structure of niosomes

Nonionic surfactant vesicles (NSVs or niosomes) result from the self assembly of hydrated surfactant monomers. They are similar in physical structure and form to the more widely studied phospholipid vesicles (liposomes) [1], consisting of single or multiple surfactant bilayers (lamellae) enclosing an aqueous core. A schematic diagram of a non-ionic surfactant vesicle is shown in Fig. 1 Preliminary X-ray scattering data on unilamellar sorbitan monostearate (C18-sorbitan monoester)-cholesterol niosomes suggest a bilayer spacing of 15 nm and a bilayer thickness of 3.3-3.4 nm [25], the latter similar to the figure obtained for the bilayer thickness of phospholipid vesicles (3.4-3.9 nm) [26]. Although terminology suggests that distinctions exist between liposomes and niosomes, of which the basic unit of assembly is the amphiphile, their properties are largely similar and the differences between liposomes (phospholipid vesicles) and non-ionic surfactant vesicles are sometimes blurred as liposomes are often prepared incorporating a non-ionic surfactant component [27,28], while non-ionic surfactant vesicles may also be formulated with various ionic amphiphiles such as stearylamine and dicetylphosphate [29,30] to achieve greater protection against flocculation in vesicle suspensions. The association of nonionic surfactant monomers into vesicles on hydration is a result of the fact that there exists a high interfacial tension between water and the hydrocarbon portion (or any other hydrophobic group) of the amphiphile which causes these groups to associate. Simultaneously, the steric, hydrophilic and/or ionic repulsion between the head groups ensures that these groups are in contact with water. These two opposing forces result in a supramolecular assembly.

3. Method of preparation of niosomes

Various methods are reported for the preparation of niosomes such as:

3.1. Ether injection method

3.2. Hand shaking method (Thin film hydration technique)

3.3. Sonication method

3.4. Reverse phase evaporation technique (REV)

3.5. Microfluidization

3.6. Multiple membrane extrusion method

3.7. Trans membrane pH gradient (inside acidic) drug uptake process (remote


3.8. Bubble method

3.9. Formation of niosomes from proniosomes

3.1. Ether injection method

This method provides a means of making niosomes by slowly introducing a solution of surfactant dissolved in diethyl ether (volatile organic solvent) 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 (volatile organic solvent) leads to formation of single layered vesicles. Depending upon the conditions used, the diameter of the vesicle range from 50 to 1000 nm [3,32].

3.2. Hand shaking method (Thin film hydration technique)

The mixture of vesicles forming ingredients like surfactant and cholesterol are dissolved in a volatile organic solvent (diethyl ether, chloroform or methanol) in a round bottom flask. The organic solvent is removed at room temperature (20°C) 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 [32].

3.3. Sonication

In this method an aliquot 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 [32].

3.4. 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 niosome suspension is diluted with PBS and heated on a water bath at 60°C for 10 min to yield niosomes [33].

3.5. Micro fluidization

It 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 [34]. The result is a smaller size, greater uniformity and better reproducibility of niosomes formed.

3.6. 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. Multiple membrane extrusion method is better for the controlling of niosome size [34].

3.7. Trans membrane pH gradient (inside acidic) drug uptake process (remote loading)

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 film is hydrated with 300 mM citric acid (pH 4.0) by vortex mixing. The multilamellar vesicles are frozen and thawed 3 times and later sonicated. To this niosomal suspension, aqueous solution containing 10 mg/ml of drug is added and vortexed. 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 to give niosomes [35].

3.8. Bubble method

It is novel technique for the one step preparation of liposomes and niosomes without the 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 [36]. 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.

3.9. 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 [37]. In which each water-soluble particle is covered with a thin film of dry surfactant. This preparation is termed "Proniosomes".

4. Modified nonionic surfactants

Different types of modified nonionic surfactant vesicles, which are discussed below.

4.1. Sterically Stabilized Niosomes

4.2. Polymerized Nonionic Surfactant Vesicles

4.3. Emulsified Niosomal Dispersion

4.1. Sterically stabilized niosomes

Colloidal carriers are removed from circulation mainly by cells of mononuclear phagocytic system (MPS). Modifying the surface properties by coating the carrier with polymers is known to alter the rate of uptake by the MPS [38]. Chouhan and Lowrence synthesized a non-ionic surfactant polyoxyethylene 20 glycerol 1, 2 distearoyl ether bearing polyoyethylene glycol (PEG) as its hydrophilic chain and determined volume and diameter of niosomes prepared by different methods [36]. The presence of PEG, by increasing the steric stabilization of the particles, should reduce its uptake by cells of the MPS. Incorporation of cholesterol, polyoxyethylene ether (soluans) also provides sterical stability and modifies surface properties. Cablew reported sustained and higher plasma level of doxorubicin administered in solulan modified niosomes [39].

4.2. Polymerized nonionic surfactant vesicles

Since vesicle system are more or less thermodynamically unstable, proximity and regular orientation of surface-active molecules at interface has been exploited to increase stability by controlled polymerization at vesicular bilayer made up of non-ionic surfactant bearing a polymerizable residue. Polymerizable surfactant used were

Diamethyl-n-hexadecyl [{(1-iso-cynoethyl) carbonyloxy} methyl] ammonium bromide.

N, N (dihexadecanoyloxyethyl) maleyl amide.

Dihexadecyl N, methyl N, maleyl ammonium bromide.

The vesicles formed from these surfactants were polymerized by radiation or radical initiation. Kippenberger observed that UV exposure brought closing of both surfaces while additions of radical initiator lead to selective "Zipping up" of outer surfaces only [40]. This allows for selective polymerization of surface. Polymerization restricts mobility of hydrocarbon core and improves the stability of niosomes, size of the vesicles on polymerization remains unchanged but change in appearance depends upon location of polymerizable group.

The combine advantage of polymer and membrane is that, they have stabilities and intriguing structural properties like polymers while retaining beneficial fluidity and organizational abilities of membrane. In terms of drug delivery they might serve as unique poly-disperse, timed release carriers.

4.3. Emulsified niosomal dispersion

Yoshioka formulated a range of double emulsion (V/W/O emulsion) from niosomes made from spans( 20,40,60,80)in the size range 600 nm to 3.4 um, dispersed in water droplet of around 5-25 um, themselves dispersed in oil ( octane, hexadecane, isopropyl myristate) [5]. This system showed release of CF slower than vesicle suspension and W/O emulsion. On increasing hydrophobicity of surfactant used the release rate decreased until HLB 4.7 (span 60) and then increased. Also the nature of oil affected the release depending upon the partitioning behavior of solute. Faster release was observed at higher temperature but span 60 formulations were unaffected due to maintenance of gel phase. Thus, delivery rate of a drug can be regulated by appropriate choice of surfactant, oil and temperature of dialysis media.

This system allows administration or application of vesicles in an external non-aqueous phase while maintaining normal vesicular structure in an aqueous phase and can be of potential use in drug delivery or a vaccine vesicle. Albert has patented a similar system for cosmetic application [41].

5. Stability and toxicity of niosomes

Compared to liposomes, niosomes are relatively stable structures some concern has been expressed regarding the stability of niosomes in vitro and their toxicity in vivo. Surfactants are used in the preparation of niosomes, which may be a cause of toxicity. However, there are virtually no reports available on the in vivo toxicity of niosomes linked with the concentration of ether or esters surfactants used in the preparation of vesicles.

Azmin performed first in vivo experiment on drug delivery by means of synthetic non-ionic surfactant vesicles and reported that no adverse effects were observed in the experiment carried out [29].

Rogerson performed in vivo experiment over 70 male BALB/C mice and reported that no facilities were encountered that could be attributed to the preparation. The toxic or side effects directly related to drug are reduced [31].

6. Factors affecting vesicles size, entrapment efficiency and release characteristics

Various factor which affect the vesicle size, entrapment efficiency and release characteristics, most of them are as follows: drug, amount and type of surfactant, Cholesterol content and charge, Methods of preparation and Resistance to osmotic stress.

6.1. Drug

Entrapment of drug in niosomes increases vesicle size, probably by interaction of solute with surfactant head groups, increasing the charge and mutual repulsion of the surfactant bilayers, thereby increasing vesicle size [42,43]. The hydrophilic lipophilic balance of the drug affects degree of entrapment.

6.2. Amount and type of surfactant

The mean size of niosomes increases proportionally with increase in the HLB of surfactants like Span 85 (HLB 1.8) to Span 20 (HLB 8.6) because the surface free energy decreases with an increase in hydrophobicity of surfactant. The bilayers of the vesicles are either in the so-called liquid state or in gel state, depending on the temperature, the type of lipid or surfactant and the presence of other components such as cholesterol. In the gel state, alkyl chains are present in a well-ordered structure, and in the liquid state, the structure of the bilayers is more disordered. The surfactants and lipids are characterized by the gel-liquid phase transition temperature (TC) [5].  Phase transition temperature (TC) of surfactant also effects entrapment efficiency i.e. Span 60 having higher TC, provides better entrapment.

6.3. Cholesterol content and charge

Inclusion of cholesterol in niosomes increases its hydrodynamic diameter and entrapment efficiency [5]. 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 [50].

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 [43,44,45]. Presence of charge tends to increase the interlamellar distance between successive bilayers in multilamellar vesicle structure and leads to greater overall entrapped volume.

6.4. Methods of preparation

Methods of preparation of niosomes such as hand shaking, ether injection and sonication have been reviewed by Khandare et al [34]. Hand shaking method forms vesicles with greater diameter (0.35-13nm) compared to the ether injection method (50-1000nm) [34].

Small sized niosomes can be produced by Reverse Phase Evaporation (REV) method [15,33]. Microfluidization [34] method gives greater uniformity and small size vesicles. Parthasarthi et al [15] prepared niosomes by trans membrane pH gradient (inside acidic) drug uptake process. Niosomes obtained by this method showed greater entrapment efficiency and better retention of drug.

6.5. 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 [46,47].

7. Characterization of niosomes

7.1. Entrapment efficiency

After preparing niosomal dispersion, unentrapped drug is separated by dialysis [36], centrifugation [43,44], or gel filtration [48] 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 analysing the resultant solution by appropriate assay method for the drug. Where,

% Entrapment efficiency (% EF) = (Amount of drug entrapped/ total amount of drug) x 100

7.2. Vesicle diameter

Niosomes diameter can be determined using light microscopy, photon correlation microscopy and freeze fracture electron microscopy. Freeze thawing [34] (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.

7.3. In-vitro release

A method of in-vitro release rate study includes the use of 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 [44].

8. Applications

Niosomal drug delivery is potentially applicable to many pharmacological agents for their action against various diseases. Some of their therapeutic applications are discussed below.

8.1. Targeting of bioactive agents to reticulo-endothelial system (RES) and to

organs other than RES

The cells of RES preferentially take up the vesicles. The uptake of niosomes by the cells is also by 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 [46].

To organs other than RES

It has been suggested that carrier system can be directed to specific sites in the body by use of antibodies [49]. Immunoglobulins seem to bind quite readily to the lipid surface, thus offering a convenient means for targeting of drug carrier. Many cells possess the intrinsic ability to recognize and bind particular carbohydrate determinants and this can be exploited to direct carriers system to particular cells50.

8.2. Neoplasia

Doxorubicin, the anthracyclic antibiotic with broad spectrum anti tumor activity, shows a 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 [51]. 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 [52,53].

8.3. Leishmaniasis

Niosomes can be used for targeting of drug in the treatment of diseases in which the infecting organism resides in the organ of reticulo-endothelial system. Leishmaniasis is such a disease in which parasite invades cells of liver and spleen. The commonly prescribed drugs are antimonials, which are related to arsenic, and at high concentration they damage the heart, liver and kidney. The study of antimony distribution in mice, performed by Hunter et al [54] showed high liver level after intravenous administration of the carriers forms of the drug.

Baillie et al [32] reported increased sodium stibogluconate efficacy of niosomal formulation and that the effect of two doses given on successive days was additive.

8.4. Delivery of peptide drugs

Yoshida et al [45] investigated oral delivery of 9-desglycinamide, 8-arginine vasopressin entrapped in niosomes in an in-vitro intestinal loop model and reported that stability of peptide increased significantly.

8.5. Immunological application

Niosomes have been used for studying the nature of the immune response provoked by antigens. Brewer and Alexander [55] have reported niosomes as potent adjuvant in terms of immunological selectivity, low toxicity and stability.

8.6. Niosomes as carriers

Niosomes can be used as a carrier for hemoglobin. Niosomal suspension shows a visible spectrum superimposable onto that of free hemoglobin. Vesicles are permeable to oxygen and hemoglobin dissociation curve can be modified similarly to non-encapsulated hemoglobin [56,57].

8.7. Transdermal delivery of drugs

The major drawback of transdermal route of delivery is slow penetration of drug through skin. An increase in the penetration rate has been achieved by transdermal delivery of drug incorporated in niosomes. Jayraman et al [58] has studied the topical delivery of erythromycin from various formulations including niosomes or hairless mouse. From the studies, and confocal microscopy, it was seen that non-ionic vesicles could be formulated to target pilosebaceous glands.

8.8. Sustained Release and Localized drug action

Sustained Release

Azmin et al [29] suggested the role of liver as a depot for methotrexate after niosomes are taken up by the liver cells. Sustained release action of niosomes can be applied to drugs with low therapeutic index and low water solubility since those could be maintained in the circulation via niosomal encapsulation.

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 [36,54]. 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.

9. Current status and future prospects

They have better stability than liposomes and hence have greater interest for industrial adoption. The non-ionic surfactant systems make niosomes inherently target-specific to tumor, liver and brain. They have been reported to be useful as targeting systems of drugs for treatment of cancer and in therapy of microbial diseases caused particularly by virus and parasites. Tumor targeting of Methotrexate

in mice model have been highly successful. Other drugs such as sodium stibogluconate, doxorubicin, etoposide, used systemically and certain dermal therapeutic agents such as 5-􀁆-dihydrotestosterone, triamcinolone acetonide, etc. have been found to be of improved efficacy when formulated as niosomes. Since no special handling / storage precautions are required for niosomes, their commercial exploitation would be easier. They are biodegradable and reduce systemic toxicity of various antitumor and antimicrobial agents by localizing the drug to specific sites of action. Also, being surfactant in composition, they have got an ability to fool body's phagocytic defense mechanism and act as stealth drug carriers making their effective circulation time longer than the drug given Inc conventional forms [59].

10. Conclusions

Over the years, there has been a great evolution in drug delivery technologies. The concept of incorporating the drug into niosomes for a better targeting of the drug at appropriate tissue destination is widely accepted by researchers and academicians. It is obvious that niosome appears to be a well preferred drug delivery system over liposome as niosome being stable and economic. Also niosomes have great drug delivery potential for targeted delivery of anti-cancer, antiinfective agents.Drug delivery potential of niosome can enhance by using novel concepts like proniosomes, discomes and aquasome. Niosomes also serve better aid in diagnostic imaging and as a vaccine adjuvant. Thus these areas need further exploration and research so as to bring out commercially available niosomal preparation.