Dubey Subodh et al.

/ Drug Invention Today 2010,2(1),72-77

ISSN: 0975-7619

Available online through www.ditonline.info Review Article

Niosomes: The ultimate drug carrier

Dubey Subodh 1*, Jain Amit1, Mehta S.C.2, Gupta Pavan3, Jain Sandeep3, Sahu Jagdish1 1IPS, College of Pharmacy, Gwalior (M.P) India, 474001,India. 2G.R. Medical College Gwalior (M.P) India, 474009,India. 3 R N S College of Pharmacy, Sitholi, Gwalior,M.P.,India. Received on: 20-05-2009; Revised on: 23-06- 2009; Accepted on:17-12-2009 ABSTRACT
Niosomes or non-ionic surfactant vesicles are microscopic lamellar structures formed on admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media. The method of preparation of niosome is based on liposome technology. The basic process of preparation is the same i.e. hydration by aqueous phase of the lipid phase which may be either a pure surfactant or a mixture of surfactant with cholesterol. After preparing niosomal dispersion, unentrapped drug is separated by dialysis centrifugation or gel filtration. A method of in-vitro release rate study includes the use of dialysis tubing. Niosomes are unilamellar or multilamellar vesicles formed from synthetic non-ionic surfactants. Niosomal drug delivery is potentially applicable to many pharmacological agents for their action against various diseases.

Keywords: Niosomes, Encapsulation, Surfactants, Vesicles INTRODUCTION Niosomes or non-ionic surfactant vesicles are microscopic lamellar structures formed on admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media [1].Niosomes can be changed or modified by the incorporation of other excipients like cholesterol, into the membrane and they can possess one or more lipid bilayers encapsulating an aqueous core. A diverse range of materials have been used to form niosomes such as sucrose ester surfactants and polyoxyethylene alkyl ether surfactants. Niosome vesicles were prepared with the thin layer evaporation method and were physico-chemically characterized. In comparison with classical formulations such as emulsions, these systems exhibit lower toxicity and permit closer control of the availability of active substances at the stratum corneum[2]. Salient Features of Niosomes Niosomes can entrap solutes in a manner analogous to liposomes. Niosomes are osmotically active and stable. Niosome possess an infra structure consisting of hydrophobic and hydrophilic mostly together and so also accommodate the drug molecules with a wide range of solubility. Niosomes exhibits flexibility in their structural characteristics (composition, fluidity and size) and can be designed according to the desired situation. *Corresponding author.
Mr.Dubey Subodh IPS College of Pharmacy, Gwalior, M.P. Tel.: + 91-992621098 E-mail: sarapharma200389@yahoo.com

This is one of the representation of the Niosome. Here o represents Hydrophilic head groupand represents Hydrophobic tail

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Niosomes can improve the performance of the drug molecules by: Delayed clearance from the circulation. Better availability to the particular site, just by protecting the drug from biological environment. Controlled delivery of drug at a particular site. No special conditions are required for handling and storage of Niosomes. Niosomes surfactants are biodegradable, biocompatible and non-immunogenic. METHOD OF PREPARATION OF NIOSOMES Niosomes widely differ in their properties depending on the method used for production and composition of bilayer. The method of preparation of niosome is based on liposome technology. The basic process of preparation is the same i.e. hydration by aqueous phase of the lipid phase which may be either a pure surfactant or a mixture of 72-77

Dubey Subodh et al. / Drug Invention Today 2010,2(1),72-77 surfactant with cholesterol. The bioactive material, which is to be entrapped, is dissolved in the aqueous phase/organic phase. The methods used for preparation of niosomes are listed as follows: Ether Injection method This method was reported in 1976 by Deamer and Bangham, in which a lipid solution in di-ethyl ether is slowly introduced into warm water typically the lipid mixture is injected into an aqueous solution of the material to be encapsulated (using syringe type infusion pump) at 55-65oC and under reduced pressure. Vaporization of ether leads to the formation of single layered vesicles (SLVs) depending upon the conditions used, the diameter of vesicles varies.Baillie et al., used this method for entrapment of 5, 6 carboxy florescein whereas, Hunter et al., and Carter et al., used it for the entrapment of sodium stibogluconate (pentosam). Lipid Film Formation (Hand Shaking Method) Surfactant/cholesterol mixture was dissolved in di-ethyl ether in a round bottom flask and ether was removed at room temperature under reduced pressure, in a rotary evaporator. The dried surfactant film was hydrated with aqueous phase at 50 - 60C with gentle agitation; this method produces multilamellar vesicles (ML V) with large diameter.Baillie et al reported Hand shaking method for the entrapment of 5, 6 carboxy fluorescein [3]. Chandraprakash et al entrapped methotrexate in niosomes prepared by Hand shaking method using lipophilic surfactants like span 40, span 60 and span 80, cholesterol and di-cetyl phosphate in ratio of 47.5: 47.5: 5. The tissue distribution of methotrexate was improved after entrapping with niosomes [4].Rogerson et al prepared doxorubicin entrapped niosomes using pure surfactant or a mixture of surfactants and cholesterol[5]. Azmin et al modified this method for preparation of methotrexate entrapped niosomes [6]. Sonication Method Aqueous phase was added to the surfactant/cholesterol mixture and the mixture was probe sonicated at 60 C for 3 minutes to produce niosomes.Baillie et al prepared 5,6 carboxy fluorescein in entrapped niosomes by sonication method[3].Carter et al prepared sonicated niosomes by sonication of multilamellar niosomes being prepared by Ether injection method [7]. Yoshida et al modified this method for entrapment of 9-desglycinamide 8-arginine vasopressin (DGA VP) [ 8 ].Hofland et al prepared niosomes by sonication of transdermal delivery of estradiol by niosomes in vitro [9]. Microfludisation This is a recent technique to prepare small MLVS. A Microfludizer is used to pump the fluid at a very high pressure (10,000 psi) through a 5 pm screen. Thereafter; it is forced along defined micro channels, which direct two streams of fluid to collide together at right angles, thereby affecting a very efficient transfer of energy. The lipids can be introduced into the fluidizer. The fluid collected can be recycled through the pump until vesicles of spherical dimensions are obtained. This results in greater uniformity, small size and better reproducible niosomes [10]. Reverse phase evaporation The novel key in this method is the removal of solvent from an emulsion by evaporation. Water in oil emulsion is formed by bath sonication of a mixture of two phases, and then the emulsion is dried to a semi-solid gel in a rotary evaporator under reduced pressure. The next step is to bring about the collapse of certain portion of water droplets by vigorous mechanical shaking with a vortex mixture. In these circumstances, the lipid monolayer, which encloses the collapse vesicles, is contributed to adjacent intact vesicles to form the outer leaflet of the bilayer of large unilamellar niosomes. The vesicles formed are unilamellar and have a diameter of 0.5 m. Recently a great deal of interest is being shown in formulation of proniosomes. Proniosomes are dry formulations of surfactantcoated carrier, which on rehydration and mild agitation give niosomes. Proniosomes have the advantage of circumventing the problems of physical stability such as aggregation, fusion and leaking, chemical stability such as hydrolysis, providing the convenience of transportation, distribution, storage and dosing. Proniosomes are usually prepared by dissolving spray coated surfactant in a organic solvent on to inert carriers such as sorbitol and maltodextrin [11-12]. 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 upto 8 passages. It is a good method for controlling niosome size [13]. 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 60C for 10 minutes to give niosomes [14]. The 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. Cholesterol and surfactant are dispersed together in this buffer (pH 7.4) at 70C, the dispersion mixed for 15 seconds with high shear homogenizer and immediately afterwards bubbled at 70C using nitrogen gas [15].

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Dubey Subodh et al. / Drug Invention Today 2010,2(1),72-77 Surfactant 1 was used for the preparation of niosomes [3]. Formation of niosomes from proniosomes Another method of producing niosomes is to coat a water-soluble The effect of surfactant 1 based niosomes on absorption, metabolism [20] carrier such as sorbitol with surfactant. The result of the coating and excretion of methotrexate in the mice was studied . The drug process is a dry formulation. In which each water-soluble particle is entrapment, stability and release of drug from adrimycin loaded covered with a thin film of dry surfactant. This preparation is termed niosomes based on surfactant 1 was studied. Effect on the absorpProniosomes. The niosomes are recognized by the addition of aque- tion and distribution of methotrexate entrapped in niosomes was studied. Surfactant 1 based stibogluconate bearing niosomes were preous phase at T > Tm and brief agitation. pared and evaluated for various parameters for their effect on the inT=Temperature. vivo absorption, distribution and elimination of the contained drug [16] Tm = mean phase transition temperature . [21]. Di-alkyl chain surfactant: CHARACTERIZATION OF NIOSOMES Surfactant was used as a principal component of niosomal preparaEntrapment efficiency After preparing niosomal dispersion, unentrapped drug is separated tion of stibogluconate and its potential in delivering sodium by dialysis [15] centrifugation [17-18] or gel filtration[19] as described stibogluconate in experimental marine visceral leishmaniasis has been above and the drug remained entrapped in niosomes is determined explored. by complete vesicle disruption using 50% n-propanol or 0.1% Triton X-100 and analysing the resultant solution by appropriate assay C16 H33 CH-O[-CH2 -CH-O]7 -H method for the drug. Where, | | Entrapment efficiency (EF) = (Amount entrapped total amount) x CH CH OH 2 2 100 | Vesicle diameter C H -O Surfactant11, mol. Wt. 972 Niosomes, similar to liposomes, assume spherical shape and so their 12 25 diameter can be determined using light microscopy, photon correlation microscopy and freeze fracture electron microscopy. Freeze thawing [13] (keeping vesicles suspension at 20C for 24 hrs and then Ester linked: Surfactants in which hydrophilic and hydrophobic moieties heating to ambient temperature) of niosomes increases the vesicle are ester linked. Ester linked surfactant, diameter, which might be attributed to fusion of vesicles during the cycle. C15H31CO[O-CH2-CH-CH2]2-OH In-vitro release | A method of in-vitro release rate study includes the use of dialysis OH Surfactant 11 mol. Wt. 393 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 Surfactant 11was also studied for its use in the preparation solution in a 250 ml beaker with constant shaking at 25C or 37C. At of stibogluconate bearing niosomes and in delivery of sodium various time intervals, the buffer is analyzed for the drug content by [17] stibogluconate to the experimental marine visceral leishmaniasis folan appropriate assay method . lowing administration of niosomal system [21]. SURFACTANTS USED IN THE PREPARATION OF NIOSOMES Niosomes are unilamellar or multilamellar vesicles formed Sorbitan Esters from synthetic non-ionic surfactants. The surfactants that are reported to form niosomes are as follows: Ether linked surfactant: CH2 where, R is H or an alkyl chain. In which the hydrophilic hydrophobic moieties are ether | linked, polyoxyethylene alkyl ethers with the general formula H-C-OH (CnEOm), where n; i.e. number of carbon atoms varies between 12 | and 18 and m; i.e. number of oxyethylene unit varies between 3 and RCOO- C-H 7. The surfactants used were C12EO3, C12EO7, C18EO3, and C3EO7 . | - The commercial sorbitan esters are Single alkyl chain surfactant C16 mono alkyl glycerol ether with an H-C-OH mixtures of the partial esters of average of three glycerol units [surfactant 1]. | sorbital and its mono and di-anH-C-OOC-R hydrides with oleic acid. C16 H33 O [CH2 -CH-O]3 -H | CH2OOC-R

CH2 OH

Mol. Weight =473

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Dubey Subodh et al. / Drug Invention Today 2010,2(1),72-77 If < CPP < 1 formation of bilayer micelles, If CPP > 1 formation inverted micelles. The formula of a representative component is shown above. Sorbitan esters based niosomes bearing methotrexate were prepared and evaluated for pharmacokinetics of the entrapped methotrexate in tumor bearing mice. Poly sorbates: The typical structural formula of polysorbates is 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 their 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 solulan C24 (cholesteryl poly-24-oxyethylene ether), which prevents aggregation due to development of steric hindrance[26]. In contrast spherical Niosomes are formed by C16G2: cholesterol:solulan (49:49:2) [26].The mean size of niosomes is influenced by membrane composition such as Polyhedral niosomes formed by C16G2: solulan C24 in ratio (91:9) having bigger size (8.0 0.03mm) than spherical/tubular niosomes formed by C16G2: cholesterol:solulan C24 in ratio (49:49:2) (6.60.2mm) [26]. Addition of cholesterol molecule to niosomal system provides rigidity to the membrane and reduces the leakage of drug from noisome [27]. Nature of encapsulated drug The physico-chemical properties of encapsulated drug influence charge and rigidity of the niosome bilayer. The drug interacts with surfactant head groups and develops the charge that creates mutual repulsion between surfactant bilayers and hence increases vesicle size [28]. The aggregation of vesicles is prevented due to the charge development on bilayer. Temperature of hydration Hydration temperature influences the shape and size of the noisome. For ideal condition it should be above the gel to liquid phase transition temperature of system. Temperature change of niosomal system affects assembly of surfactants into vesicles and also induces vesicle shape transformation[22,26]. Arunothayanun et al. reported that a polyhedral vesicle formed by C16G2: solulan C24 (91:9) at 25C which on heating transformed into spherical vesicle at 48C, but on cooling from 55C, the vesicle produced a cluster of smaller spherical niosomes at 49C before changing to the polyhedral structures at 35C. In contrast vesicle formed by C16G2: cholesterol: solulanC24 (49:49:2) shows no shape transformation on heating or cooling [26].Along with the above mentioned factors, volume of hydration medium and time of hydration of niosomes are also critical factors. Improper selection of these factors may result in formation of fragile niosomes or creation of drug leakage problems. THERAPEUTIC APPLICATIONS OF NIOSOMES Niosomal drug delivery is potentially applicable to many pharmacological agents for their action against various diseases. Some of their therapeutic applications are discussed below. Targeting of bioactive agents To reticulo-endothelial system (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 72-77

CH2 | H-C-O(CH2 -CH2 -O) H | (OCH-CH2 )-O-C-H | H-C-O-(CH2 -CH2 -O)y H | CH2 -O(CH2 -CH2 -O)z OCR
When n=X+Y+Z+2 and R is an alkyl chain this series of surfactants has been used to study the pharmacokinetics of niosomal entrapped methotrexate. FACTORS AFFECTING FORMATION OF NIOSOMES Nature of surfactants A surfactant used for preparation of niosomes must 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 group [22]. The ether type surfactants with single chain alkyl as hydrophobic tail is more toxic than corresponding dialkylether chain [21]. 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 vivo [21]. The surfactants with alkyl chain length from C12-C18 are suitable for preparation of niosome [23-24]. Surfactants such as C16EO5 (poly-oxyethylene cetyl ether) or C18EO5 (polyoxyethylene steryl ether) are used for preparation of polyhedral vesicles [25]. Span series surfactants having HLB number of between 4 and 8 can form vesicles [17]. Structure of surfactants The geometry of vesicle to be formed from surfactants is affected by its structure, which is related to critical packing parameters. On the basis of critical packing parameters of Surfactants can predicate geometry of vesicle to be formed. Critical packing parameters can be defined using following equation, CPP (Critical Packing Parameters) = v/lc a0 Where v = hydrophobic group volume,, lc = the critical hydrophobic group length,, a0= the area of hydrophilic head group. From the critical packing parameter value type of miceller structure formed can be ascertained as given below, If CPP < then formation of spherical micelles, Drug Invention Today Vol.2.Issue.1.January 2010

Dubey Subodh et al. / Drug Invention Today 2010,2(1),72-77 non-ionic vesicles could be formulated to target pilosebaceous glands. opsonins, which mark them for clearance. Such localized drug accuSTABILITY AND TOXICITY OF NIOSOMES mulation has, however, been exploited in treatment of animal tumors Compared to liposomes, niosomes are relatively stable strucknown to metastasize to the liver and spleen and in parasitic infestatures some concern has been expressed regarding the stability of tion of liver[1]. niosomes in vitro and their toxicity in vivo. Surfactants are used in To organs other than RES the preparation of niosomes, which may be a cause of toxicity. HowIt has been suggested that carrier system can be directed to specific ever, there are virtually no reports available on the in vivo toxicity of sites in the body by use of antibodies [29]. Immunoglobulins seem to niosomes linked with the concentration of ether or esters surfactants bind quite readily to the lipid surface, thus offering a convenient used in the preparation of vesicles. means for targeting of drug carrier[30]. Many cells possess the intrinAzmin et al performed first in vivo experiment on drug delivsic ability to recognize and bind particular carbohydrate determinants ery by means of synthetic non-ionic surfactant vesicles and reported and this can be exploited to direct carriers system to particular cells. that no adverse effects were observed in the experiment carried out[6] . Neoplasia Rogerson et al performed in vivo experiment over 70 male Doxorubicin, the anthracyclic antibiotic with broad specBALB/C mice and reported that no fatalities were encountered that trum anti tumor activity, shows a dose dependant irreversible cardio could be attributed to the preparation. The toxic or side effect directly toxic effect. Niosomal delivery of this drug to mice bearing S-180 related to drug are reduced[27]. tumor increased their life span and decreased the rate of proliferation of sarcoma [31]. Niosomal entrapment increased the half-life of the REFERENCES drug, prolonged its circulation and altered its metabolism. Intravenous administration of methotrexate entrapped in niosomes to S-180 1. Malhotra M and Jain NK. Niosomes as Drug Carriers. Indian Drugs 31 tumor bearing mice resulted in total regression of tumor and also (3), 1994, 81-86. higher plasma level and slower elimination [32-33]. 2. Handjani-Vila RM., Ribier A, Rondot B and Vanlerberghie G. Dispersions Leishmaniasis of lamellar phases of non-ionic lipids in cosmetic products. International Journal of Cosmetic Science 1 (5), 1979, 303-314. Niosomes can be used for targeting of drug in the treatment of dis3. 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