Journal of Pharmaceutical and Biological Sciences

Journal of Pharmaceutical and Biological Sciences ISSN: 2320-1924; CODEN: JPBSEV Published by Atom and Cell Publishers © All Rights Reserved Available online at: http://www.jpabs.org/ Review Article

Niosomes: A vesicular system for drug targeting Safura Ayesha Mujeeb1 and Krishna Sailaja A2 Project Assistant, RBVRR Women’s College of Pharmacy, Barkathpura, Hyderabad -27, India 2 Associate Professor, RBVRR Women’s College of Pharmacy, Osmania University, Hyderabad 27 1

Received: 17-05-2015 / Revised Accepted: 25-06-2015 / Published: 29-06-2015

ABSTRACT Drug targeting is a phenomenon in which the distribution of drug in the body is in such a manner that the major fraction of the drug interacts with the target tissue at a cellular or subcellular level to achieve a desired pharmacological response at a selected site without undesirable interactions at other sites. This can be achieved by using novel drug delivery system such as niosomes, these are the non-ionic surfactant vesicles obtained on hydration of synthetic nonionic surfactants, with incorporation of cholesterol. They are vesicular systems similar to liposomes that can be used as carriers of amphiphilic and lipophilic drugs. Niosomes are promising vehicle for drug delivery and it has been widely evaluated for controlled release and targeted delivery for the treatment of cancer, auto immune disorders (rheumatoid arthritis), viral infections and other microbial diseases. Encapsulation of drug in vesicular system can be predicted to prolong the existence of drug in the systemic circulation and enhance penetration into target tissue, perhaps reduce toxicity if selective uptake can be achieved. The present articles focuses on the various method of preparation, factors affecting niosomes and its applications. Keywords:-niosomes, hydrophobic drug, ampiphiles, cholesterol, non-ionic surfactant, factors, applications.

INTRODUCTION Vanlerbeghe et al. (1972) first reported the niosomes as a feature of cosmetic industry. In 1979, Handjanivila et al. reported that the hydration of a mixture of cholesterol and single alkyl chain, resulted in formation of non-ionic surfactant vesicular system niosomes. The concept of site specific drug delivery was introduced by Paul Elrich in 1909, when he reported ‘magic bullet’ to deliver a drug to the desired site of action without affecting the non-target organs/ tissue by associating the drug with a pharmacologically “inactive carrier” capable of conveying the drug selectively towards its target cells. Niosomes are non-ionic surfactant-based microscopic lamellar structures obtained on admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media. Due to the incorporation of nonionic surfactants niosomes have more penetrating property. They are structurally similar

to liposomes in having a bilayer, however they differ in the materials used to prepare Niosomes which makes them more stable and thus niosomes offer many more advantages over liposomes. The sizes of niosomes are microscopic of ranging from 10nm-100nm. Niosomes are the bilayer structure, consisting of hydrophobic part oriented away from the aqueous solvent, and hydrophilic head which remain in contact with the aqueous solvent. The properties of the vesicles can be changed by varying the composition of the vesicles i.e., concentration of surfactant, cholesterol, drug which effects the lamellarity, entrapped volume of drug, surface charge etc.

Figure 1:-Bilayered niosomal vesicle.

*Corresponding Author Address: Krishna Sailaja A, Associate professor, RBVRR women’s college of pharmacy, Osmania university, Hyderabad -27, India; E-mail:[email protected], [email protected]

Sailaja and Safura, J Pharm Biol Sci 2015; 3(1): 24-31

* Large niosomes (800 nm – 900 nm). * Big niosomes (2 μm – 4 μm).

Niosomes act as a depot, releasing the drug in a controlled manner. It can be used as a carrier for the drugs which have poor bioavailability or absorption. It enhances the bioavailability by crossing the anatomical barrier of gastrointestinal tract via transcytosis of M cells of Peyer's patches in the intestinal lymphatic tissues this novel drug delivery also helps in protecting the drug from biological environment and restricting effects to target cells.

Composition Of Niosomes: -The components used for the preparation of niosomes are:(i)Cholesterol (ii)Nonionic surfactants (iii)other additives Cholesterol provides rigidity and proper shape to the niosomes. Cholesterol act as fluidity buffer after intercalation with surfactant molecules. They alter the freedom of motion of carbon molecules in the acyl Chain and restricts the transformations from Trans to gauche Conformations. Addition of cholesterol in niosomes increases the vesicle diameter and entrapment efficiency (EE). Cholesterol concentration is inversely proportional to Release rate and directly proportional to the Rigidity of bilayer.

Types of Niosomes:-The niosomes can be classified as a function of the number of bilayer or as a function of size. The various types of niosomes are follows. a) According to the nature of lamellarity (Biju. et al., 2006):* Multilamellar vesicles (MLV) 1-5 um in size. * Large unilamellar vesicles (LUV) 0.1 – 1μm in size. * Small unilamellar vesicles (SUV) 25 – 500 nm in size. b) According to the size (Jain. et al., 2005):* Small niosomes (100 nm – 200 nm).

Nonionic surfactants play a major role in the niosomes formulation. The vesicle size of niosomes is directly proportional to the HLB values of surfactant.

Table 1:- Different Types Of Non Ionic Surfactants Used In The Preparation Of Niosomes.

TYPE OF NON IONIC SURFACTANT

Ethers

EXAMPLES Cetyl alcohol, Steryl alcohol, Cetosteryl alcohol, oleyl alcohol Brij, Decyl glucoside, Lauryl glucoside, Octyl glucoside, Triton X-100, Nonoxynol-9

Esters

Glyceryl laurate, Polysorbates, Spans

Fatty alcohol

Block co polymers polaxamers Table 2:-Commonly used nonionic surfactant in the preparation of niosomes.

S.NO

NAME OF SURFACTANT

THE

TRADE NAME

HLB VALUE

DENSITY (g/cm3)

1. Sorbitan mono laurate

Span20

8.6

1.01

2. Sorbitan mono palmitate

Span40

6.7

1.07

3. Sorbitan mono stearate

Span60

4.7

-

4. Sorbitan mono oleate

Span80

4.3

1.01

5. Sorbitan mono trioleate

Span85

1.8

0.956

6. Polysoxyethylene Sorbitan mono laurate

Tween 20

16.7

1.1

25


7. polyoxyethylene Sorbitan monopalmitate

Tween40

15.6

1.08

8. polysoxyethylene Sorbitan monostearate

Tween 60

14.9

1.1

9. polysoxyethylene Sorbitan monooleate

Tween 80

15.0

1.08

Other additive:-Charge inducers are one of the membrane additive which are often included in niosomes because they increase the surface charge density and prevent vesicle aggregation. Positively and negatively charged molecules are used for the induction of charge in niosomes. Examples include dicetyl phosphate (dcp) and stearylamine (sa) which induces positive and negative charges.

Type of Surfactant:-Type of the surfactants influences encapsulation efficiency, toxicity, and stability of niosomes. The hydrophilic- lipophilic balance (HLB) is a good indicator of the vesicle forming ability of any surfactant. Uchegbu et al., (1995, 1998) reported that the sorbitan monostearate (Span) surfactants with HLB values between 4 and 8 were found to be compatible with vesicle formation. Ester type ampiphillic surfactants are also used for niosome formulation but they are less stable and less toxic as they easily get degraded by esterases to triglycerides and fatty acid in vivo when compared to ether type surfactant which are more stable.

Advantages:*Niosomes increases the stability of entrapped drug as they are stable. *Handling and storage of niosomal formulation requires no special conditions. *Niosomes improves oral bioavailability of the drugs and enhances the permeation of the drugs through the skin because of the presence of surfactants. *They help in reaching the target site of action by various routes such as oral, parenteral, ocular, nasal as well as topical routes. *Niosomes are nontoxic, biodegradable, biocompatible and non-immunogenic. *Niosomes improve the therapeutic performance of the drug, since the drug is not distributed to nontarget sites and reduces the chances of drug toxicity. *Niosomes help to sustain the drug release by forming a depot and offer a controlled release.

Amount and type of surfactant:-The mean size of niosomes increases proportionally with increase in the HLB of surfactants like Span 80 (HLB 4.3) 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 liquid state or in a gel state, depending on the temperature, the type of surfactant and the presence of other components. 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). Phase transition temperature (TC) of surfactant also effects entrapment efficiency i.e. Span 60 having higher TC, provides better entrapment.

Disadvantages:1. Physical instability. 2. Aggregation. 3. Leakage of entrapped drug. 4. Hydrolysis of encapsulated drugs which limits the shelf life of the dispersion.

Nature of encapsulated Drug: - Entrapment of drug in niosomes increases vesicle size, the physico-chemical properties of encapsulated drug influences charge and rigidity of the niosome bilayer. The drug interacts. The hydrophilic lipophilic balance of the drug affects degree of entrapment.

Factors Affecting The Formation Of Niosomes:Cholesterol:- Cholesterol presence in membranes brings about significant changes with regard to bilayer stability, fluidity and permeability. It is used as a membrane additive and can be incorporated in high molar ratios. It itself, does not form bilayers but used to modify bilayer characteristics and prevent vesicle aggregation stabilize the system against the formation of aggregates. As a result, niosomes become less leaky.

Structure of Surfactants:-The 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, we can predict the vesicle formation. Critical packing parameters can be defined using following equation

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larger unilamellar vesicles due to the slow vaporization of solvent. The disadvantages of this method are that a small amount of ether is frequently present in the vesicles suspension and is difficult to remove.

Critical Packing Parameters (Cpp) = V/ IC x 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 micellar structure formed can be ascertained as given below, If CPP < 0.5, formation of spherical micelles. If CPP 0.5-1, formation of bilayer micelles. If CPP > 1, formation inverted micelles.

(b) Reverse phase evaporation technique (REV): In this method, cholesterol and surfactant are dissolved in a mixture of ether and chloroform. An aqueous phase containing drug is added to organic phase and the resulting two phases are sonicated at 4-5°C resulting in the formation of clear gel which is further sonicated after the addition of a small amount of phosphate buffer solution. The organic phase is removed at 40°C under low pressure. The resulting viscous niosomal suspension is diluted with phosphate-buffer and heated in a water bath at 60°C for 10 min to yield large unilamellar vesicles.

Hydration temperature of niosomes:-Hydration temperature influences the shape and size of the niosomes. 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 vesicles shape transformation. Improper selection of these factors may result in formation of fragile niosomes or drug leakage problems.

(iii) Preparation of Small Unilamellar Vesicles:(a) Sonication: The aqueous phase containing drug is added to the mixture of surfactant and cholesterol in a scintillation vial. The mixture is then probe sonicated at 60°C for 3 minutes to produce small and uniform sized vesicular niosomes.

Method of Preparation:(i) Preparation of Multilamellar Vesicles:(a) Thin film hydration technique (Hand shaking method): In this method, surfactant and cholesterol are dissolved in a volatile organic solvent (such as diethyl ether, chloroform or methanol) in a round bottom flask. The organic solvent is removed at room temperature (20°C30C) using rotary evaporator leaving a thin layer of film deposited on the wall of the round bottomed flask. The dried surfactant film is hydrated with aqueous phase i.e., phosphate buffer containing drug maintained at 50-60°C with gentle agitation. This results in the formation of Multilamellar niosomes.

(b)Micro fluidization: - Micro fluidization is used to prepare small unilamellar vesicles of uniform size distribution. The principle involved in this method is submerged jet principle in which two fluidized streams interact at high velocities, in 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 (Mayer et al., 1985)

(b) Trans membranes PH gradient (inside acidic) Drug Uptake Process or Remote Loading Technique:-Surfactant and cholesterol are dissolved in chloroform. The organic solvent is then evaporated under reduced pressure to get a thin film around the wall of the round bottom flask. The film is then hydrated with 300mM citric acid (PH 4.0) by vortex mixing. This results in the formation of MLV’s which are 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 7.2 with 1M disodium phosphate. This mixture is later heated at 60°c for 10 minutes to produce desired MLV’S.

(iv)Other Methods:(a)Formation of niosomes from proniosomes:This method involves production of niosomes by coating a water-soluble carrier such as sorbitol with surfactant. The result of the coating process is a dry formulation in which each water-soluble particle is covered with a thin film of dry surfactant. This preparation is termed “Proniosomes”. The niosomes are recognized by the addition of aqueous phase at T > Tm with mild agitation (Blazek et al., 2001). T=Temperature. Tm = mean phase transition temperature. (b)The “Bubble” Method: - It is a novel technique for the preparation of 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

(ii) Preparation Of Large Unilamellar Vesicles:(a)Ether injection method: This method is based on slow injection of organic phase (surfactant and cholesterol dissolved in diethyl ether) through a 14gauge needle into a preheated aqueous phase maintained at60°C. This results in the formation of 27


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.

observed for morphological characterization using a gaseous secondary electron detector working at a pressure: 0.8 torr, acceleration voltage: 30.00 KV) XL 30, (Philips, Netherlands). Optical Microscopy:-A drop of niosomal dispersion was mounted on glass slides and viewed under a microscope (Medilux-207RII, KyowaGetner, and Ambala, India) with a magnification of 1200X for morphological observation after suitable dilution. The photo micrographic pictures of the preparation was obtained from the microscope by using a digital SLR camera.

(c)Multiple Membrane Extrusion Method:-in this method, Mixture of surfactant, cholesterol and dicetyl phosphate in chloroform is made into thin film by evaporation in rotary evaporator. The film is hydrated with aqueous buffer solution containing drug and the resultant suspension is then extruded through polycarbonate membranes which are placed in series for up to 8 passages. It is a good method for getting niosome of uniform size. Characterization of Niosomes:-Vesicles are characterized for vesicle size and morphology, zeta potential, entrapment efficiency, In vitro release and permeation studies, In vivo studies, stability studies etc.

Entrapment efficiency:- Entrapment efficiency of the niosomal dispersion can be done by separating the unentrapped drug by dialysis , centrifugation or gel filtration .The drug remained entrapped in niosomes is determined by complete vesicle disruption using 50% n-propanol or 0.1% Triton X100 and analyzing the sample spectrophotometrically. Where,

Vesicle size and morphology:-Vesicle morphology involves the measurement of size and shape. The size of the vesicles can be measured by two methods light scattering method and optical microscopy in two conditions i.e.: with agitation and without agitation. Hydration without agitation results in largest vesicle size. Surface morphology means roundness, smoothness and formation of aggregation; it can be studied by scanning electron microscopy and transmission electron microscopy.

Percentage entrapment = total drug –diffused drug / total drug Osmotic shock:-The change in the vesicle size can be determined by osmotic studies. Niosomes 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.

Measurement of vesicle size:-The niosomal dispersion was diluted about 100 times in phosphate buffer solution and the vesicle size was measured on a particle size analyzer (Laser diffraction particle size analyzer, Sympatec, Germany). It consists of a He-Ne laser beam of 632.8 nm focused with a minimum power of 5 mW using a Fourier lens 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. Rhodes in 1999 reported that the average particle size of niosomes derived niosomes is approximately 6µm while that of conventional niosomes is about 14µm.

Stability studies:-To determine the stability of niosomes, the optimized batch was stored in airtight sealed vials at different temperatures i.e., (40c, 250c, 450c). Surface characteristics and percentage drug retained in niosomes were determined. Samples were taken 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 analyzed by suitable analytical methods(UV spectroscopy, HPLC methods etc.). Zeta potential analysis:-This method is used for determining the colloidal properties of the prepared formulations. The niosomes derived after hydration with phosphate buffer 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 mean zeta potential values with standard deviation of measurements were obtained directly from the measurement.

Scanning electron microscopy: - Particle size of niosomes is characterized using SEM. The surface morphology (spherical shape, smoothness, and formation of aggregates /lumps) and the size distribution of niosomes were studied by Scanning Electron Microscopy (SEM). Niosomes 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 then 28


In vitro Release Study:-This studies can be carried out with the help of dialysis tubing. A dialysis sac was washed and soaked in phosphate buffer solution. The niosomal suspension containing 10 mg equivalent drug was pipetted into a bag made up of the tubing and sealed. The bag containing the niosomal dispersion act as a donor compartment and this was then placed in 200 ml buffer solution in a 250 ml beaker with constant shaking at 25°C or 37°C. The samples were withdrawn at subsequent time intervals and analyzed for the drug content using UVspectrophotometer.

drug release that is sustaining the action of Aceclofenac sodium, thereby reducing its severe adverse effects. 4.Anti-Diabetic:-M. Madhavi et al., worked on to improve the oral bioavailability and penetration property of an oral antidiabetic drug metformin. Drug entrapment in nonionic surfactant vesicles and the release was sustained over a period of 24 hours for better therapeutic efficacy. 5. Delivery Of Peptide Drugs:-Yoshida et al. formulated 9-desglycinamide, 8-arginine vasopressin entrapped in niosomes to improve the stability of peptide when given through oral route and the stability increased significantly. 6.Cosmetics:-Niosomes can be formulated for effective treatment of androgenetic alopecia and can be used to treat hyper pigmentation disorders as niosomes has better penetration/permeation property through the skin because of the presence surfactants.

Applications of Niosomes:-vesicular drug delivery systems is applicable to many pharmacological agents for their action against various diseases. 1. Anti-Neoplastic Agents:-Methotrexate loaded niosomes exhibited much more consistent plasma levels when compared to methotrexate liposomes. During in vivo experimentation on mice, liver MTX levels at sampling times were higher when compared with that of MTX solution. Studies have indicated that MTX loaded niosomes are taken up intact by liver due to selective uptake of vesicular system. These are then broken down to release MTX into systemic circulation, thus minimizing the side effects of MTX.

7.Anti-Fungal Agents:-Miconazole is an antifungal agent used in the treatment of candida infections, fungal infections. Niosome was prepared by Thin Film hydration, it was concluded that topically applied niosomes can increase residence time of drug in the stratum corneum and epidermis, while reducing the systemic absorption of the drug. It also improves the horny layer properties both by reducing Trans epidermal water loss and by increasing smoothness via replenishing lost skin lipids. (P.U.Mohamed Firthouse et al.) 8.Anti-Viral Agents:-zidovudine (zdv), an anti-hiv drug was formulated as niosomes and the distributions of drug in lungs, kidney, heart, liver and spleen of mice were studied after intravenous bolus injection.it was concluded that niosomes were site specific and increased half-life, mean residence time and reduced leakage of drug when stored at 4⁰c (ruckmani et al., 2010).

2. Transdermal Delivery of Drugs by Niosomes:Shivhare UD et al., 2013 developed carvedilol niosomal gel as a vesicular drug carrier system. Carvedilol has an oral bioavailability 25% due to high first pass metabolism (80%) and presence of food decreases its absorption rate in gastrointestinal tract. Short half-life of the Carvedilol (4 to 6 h) indicates need of controlled release delivery. To overcome these limitations Carvedilol was incorporated in niosomes for transdermal delivery. Niosomal drug delivery system was preferred due to improved stability and it carries significant quantity of drug across the skin thus enhancing the systemic absorption of drug.

9. Immunological Application of Niosomes:Niosomes is also used in studying the nature of the immune response provoked by antigens. To induce the immunity i.e., both humoral and cellular immunity Mannosylated niosomes were formulated as a topical vaccine delivery carrier and adjuvant (Jain and Vyas, 2005).

3.Anti-Inflammatory(Nsaids):-Punitha Sundaresan et al., developed Aceclofenac sodium niosomes as the conventional dosage forms is associated with gastrointestinal adverse effects and cardiac toxicities. So to reduce its side effects and toxicities it was encapsulated in niosomal formulation. The niosomal gel showed prolong Table 3:-Marketed Formulations of Niosomes S.NO 1

BRAND

NAME OF THE PRODUCT

Lancome - Foundation & Complexion

Flash Retouch Brush On Concealer

2

Britney Spears - Curious

Curious Coffret: Edp Spray 100ml+ Dualended Parfum & Pink Lipgloss+ Body Souffle 29


100ml

3

Loris Azzaro – Chrome

Chrome Eau De Toilette Spray 200ml

4

Helena Rubinstein - HR - Golden Beauty - Body Care

Golden Beauty After Sun Soothing Moisturizer 150ml

5

Givenchy - Amarige

Amarige Eau De Toilette Spray 100ml

6

Estee Lauder - Beyond Paradise

Beyond Paradise After Shave Lotion 100ml

7

Orlane - Lipcolor & Lipstick

Lip Gloss

8

Liz Claiborne – Realities

Realities Shower Gel 200ml

9

White Shoulders

White Shoulders Eau De Cologne Spray 130ml

10

Jean Paul Gaultier - Le Classique

Le Classique Eau De Toilette Spray 100ml

11

Hugo Boss - Boss Soul

Boss Soul After Shave 90ml

12

Lancaster - Suractif - Night Care

Suractif Non Stop Lifting Advanced Night Cream 50ml

13

Givenchy - Blanc Parfait - Day Care

Blanc Parfait W4-L Universal Brightening Spots Corrector SPF 45 1.6ml and biologicals can be unsubstantiated with a wide scope in encapsulating toxic drugs such as anticancer drugs and anti-viral drugs. Drug delivery potential of niosome can be enhanced by using novel concepts like proniosomes, discomes and aspasome. Niosomes also serve better aid in diagnostic imaging and as a vaccine adjuvant but they are at initial stage and thus these areas need further exploration and research so as to bring out commercially available niosomal preparation. Various routes of application can be possible using niosomes like targeting, ophthalmic, topical, parenteral, and oral.

CONCLUSION The vesicular systems have been gaining a lot of interest of various researchers and scholars, because of their advantages of sustained and controlled release action, stability and versatility as a drug carrier. These carrier systems have immense scope in future, especially in the area of transdermal drug delivery. Niosomes are considered to be better candidates for drug delivery when compared to liposomes due to various factors like cost and stability. These advantages over the liposomes make it a better targeting agent. The usefulness of niosomes in the delivery of proteins

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