NIOSOMES

PRESENTED BY:

KALYAN POTHAKAMURIM.Pharmacy (Pharmaceutics) 2

nd semester

PRESENTATION FLOW

Introduction

Methods of Preparation

Factors Affecting Niosomes Preparation

Stability of Niosomes

Applications of Niosomes.

Introduction

NIOSOMES Niosomes are a novel drug delivery system, in which the medication is encapsulated in a vesicle composed of a bilayer of non-ionic surface active agents .

These are very small, and microscopic in size that lies in the nanometric scale. Although structurally similar to liposomes, they offer several advantages over them.

Niosomes have recently been shown to greatly increase transdermal drug delivery and also in targeted drug delivery.

WHY ? WHY? WHY?

Used for a variety of drugs : accommodate hydrophilic, lipophilic as well as amphiphilic moieties.Act as a depot to release the drug slowly and offer a controlled release .Osmotically active and stable.Increase the stability of the entrapped drug. Handling and storage of surfactants do not require any special conditions Enhance the skin penetration of drugs

Structure of Niosomes Niosomes are microscopic lamellar structures, which are formed on the admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media. Niosomes may be unilamellar or multilamellar depending on the method used to prepare them. The hydrophilic ends areexposed on the outside and inside of the vesicle, while the hydrophobic chains face each other ` within the bilayer. Hence, the vesicle holds hydrophilic drugs within the space enclosed in the vesicle, while hydrophobic drugs are embedded within the bilayer itself.

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Contd…

SmallUnilamellarVesicle(SUV)

LargeUnilamellarVesicle(LUV)

MultilamellarVesicle(MLV)

Typical Size Ranges: SLV: 20-50 nm – MLV:100-1000 nm

Niosomes Vs Liposomes

In both basic unit of assembly is Amphiphiles, but they phospholipids in liposomes and nonionic surfactants in niosomes.

Both can entrap hydrophilic and lipophilic drugs. Both have same physical properties but differ in their chemical

composition. Niosomes has higher chemical stability than liposomes. Niosomes made of uncharged single chain

surfactant molecules Liposomes made of neutral or charged double

chain phospholipids.

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Similarity : Niosomes & Liposomes

Function Increase the bioavailability Decrease the clearence Used for targeted drug delivery Properties depends on both composition of bilayer and

method of preparation

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Advantages : Niosomes Over Liposomes

o Ester bonds of phospholipids are easily hydrolyzed, this can lead to phosphoryl migration at low PH.

o Peroxidation of unsaturated phospholipids. o As liposomes have purified phospholipids they are to be

stored and handled at inert(N2) atmospheres where as Niosomes are are made of non ionic surfactants and are easy to handle and store.

o Phospholipid raw materials are naturally occurring substances and as such require extensive purification thus making them costly

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Niosomes : Types

1.Bola-Surfactant containing Niosomes: Niosomes made of alpha,omega-hexadecyl-bis-(1-aza-18-

crown-6) (Bola-surfactant)-Span 80-cholesterol (2:3:1 molar ratio) are named as Bola-Surfactant containing Niosomes.

2. Proniosomes: A dry product which may be hydrated immediately before

use to yield aqueous Niosome dispersions. These ‘proniosomes’ minimize problems of Niosome physical stability such as aggregation, fusion and leaking, and provide additional convenience in transportation, distribution, storage, and dosing.

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Formation of niosomes from proniosomes

Factors Affecting Niosomes Formation

Factors affecting niosomes formation

Non-ionic surfactant

nature

Membrane additives

Nature of encapsulated

drug

Surfactants and lipid

levels

Hydration Temperature

Contd…

Nature of non-ionic surfactantType of surfactant influences encapsulation efficiency, toxicity, and stability of niosomes

SURFACTANT

Hydrophobic tail Hydrophilic headLinked via ether , amide or ester bonds

Consist of one or two alkyl or perfluroroalkyl groups or in some

cases a single steriodal group.

Contd…

• The alkyl group chain length is usually from C12-C18

• Uchegbu et al reported that Span surfactants with HLB values between 4 and 8 were found to be compatible with vesicle formation

• The water soluble detergent polysorbate 20 (HLB value 16.7) also forms niosomes with cholesterol

• Polyglycerol monoalkyl ethers and polyoxylate analogues are the most widely used single-chain surfactants

Contd…

Membrane additivesCholesterol, a natural steriod, is the most commonly used membrane additiveUsually incorporated in 1:1 molar ratioPrevent vesicle aggregation by the inclusion of molecules that stabilize the system against the formation of aggregates by repulsive steric or electrostatic effects Leads to the transition from the gel state to liquid phase in niosomes systemsAs the result, niosomes become less leakyCholesterol

Dicetyl phosphate provides negative charge to vesiclesIt is used to prevent aggregation of hexadecyl diglycerol ether (C16G2) niosomesStearic acid is used in the preparation of cationic niosomes

Dicetyl phosphate and Stearic acid

Contd…

Surfactant and lipid levels• The surfactant/lipid ratio is generally 10-30 mM (1-2.5%

w/w)• If the level of surfactant/lipid is too high, increasing the

surfactant/lipid level increases the total amount of drug encapsulated

Hydration temperature• The hydrating temperatures used to make niosomes should

usually be above the gel to liquid phase transition temperature of the system

Methods Of Preparation

Ether injection method

Film method

Sonication

Reverse phase evaporation

The “Bubble” method

Micro fluidization.

Contd…

Ether injection method• Slow injection of an ether solution of niosomal ingredients

into an aqueous medium at high temperature• A mixture of surfactant and cholesterol (150 μmol) is

dissolved in ether (20 ml) and injected into an aqueous phase (4 ml) using a 14- gauge needle syringe

• Temperature of the system is maintained at 60oC during the process

• Niosomes in the form of large unilamellar vesicles (LUV) are formed

Contd…

Film method• The mixture of surfactant and cholesterol is dissolved in an

organic solvent (e.g. diethyl ether, chloroform, etc.) in a round-bottomed flask

• The organic solvent is removed by low pressure/vacuum at room temperature

• The resultant dry surfactant film is hydrated by agitation at 50-60oC

• Multilamellar vesicles (MLV) are formed

Contd…

Sonication• The aqueous phase is added into the mixture of surfactant

and cholesterol in a scintillation vial• Homogenized using a sonic probe• The resultant vesicles are of small unilamellar (SUV) type

niosomes• The SUV type niosomes are larger than SUV liposomes• It is possible to obtain SUV niosomes by sonication of MLV

type vesicles

Contd…

Reverse phase evaporation• Surface-active agents are dissolved in chlorofom, and 0.25

volume of phosphate saline buffer (PBS) is emulsified to get w/o emulsion

• The mixture is sonicated and subsequently chloroform is evaporated under reduced pressure

• The surfactant first forms a gel and then hydrates to form niosomal vesicles

• The vesicles formed are unilamellar and 0.5 μ in diameter

Contd…

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 are positioned in the

first and second neck and nitrogen supply through the third neck

Cholesterol and surfactant are dispersed together in the buffer (pH 7.4) at 70°C, the dispersion mixed for 15 secs with high shear homogenizer and immediately afterwards “bubbled” at 70°C using nitrogen gas

Contd…

Micro fluidization 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 It is then 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/surfactants can be introduced into the fluidizer The fluid collected can be recycled until spherical vesicles are

obtained Uniform and small sized vesicles are obtained

Contd…

Post-Preparation Processes

Downsizing Separation of unentrapped material

Contd…

Size reduction of

niosomes

Probe sonication

Extrusion through filters

Combination of sonication and

filtrationMicrofluidization

High-pressure homogenization

Separation of unentrapped material from

niosomes

Dialysis

Centrifugation

Ultracentrifugation

Gel filtration

Charecrisation of niosoms

Entrapment efficiency Depend on the method of preparation Niosomes prepared by ether injection method have better

entrapment efficiency than those prepared by the film or sonication

Addition of cholesterol to non-ionic surfactants with single- or dialkyl-chain significantly alters the entrapment efficiency

Surfactants of glycerol type lead to reduction in entrapment capacity as the amount of cholesterol increases

Niosomes in the form of liquid crystals possess better entrapment efficiency than gel type vesicles

contd…

Entrapment efficiency (EF) = (Amount entrapped total amount) x100

Niosomes, similar to liposomes, assume spherical shape and so their diameter can be determined using light microscopy, photon correlation microscopy and freeze fracture electron microscopy.

Freeze thawing (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.

contd…

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 methodof vesicles during the cycle.

Stability Of Niosomes

Vesicles are stabilised based upon formation of following forces: van der Waals forces among surfactant molecules

Electrostatic repulsive forces are formed among vesicles upon addition of charged surfactants to the double layer, enhancing the stability of the system

Contd…

Niosomes in the form of liquid crystal and gel can remain stable at both room temperature and 4oC for 2 months Recommended temperature of storage 4oCIdeally niosomes should be stored dry for reconstitutionThe factors which affect the stability of niosomes: Type of surfactant Nature of encapsulated drug Storage temperature Detergents Use of membrane spanning lipids Inclusion of charged molecule

Applications Of Niosomes

Applications

Transdermal

Parenteral Peroral

Radiopharm-

aceuticals

Opthhalmic

Drug delivery

Contd…

Transdermal ApplicationsSlow penetration of drug through skin is the major drawback of

transdermal route of delivery. An increase in the penetration rate has been achieved by transdermal delivery of drug incorporated in niosomes. has studied the topical delivery of erythromycin from various formulations including niosomes or hairless mouse.

parenteral Applications Niosomes in sub-micron size are used for parenteral administration Niosomal vesicles upto 10 μm are administered via i.p. or i.m.

Contd…

Radiopharmaceuticals First application of niosomes as radiopharmaceuticals demonstrated by

Erdogan et al. in 1996.

• Delivery of peptide drugs

Oral delivery of 9-desglycinamide, 8-arginine vasopressin entrapped in niosomes increase stability of peptide significantly.

Contd…

Ophthalmic Drug Delivery Saettone et al. (1996) reported on the biological evaluation of a

niosomal Cyclopentolate delivery system for opthalmic delivery Polysorbate 20 and cholesterol were used for niosomes formulation Optimum pH for peak permation values was pH 5.5, permeatiom

decreased at pH 7.4 But in vivo data showed no such dependent on pH Niosomes> 10 μm are suitable for drug administration to eye

Recent advances in niosomes

 Combination of PEG and glucose conjugates on the surface of niosomes significantly improved tumor targeting of an encapsulated paramagnetic agent assessed with MR imaging in a human carcinoma xenograft model.

Phase I and phase II studies were conducted for Niosomal methotrexate gel in the treatment of localized psoriasis. These studies suggest that niosomal methotrexate gel is more efficacious than placebo and marketed methotrexate gel.

A research article was published that Acyclovir entrapped niosomes were prepared by Hand shaking and Ether injection methods increases the oral bioavailability

Lancome has come out with a variety of anti-ageing products which are based on niosome formulations

Conclusion

The concept of incorporating the drug into liposomes or niosomes for a better targeting of the drug at appropriate tissue destination is widely accepted by researchers and academicians.

Niosomes represent a promising drug delivery module. Niosomes are thoughts to be better candidates drug delivery

as compared to liposomes due to various factors like cost, stability etc .

Various type of drug deliveries can be possible using niosomes like targeting, ophthalmic, topical, parenteral, etc.

 Niosomes can also serve better aid in diagnostic imaging and vaccine adjuvant in pharmaceutical industry.

References

1. Malhotra M and Jain NK. Niosomes as Drug Carriers. Indian Drugs 31 (3), 1994, 81-86.

2. Handjani-Vila RM., Ribier A, Rondot B and Vanlerberghie G. Dispersions of lamellar phases of non-ionic lipids in cosmetic products. International Journal of Cosmetic Science 1 (5), 1979, 303-314.

3. Baillie AJ, Florence AT, Hume LR, Rogerson A, and Muirhead GT ,The preparation and properties of niosomes-non-ionic surfactant vesicles. J. Pharm Pharmacol. 37(12), 1985, 863–868.

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