INTRODUCTION:

The novel drug delivery system is a smart drug delivery which has been developed to optimize regenerative techniques¹. Novel drug delivery system is such a delivery system which improves the therapeutic efficacy of new as well as pre-existing drugs and provides controlled and sustained drug delivery². Novel drug delivery system can localize drug action by placing release system in a controlled manner, in the diseased tissue or organ or target drug action by using carriers^3,4. In 1909, Paul Ehrlich, initiated the development for targeted delivery⁵. In 70s, the self-assembly of non-ionic surfactant in vesicles was firstly discovered by a cosmetic industry (L'oreal)⁶. Niosomes having size range between 10 to 1000 nm are vesicular carrier of non-ionic surfactant which can encapsulate the both hydrophilic and hydrophobic drug with or without Cholesterol and Dicetyl Phosphate⁷. Vesicular drug delivery system can achieve the constant plasma drug concentration for an extended period of time⁸.

The surfactant molecules orient them selfs in such a manner that hydrophilic ends of non-ionic surfactant remain outwards, while the hydrophobic ends face each other and forms a bilayer⁹. This vesicular structure of noisome maintained by various forces acts inside the vesicle such as vander waal forces among surfactant, repulsive forces result by electrostatic interaction in between charged group of surfactant molecule., entropic repulsive forces generated by head group of surfactants ¹⁰. Niosomes releases the drug in a controlled manner hence act as a depot. Protection of drug from biological environment, delayed clearance of drug molecule from circulation enhances the therapeutic performance of drug¹¹.

Components and Factors Influencing Structure and Stability of Vesicular Structure of Niosomes:

Nonionic surfactant and the additives (cholesterol and charge inducers) are used as main components having different properties, which effects the formation and stability of niosomes.

Nonionic Surfactants:

Nonionic surfactants have no charged groups in their hydrophilic heads and more stable, biocompatible and less toxic than their anionic, amphoteric, or cationic forms¹². Therefore, these surfactants have ability to form stable niosome for in vitro and in vivo applications. In recent a new Gemini non-ionic surfactant have been introduced, which have two hydrophilic head and hydrophobic chains. The positive (sterylamine and cetylpyridinium chloride) and negative (dicetyl phosphate, dihexadecyl phosphate and lipoamine acid) charge inducer helps in the electrostatic stabilization of the vesicular systems.^13,14.

Hydrophilic-Lipophilic Balance (HLB):

HLB indicates the solubility of the surfactant molecule and describes the balance between the hydrophilic and lipophilic portion of the non-ionic surfactant. Surfactants having HLB between 4-8 can be used for vesicle formation¹⁵. Hydrophilic surfactants with a HLB value 14to17 having high aqueous solubility hence not suitable for the formation of bilayer membrane due¹⁶. Niosomes are virtualy formed from polysorbate 80 (HLB value = 15) and Tween 20 (HLB value = 16.7), on addition of an optimum level of cholesterol^17,18. Tween 20 forms stable niosome in the presence of equimolar cholesterol concentration. The hydrophobic part of amphiphile interacts with 3-OH group of cholesterol at an equimolar ratio. This interaction represents the effect of cholesterol on the formation and hydration behaviour of niosomal membranes formed by Tween 20^19,20. HLB value of surfactant also affects the drug entrapment efficiency of the niosomes²¹. Shahiwala et al. have found that the entrapment efficiency of niosomes decreases with decrease in HLB value of surfactant from 8.6 to 1.7,^16,22.

Critical Packing Parameter (CPP):

The geometry of the vesicle depends upon the critical packing parameter. The shape of nanostructures formed by self-assembly of amphiphilic molecules can be predicted on the basis of CPP. Critical packing parameter can be defined using following equation^23,24.

CPP =V/𝑙𝑐×𝑎 ₀,

Where V = hydrophobic group volume, 𝑙𝑐 = critical hydrophobic group length, and 𝑎₀= area of hydrophilic head group²⁵.

Cholesterol:

Cholesterol forms hydrogen bonds with hydrophilic head of a surfactant^26,27. Structure of niosomes and some physical properties such as entrapment efficiency, long time stability, release of payload, and biostability can be influenced by the presence of cholesterol^28,19. Plasma and serum induced destabilizing effects on noisome which can be improves by addition of cholesterol. It also inhibits the leakage of entrapped molecules by decreasing the permeability of vesicles²⁹. Agarwal et al. observed that cholesterol improves the stability of niosome with increasing cholesterol content, which increases the entrapment efficiency of drug³⁰. According to Mokhtar et al.it was found that when cholesterol was added with span 20 and span 80 for the entrapment of flurbiprofen it reveals significant increase was obtained after incorporation of 10% cholesterol with span 40 and span 60. On further increase in cholesterol level the encapsulation efficiency of niosomes was decreased³¹.

Charged Molecule and nature of encapsulated drug:

These molecules added charge group on the bilayer of vesicles and also prevents the vesicle aggregation and increases surface charge density, which enhance the stability of vesicular system. Negatively charged molecules (Dicetyl phosphate and phosphatidic acid) and positively charged molecules (amine and stearyl pyridinium chloride) are mostly used for the preparation of niosomes³². The encapsulated drug influences the charge and rigidity of the bilayer by and intract with the head groups of surfactants, resulting charge development which creates repulsion between the bilayers of surfactant and hence vesicle size increases. polyoxyethylene glycol (PEG) reduces the tendency to increase the size of vesicles by entrapping the, drug in the long PEG chains^33,34.

Methods of preparation of niosomes:

On the basis of the types of niosomes may be prepared by different methods:

Sonication:

Small unilamellar vesicles are forms by the sonication of the drug solution. This method was described by the Cable. Aliquot of drug solution in buffer was prepared and added it in to the mixture of surfactant and cholesterol in a 10ml glass vial. After that mixture is sonicated at 60°C for 3 min for the preparation of noisome by using titanium probe sonicator^5,35.

Micro fluidization:

This method is based on submerged jet principle in two fluidized streams interact in precisely defined micro channels within the interaction chamber at ultra-high velocities. The impact of thin liquid sheet along a common front is arranged in such a manner that the energy involved in system remains and leads to formation of small uniform niosome. The resultant niosome has greater uniformity, smaller size and better reproducibility³⁶.

Hand shaking method (Thin film hydration technique)³⁷:

In this technique some cases the dried surfactant film is rehydrated with aqueous phase containing drug. This process forms multilamellar vesicular type niosomes³⁸.

Fig. 1: Hand shaking method (Thin film hydration technique)

Ether injection method:

In this method the size of vesicles can be controlled by controlling the size of needle and other parameters. But it suffers as disadvantageous method due the limited solubility of component in ether and hence removal of ether from final formulation is difficult. In this method the solution of niosomal ingredients in ether is slowly injected into preheated aqueous phase (60 C) by 14-gauge needle at 0.25ml/min rate^11,26. After the slow vapourisation of solvent the ether gradient extends towards the aqueous- nonaqueous interface which leads large unilamellar vesicle formation.

Trans-membrane pH gradient drug uptake process (remote loading) :³⁸

Fig. 2: Trans-membrane pH gradient drug uptake process

Reverse phase evaporation technique (REV):

The removal of the solvent from an emulsion by evaporation is novel key in this method. Due the reduce pressure this emulsion gets converted into semi solid gel. ^4,39

Fig. 3: Reverse phase evaporation technique (REV) Miscellaneous

a. Multiple membrane extrusion method:

A thin film of mixture made by dissolving surfactant, chlolesterol and diacetyl phosphate in chloroform obtained by evaporation. This film hydrated with aqueous solution and resultant suspension recaptured through polycarbonate membranes. By this method size of niosomes can be controlled.⁴¹

b. Emulsion method:

Oil in water (o/w) emulsion is prepared by using aqueous solution of drug and organic solution containing surfactant, cholesterol. Niosome obtained after evaporation of organic solvent and dispersed in the aqueous phase.^40,42

c. The “Bubble” Method:

This is novel technique for the preparation of liposomes and niosomes without using organic solvents⁴³.

Fig. 4: The “Bubble” Method

d. Formation of niosomes from proniosomes:

Coating of a water-soluble carrier such as sorbitol with surfactant is another method of producing niosomes. 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” .⁴⁴

Evaluation parameters of niosomes:

Evaluation studies are further carried out for the prepared proniosomes in order to find out the:

Table 1: Different methods to evaluate parameters of niosomes

Parameters	Methods
Size and Morphology^46-50	Dynamic light scattering (DLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), freeze fracture replication electron microscopy, and cryo-transmission electron microscopy (cryo-TEM)
Zeta Potential⁴⁵	zeta sizer and DLS instruments
Bilayer Characterization ⁵¹	Atomic force microscopy (AFM), Nuclear Magnetic Resonance (NMR) and small angle X-ray scattering (SAXS).
Entrapment Efficiency^{52- 56}	centrifugation, dialysis, or gel chromatography

Stability:

The stability of niosomes can be evaluated by determining mean vesicle size, size distribution, and entrapment efficiency over several month storage periods at different temperatures. ^55,56

In-Vitro Release:

One often applied method to study in vitro release is based on using of dialysis tubing. A dialysis bag is washed and soaked in distilled water. The bag containing the vesicles is immersed in buffer solution with constant shaking at 25^∘C or 37^∘C. At specific time intervals, samples were removed and analysed for the drug content by an appropriate assay method.⁵⁸

Applications:

1. Ophthalmic drug delivery:

Some ophthalmic preparation based on niosome can enhace the penetration of drug through cornea in a pH dependant manner as example. Cyclopentolate encapsulated within niosomes (polysorbate 20 and cholesterol) having higher Permeation of cyclopentolate at pH 5.5. Altered permeability characteristics of the conjunctival and sclera membranes due to niosomal ophthalmic formulations absorption can also be increased⁵⁹. Abdelbary and ElGendy examined the cabability of the niosomes as a carrier for the ophthalmic controlled delivery of gentamicin. After evaluation, obtained result revealed that entrapment efficiency and the release rate of gentamicin is affected by cholesterol content, type of surfactant, and the presence of charge inducer and showed prolonged in vitro drug release.⁶⁰

2. Targeted Delivery:

The ability to target particular drug in a particular site is one of the most useful aspects of niosomes. A carrier system (such as antibodies) can be attached to niosomes (as immunoglobulin’s bind readily to the lipid surface of the niosome) to target them to specific organs⁶¹. For targeting the surfaces of niosomes can be conjugated with small molecules and/or macromolecular targeting ligands to enable cell specific targeting.⁶² There are some most commonly used molecules such as proteins and peptides, carbohydrates, aptamers, antibodies, and antibody fragments, that specifically binds to an over expressed target on the cell surface.^63-65

3. Anticancer Drug Delivery:

· Breast Cancer:

Cosco et al prepared 5-FU-loaded polyethylene glycol-(PEG-) coated and uncoated bola-niosomes. Both bola-niosome formulations provided an increased cytotoxic effect with respect to the free drug.⁶⁶ Recently, tamoxifen citrate niosomes were prepared by film hydration technique for localized cancer and it was showed that the niosomal formulation of tamoxifen significantly enhanced cellular uptake (2.8-fold) and exhibited significantly greater cytotoxic activity.⁶⁷

· Melanoma:

Dwivedi et al. encapsulated artemisone (10-amino-artemisinin derivative exhibiting antimalarial activity and also possessing antitumor activity) in niosomes and observed that the encapsulated drug have highly selective cytotoxicity towards the melanoma cells but negligible toxicity towards the normal skin cells.⁶⁸ Gude et al. synthesized niosomal cisplatin to reduce limitations due to the severe toxic effects and investigated that cisplatin encapsulated in niosomes has significant antimetastatic activity and reduced toxicity when compared to free cisplatin.⁶⁹

4. Codrug Delivery:

In recent years, combinational therapies are implementing to enhance therapeutic efficacy and decrease the dosage for this purpose nanoparticles have emerged as a promising delivery system of carriers in codelivery of multiple drugs.⁷⁰ Pasutet al. conjugated nitric oxide and epirubicin covalently to each terminal of PEG and have developed simultaneous anticancer drug epirubicin and nitric oxide carrying system. The study revealed that the branched PEG as polymer backbone can increase anticancer efficacy and enhance to protect cardiocyte ability of co delivery system.⁷¹

5. Pulmonary Delivery:

Clinical efficacy of drug used for inhalation therapy is usually dependent on the aerodynamic size distribution of the aerosol and drug output from a nebulizer. Niosomal vesicles remarkably increased the permeation rate of beclomethasone dipropionate through the mucosal membrane barrier. Niosomes containing polysorbate 20 and BDP have advantages such as high drug encapsulation efficiency, strong mucus permeation, and sustained delivery to the target site are well suited as a drug delivery system for COPD patients through pulmonary delivery.⁷²^,⁷³

6. Blood brain barrier:

Several brain and CNS diseases such as neurological diseases, neurological disorders and brain tumors are needed proper drug delivery for treatment⁷⁴. In brain zonula occludens continuous tight junctions (connected with ECs) cover the paracellular pathway which can block the free polar solutes from paracellular pathways eﬃciently.^75-78 Generally, there are three systems for drug delivery to the brain including systemic absorption through BBB and nasal and intra cerebro ventricular (ICV) administration. These methods have several disadvantages.^79-80 Niosomes are promising approach to improve natural drug delivery through the brain because it had ability to change the characteristics and the behaviour of the natural drugs after administration and protect drugs from degradation, hence delivered them to their target sites.^81-82 Niosomes have also, prolonged the blood circulation time, enhanced drug accumulation in the pathological tissues.⁸³^,⁸⁴ On the other hand the decreased toxicity could organize the application of the vesicular systems for numerous pharmaceutical Uses⁸⁵. Ligand bindings and applying the natural drug in diﬀerent surfaces of the body also increased the drug delivery efficacy due to the passive diffusion.⁸⁶^,⁸⁷

7. Delivery of antileishmanial Agents:

Niosomes can be used for targeting of drug in the treatment of leishmaniasis, in which parasite invades cells of liver and spleen.⁸⁸ Niosome and Liposome containing Amarogentin, a secoiridoid glycoside has been evaluated for antileishmanial property. In this study it was found that the niosome forms were more efficacious than the liposomal form at the same membrane microviscosity level and may have clinical application in the treatment of leishmaniasis⁸⁹. On the other hand the toxicity is the major obstacle for the most potent drug of antileishmaiatic drugs. Nanocapsulated quercetin delivery model was attempted to treat experimental leishmaniasis in the hamster model so as to increase its efficacy. This model reduced parasite burden in the spleen as well as reduced hepatotoxcity and renal toxicity as compared to free drug.⁹⁰

8. Gene Delivery:

Cationic niosomes of sorbitan monoesters conatinig Antisense oligonucleotides (OND) were delivered effectively, which showed positive cellular uptake of the antisense oligonucleotides from the prepared niosomes ⁹¹. The efficacy was shown by facilitated cellular uptake by COS-7 cells and HeLa cells and positive effect on gene expression.⁹²

CONCLUSION:

The bilayer structure of niosomes (amphiphillic in nature) offers a great opportunity for loading hydrophilic, lipophilic drugs, or both drugs together and can be used to deliver both hydrophilic (in aqueous core) and lipophilic drugs (in the bilayer of surfactants). Nisomes have greater stability due to the various charge inducers which develop a charge on the surface of niosomes and stabilize the prepared formulation by the resulting repulsive forces. The concept of incorporating the drug into niosomes for a better targeting at appropriate tissue destination is widely accepted by various researchers and numbers of studies have been performed with different kinds of niosomes for delivery of anticancer agents, antiinflammatory agents, anti-infective agents, and so forth. It can be concluded from the relevant studies that niosomes ameliorate the stability of the entrapped drug, reduce the dose, and enable targeted delivery to a specific type of tissue. On the other hand, by using novel preparations, loading, and modification methods the structural properties and characteristics of the niosomes can be enhanced. On the basis of above information, the niosomes a promising carrier for the drug delivery system and offer scope for research on various drugs for their maximum therapeutic utilization in treatment of various dreadful diseases it procures much research to be inspired to juice out all the potential in this novel drug delivery system.

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Received on 19.05.2020 Modified on 25.06.2020

Research J. Pharm. and Tech. 2021; 14(5):2896-2902.

DOI: 10.52711/0974-360X.2021.00508