Introduction. carrying the drug particles to site of

Introduction. 1Nano emulsions are negatively charged surrogates for carrying the drug particles to site of action in form of globular structure having nebulous morphology and particle size of range 10-1000 nm. Magnetic nanoparticles play an important role in increasing the definite drug targeting. Emulsion is a thermodynamically erratic dispersion in which two immiscible liquids are stabilized by presence of  emulsifying agent and one phase is scattered in other phase known as continuous and discontinuous medium respectively.While Nano emulsion is a type of emulsion of particle size 20-600nm and translucent in appearance due to their particle size. Based on continuous and discontinuous phase Nano- emulsions can be classified into three categories.1. w/o Nano- emulsions2. O/w-Nano emulsions.3. Amphiphilic Nano- emulsions. Components of mini emulsions.Mini emulsions have following integral elements.1. Hydrophobic component (oil).2. Hydrophilic component (water).3. Emulsifying agent.METHODS OF PREPARATION OF NANOEMULSIONS.They can be prepared by following method.1. High Pressure Homogenization.2. Micro fluidization.3. Phase Inversion Temperature Technique4. Solvent Displacement Method.5. Ultra-sonicationMini-emulsions are unstable dispersions 2-4.They require huge quantum of energy or emulsifying agent or blend of both for their formulation. Huge or small buoyancy method can be used for their preparation. 3 Usually high buoyancy technique is used for formulating Nano- emulsions however nowadays low buoyancy is technique is growing due to its enhanced reliability. Buoyancy is require for formulation of Nano emulsions because it is a non-reflex process. Emulsifying agent reduces the interfacial energy of water and oil phase e.g. :polyvinyl chloride.5Advantages1. Nanoemulsons increases the concentration of drug n blood.2. They can be used as alternatives to liposomes.3. They are biocompatible.4. They have improved physiochemical stability.5. Less buoyancy is required.Disadvantages.1. Formulation of nanoemulsons is a costly technique because it requires unique type of methods and instruments e.g. homogenizer.2. They have limited stability profile3. Dissolution of increased melting drugs is decreased n nanoemulsons.4. Physical parameter i-e; pH, temperature, humidity etc can alter their strength.5. Inadequate knowledge about nanoparticles and character of emulsifying agent in increasing their stability.Factors to be considered during preparation of Nano emulsion1. Nature of surfactant should promote the minimal amount of surface free energy.2. Concentration of emulsifying should be sufficient to promote stable preparation.3. Surfactant should be pliable.Characterization of Nano emulsion. 9-11Characterization of nanoemulsons can be done through following parameters.1. pH .pH of nanoemulsons can be determined by the use of pH meter.2. Dilution Test.Ultra-emulsions in which water is external phase can de diluted with water but if oil is external phase it cannot be diluted and results phenomena of phase inversion  3. Phase analysis.Nature of mini emulsion is analyzed by flowing charges through the preparation .conductivity of current indicates water s continuous phase and if abrupt current does not flow the ultra-emulsion  it indicates   that oil is discontinuous phase.4. Dye Test.Ultra-emulsions in which water s continuous phase are tinted with hydrophilic dyes whereas in w/o dyes are dispersed as droplets n discontinuous phase.5. Viscosity.Viscosity of mini-emulsions can be determined by using Brook field viscometer.  • Nano emulsions as CNS drug delivery system.Implementation of ultra-technology for prognosis, prohibition and therapeutics is core of nanomedicine thus, upgrading the standard of living by recognizing the abnormalities of disorders. 12-14.1.5 million population are suffering from aliments of central nervous system accounting 1 % deceases rate around the globe. 15 Affluence of dosage formulation for CNS depends on 16-181. Blood brain barrier.2. Blood-cerbospinalfluid.Nanoemlsons can also be termed as mini emulsions or ultra-emulsions19The Blood brain barrierIntroduction: In human body, the Central nervous system CNS is a precarious and responsive system. For the efficient working of CNS, it is important to maintain the homeostatic balance within it. (1)(2)The balance is regulated by Blood brain barrier, which separates the CNS and peripheral system of circulation to maintain the balance of different substances like ions, macromolecules, essential nutrients to brain and neurotoxins.(3) In the history, firstly Paul Ehrlich gave prove for existence of BBB by his experiment. (4) He observed that hydrophilic dye used during his experiment, stains all parts of body except brain.(8) The experiments of Ehrlich and other scientists gave insight that BBB block the transport of materials across the brain.(9) The studies reveal that there are different types of barriers other than blood brain barrier to maintain the balance in CNS. The BBB confinement of the substances is variable in different parts of CNS. (10)Composition of blood brain barrier:The CNS endothelial cells (single cell forming sheath around a capillary) play main role in maintaining the BBB, but BBB is established anatomically and physiologically by different components which include Neurovascular unit, transporters and junctions around the CNS endothelial cells. (5)(6)(7) ? Neurovascular unitIn past, it was thought that it is the only ability of endothelial cells of brain to work for maintaining the BBB. Scientists have revealed by different experiments that there are different type of cells which are involved in maintaining BBB, most important of them are astrocytes and pericytes. (11)• Astrocytes: Astrocytes are the cells present in close proximity to endothelial cells. Studies showed that mainly there are two types of astrocytes. One of them is protoplasmic form, which reside in gray matter. The processes of this type of astrocytes possess very fine branching which surrounds the cell evenly. Protoplasmic astrocytes along with other functions, also contribute to BBB regulation. Second type is fibrous astrocytes, found in white matter of CNS. They are limited in number, but they are long and function to support the axon structurally. (12)(13)The role of astrocytes is very diverse extending from regulation of neurotransmission to water content in brain. (14)(15) Astrocytes also responsible for discharge of glutathione which perform antioxidant function. They regulate the permeation in BBB by influencing the tight junctions. (16)• Pericytes: These structures are present near to blood vessels and they enclose the walls of blood capillaries of brain. The number of pericytes in peripheral vessels is limited in contrast of brain vasculature. (17) The presence of proteins which are involved in contraction of cytoskeleton attributed the pericytes role in regulation of blood flow. (18) Pericytes are also involved in discharge of proteins which regulate functions of tight junctions. (17)• Microglia: The microglias are perivascular to CNS micro vessels. There are two states of microglia in which it actively performed its function. These functions include discharge of pro inflammatory cytokines, tissue necrosis factor, vascular endothelial growth factor and also involved in repairment of tissues. (19) They are often triggered by endothelial cells. The microglia cells play their role in defensive mechanism for immunity. (20)• Basement membrane: It is also a main part of neurovascular unit. It is responsible for interaction of astrocytes, pericytes and neurons with one another. The loss in its functionality can lead to disturbance of BBB and consequently increase in permeability of substances to brain. (21)• Neurons: The microvasculature of brain is also surrounded by different types of neurons which not only work for regulation of blood flow to these micro vessels but also involved for maintenance of the restricted permeability of BBB. (22)? JunctionsThe BBB is maintained by different types of junctions which work along the neurovascular unit for effective restriction of BBB. (23) Mainly there are two major types of junctions which are present between endothelial cells; Adherent junction and tight junctions. (24)• Adherent junctions: The adherent junctions comprise of different types of proteins. Cadherins are the proteins which mainly perform their function in maintaining BBB. The Cadherin proteins include VE-cadherin, encompassing area between the cells. These cadherins are associated to ?, ? and ? catenins. (24) This type of junction is responsible to grip the endothelial cells firmly. Other than that, these junctions restrict the interaction of cells during growth process of micro vessels and also maintain the asymmetric organization of different cellular components. (25) • Tight junctions:  These junctions are present on the apical portion of endothelial cells providing with an electrical resistance of ? 1800 ?/cm2. (26) The main components of tight junctions are occludins, claudins and junctional adhesion molecules. These components are further linked to several other protiens like zonula occludens and work together for maintaining the tightness of BBB. (24) Tight junctions perform their function by inhibiting the diffusion of ions and large molecules between the cells. (27)? TransportersThere are different routes of transport present in CNS which permit the passage for different molecules to permeate through BBB. (28)• Passive diffusion: The passive diffusion allows the movement of different molecules from a high to low concentration environment. There are some characteristics which help the molecules for passive diffusion e.g hydrophobic nature, molecular weight (MW) < 400 Da, tractability, conformation and existence in ionized form. If molecules do not comply to these characteristics then they cannot pass through BBB. (29)(5) The gases like oxygen and carbon dioxide also use this mechanism of transport to pass through BBB. (5)• Carrier mediated transport: The essential nutrients and neurotransmitters whose transport is limited by the offences of passive transport follow this route for transportation with the help of solute carrier transporters. The transporters for anions and cations also included in them (5)(30)• Receptor mediated endocytosis: This transport is based on the binding of a ligand of a molecule to receptor and then transport of the molecule inside the cell by forming a cavity. This is possible because of various receptors presence on BBB. To cross the BBB the affinity of ligand and receptor is a critical parameter. (5)(31)• Efflux transporters: These transporters are responsible to throw out the molecules from brain and regulate the BBB.. They are categorized into different types e.g P-glycoprotein transporters and multi drug resistant proteins. As these transporters utilize ATP energy for efflux mechanism, so they come under the group of ATP-binding cassette (ABC) membrane transporters. These transporters help in removal of toxic substances from brain either they are endogenous or exogenous.(32)(33)Techniques to transport neurotherapeutics to brain Broadly these approaches can be classified as invasive methods or the non-invasive methods.Invasive methods deliver drug locally into CNS by physically crossing the BBB. Parenchyma of brain is targeted by intracerebroventricular injection into CSF. Enhanced penetration of the medications is by the transient disintegration of BBB either by magnetic resonance, osmotic obstruction or by the use of focussed imaging disruption. But this approach is used only under the extreme state of treatment, because • It necessitates expertise, accuracy and precision. • It is not economic to the patient requires hospitalization.• It has some unwanted effects like physiological stress and abnormal increase in the intracranial pressure.Non-invasive methods acquire extensive drug distribution by using network of blood vessels in brain. Conventionally intravenous administration is employed to deliver NT, but now a days transnasal administration via olfactory or trigeminal neuronal path is being used widely. This has several advantages as• It directly delivers NT to brain by overcoming the BBB, reducing first pass metabolism and systemic dilution.• Use of Absorption enhancers and mucoadhesives increase the residence duration by overcoming the mucociliary clearance, enzymatic degradation or the barriers imposed by epithelium and the mucus layer.Methods of nanoparticles uptake across the blood brain barrierThe mechanisms responsible for internalizing the particles are transcytosis or transcellular routes which are broadly classified into Absorptive-mediated transcytosis that involves non-specific interaction of the particles to the membranes of the cell via plasmalemmal vesicles (caveolae) or clathrin coated pits. There is also the possibility of caveolae-clathrin independent endocytosis.Receptor mediated endocytosis where the larger molecules are taken by specific receptors that are present in special transport vesicles involved in endocytosis. These receptors entail transferrin receptors, insulin receptors and the low density lipoprotein receptor related proteins.Nano-emulsion based formulations overcoming blood brain barrier for CNS disorders Treatment of Central nervous system related diseases is usually cumbersome owing to incapability of the medications to escape the blood brain barrier, blood-CSF barrier, and effluxtransporters. So regular treatments have largely been replaced by the advanced nano technological procedures such as nano-emulsion via different administration routes. And among them intranasal route is used most commonly. As it is the non-invasive way to transport the medicine directly to the CNS. Here are some of the Nanoemulsion based formulations being used to treat neurodegenerative ailments.Cationic nanoemulsion of siRNA for TNF?TNF? is responsible for neuroinflammatory signalling that aggravates the pathological process for conditions like Huntington's disease, epilepsy, Alzheimer's disease, Parkinson's disease and others. Its levels have been decreased by the use of siRNA in a cationic nanoemulsion of omega-3 fatty acids containing flaxseed oil, by the intranasal administration. In the formulation DOTAP lipid is used because of its cationic nature that facilitates higher exposure by increased mucosal residence duration, increased loading capacity and complexation with the negatively charged biomolecules, for enhanced intracellular transport. Particle size for the nanoemulsion is <400nm that provide increased surface area for absorption and interaction in olfactoryepithelium.Squanavir nanoemulsion for HIV virusHIV virus has the ability to reside inside the CNS that made the currently available anti-HIV drugs less effective. As they are not able to cross the blood brain barrier due to their less permeability so cannot completely remove the pathogen from body.cns distribution and oral bioavailability of the protease inhibitor squanavir is increased by the nanoemulsion formulation containing polyunsaturated fatty acids (PUFA) as the internal oil phase and the external consist of mixture of lipoid-80 and deoxycholic acid. Particle size of the oil droplets is in 100-200nm range. Reduced particle size and lipophilic nature enhanced permeability across the barrier and solved the problem.Nanoemulsion based antiepileptic drugs Compromised efficacy of the antiepileptic drug olanzapine due to the blood brain barrier can be enhanced by the olanzapine loaded nanoemulsion preparation delivered through intranasal route. Also the nanoemulsion preparation loaded with carbamazepine and stabilized by 1-O-alkylglycerol or lecithin demonstrated improved availability and site specific delivery on intranasal delivery, in treating generalized tonic clonic seizures. Mucoadhesive nanoemulsion loaded with risperidone administered by intranasal route shows direct delivery to the brain bypassing the barrier with enhanced efficacy and bioavailability.Ropinirole nanoemulsion for Parkinson's disease Antiparkinson's agent ropinirole has increased BBB permeability and brain translocation in nanoemulsion formulation administered by intranasal route.  

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