Nanotechnology in pharmaceutics

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NANOTECHNOLOGY:

NANOTECHNOLOGY Prepared by: Kunal Vanparia Guided by: Dr. Vaishali Thakkar

The power of 'Nano'!:

The power of ' Nano '! A nanometer (nm) is one-billionth of a meter(much smaller than the visible wavelength of light.) Nanotechnology is the design, characterization, production and application of structures, devices and systems by controlling shape and size at nanometer scale.

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It has a potential wide range of applications in agriculture, industry, communications, medicine etc. Already, nanotechnology is being used commercially; for example, sunscreens made with nanotechnology do not give a whitish tinge when applied to the skin. Nanoparticles in glass screens breaks down when UV radiation falls on it, loosening the dirt on its surface, thus making it self cleaning. A chemical coating of nanoparticles on a car windscreen can make water roll down as tiny droplets, thus improving visibility even in a heavy downpour.

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Currently, many strains of bacteria have become resistant to antibiotics. Bandages made with nanoparticles of silver are an effective medium for antibiotic delivery. Visualization of parts of the small intestine with current technologies have severe limitations. A 'pill cam ' can help to solve this problem. This 'pill' has a tiny digital camera at it's tip and tiny LED's to provide light. It take 2 pictures/second and sends it by radio signals to sensors attached to the body.

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The patient swallows the 'pill' and goes on with routine daily activities. The recorded data is downloaded later into a computer and a doctor can view the digital images to spot any abnormalities in small intestine. Other futuristic scenarios include the development of artificial red blood cells to improve blood flow, artificial mitochondria to maintain metabolism in tissues suffering from ischemic injury etc. Clearly, the sky is the limit for nanotechnology!

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Types of Nanoparticulate system…

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Polymeric NPs SLNs Nanocrystals Polymeric micelles Liposomes Dendrimers Magnetic NPs Nanoshells coated with gold Carbon nanotubes Ferrofluids

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Sr.no Types of nanoparticles Material used AppliCation 1 Polymeric nanoparticles Biodegradable polymers Controlled and targeted drug delivery 2 Solid lipid nanoparticles Melted lipid dispersed in an aqueous surfactant Least toxic and more stable colloidal carrier systems as alternative to polymers 3 Nanocrystals & nanosuspensions Drug powder is dispersed in a surfactant solution Stable systems for controlled delivery of poorly water soluble drugs 4 Polymeric micelles Amphiphilic block copolymers Systemic and controlled delivery of water insoluble drugs 5 Liposomes Phospholipid vesicles Controlled and targeted drug delivery 6 Dendrimers Tree like molecules with defined cavities Drug targeting 7 Magnetic NPs An inorganic core of iron oxide (magnetite) coated with polymer such as dextran Drug targeting, Diagnostic tool in biology and medicine 8 Gold nanoshells Dielectric (typically gold sulfide or silica) core and a metal (gold) shell Tumor targeting 9 Nanowires or Carbon nanotubes (2 dimentional ) Metals, semiconductors or carbon Gene and DNA delivery 10 Ferrofluids Iron oxide magnetic NPs surrounded by a polymeric layer For capturing cells and other biological targets from blood or other fluids and tissue samples

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NANOSUSPENSION

NANOSUSPENSION:

NANOSUSPENSION Solubility is an essential factor for drug effectiveness, independent of the route of administration. Poorly soluble drugs are often a challenging task for formulators in the industry. Conventional approaches for enhancement of solubility have limited applicability, especially when the drugs are poorly soluble simultaneously in aqueous and in non-aqueous media. Nanosuspension technology can be used to improve the stability as well as the bioavailability of poorly soluble drugs.

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DEFINATION: Nanosuspensions are biphasic systems consisting of pure drug particles dispersed in an aqueous vehicle, stabilized by surfactants. It has the advantage of delivery by various routes, including oral, parenteral, pulmonary and ocular routes

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Nanosuspensions are colloidal dispersions of nanosized drug particles stabilized by surfactants. They can also be defined as a biphasic system consisting of pure drug particles dispersed in an aqueous vehicle in which the diameter of the suspended particle is less than 1 μm in size. Nanosuspensions can be used to enhance the solubility of drugs that are poorly soluble in aqueous as well as lipid media. As a result, the rate of flooding of the active compound increases and the maximum plasma level is reached faster (e.g., oral or intravenous [IV] administration of the nanosuspension). This is one of the unique advantages that it has over other approaches for

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enhancing solubility. It is useful for molecules with poor solubility, poor permeability or both, which poses a significant challenge for the formulators. The reduced particle size renders the possibility of intravenous administration of poorly soluble drugs without blockade of the blood capillaries. The nanosuspensions can also be lyophilized or spray dried and the nanoparticles of a nanosuspension can also be incorporated in a solid matrix.

Preparation of Nanosuspensions:

Preparation of Nanosuspensions Mainly 2 methods used Bottom up technology Top down technology Bottom up technology is an assembeling method to form nanoparticles like precipitation, microemulsion , melt emulsification. Top down technology involves disintegration of larger particles into nanoparticles example of wich are High pressure homogenization and milling method.

Precipitation method:

Precipitation method Drug is dissolved in solvent and then drug solution added to solvent in which drug is insoluble. Rapid addition of solution to such solvent leads to supersaturation of drug in solution and formation of ultrafine amorphous or crystalline drug Method involves nuclei formation and crystal growth which mainly depend on temperature.

High pressure homogenization:

High pressure homogenization This method involves 3 steps Dispersion of drug powder in stabilizer solution to form presuspension Presuspension is homogenized at slow pressure. Finally it homogenized at high pressure for 10 to 25 cycle untill nanosuspension is formed with desired particle size.

Homogenization in aqueous media (Dissocubes):

Homogenization in aqueous media ( Dissocubes ) In this case, the suspension of the drug is made to pass through a small orifice that results in a reduction of the static pressure below the boiling pressure of water, which leads to boiling of water and formation of gas bubbles. When the suspension leaves the gap, the bubbles implode(called cavitation ) and normal air pressure is reached again and the surrounding part containing the drug particles rushes to the center and in the process colloids, causing a reduction in the particle size.

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Most of the cases require multiple passes or cycles through the homogenizer, which depends on the hardness of drug, the desired mean particle size and the required homogeneity.

Homogenization in non aqueous media(Nanopure):

Homogenization in non aqueous media( Nanopure ) Here suspension is homogenized in non aqueous media. It is ‘deep freeze homogenization’. In nanopure technology, the drug suspensions in the non- aqueous media were homogenized at 0 0 C or even below the freezing point. Because of very high boiling point and low vapoure pressure of water, oil and fatty acid, drop of static pressure is not enough to begin cavitation in nanopure technology.

Media milling:

Media milling Drug is subjected to media milling for nanoparticle production. Here impaction between drug and milling media gives energy for disintegration of microparticulate system into nanoparticulate system. Milling chamber is filled with miling media involving drug, stabilizer and water which is rotated at very high shear rate to generate suspension.

Dry cogrinding:

Dry cogrinding Early nanosuspension was prepared through wet grinding process by using pearl ball mill, now a days nanosuspension prepared by dry milling method. It is prepared by dry grinding of poorly soluble drug with soluble polymers and copolymers after dispersing in liquid medium

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(3)Emulsification-solvent evaporation technique This technique involves preparing a solution of drug followed by its emulsification in another liquid that is a non-solvent for the drug. Evaporation of the solvent leads to precipitation of the drug Crystal growth and particle aggregation can be controlled by creating high shear forces using a high speed stirrer.

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(4)Supercritical fluid method The various methods attempted are Rapid expansion of supercritical solution process(RESS) Precipitation with compressed anti-solvent process(PCA).

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RESS Here drug is dissolved in SCF and then it is subjected to rapid expansion by passing through nozzle at supersonic speed. This leads to supersaturation of solute and subsequent precipitation of solute(drug). Precipitation with compressd fluid antisolvent (PAS) Here drug is solubilized in solvent and then this drug solution is sprayed into supercritical CO 2 which act as antisolvent . As the removal of solvent occur, solution gets supersaturated and finally precipitation occur.

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Characterization of Nanosuspensions

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1.Mean particle size and particle size distribution Particle size distribution determines the physiochemical behavior of the formulation, such as saturation solubility, dissolution velocity, physical stability, etc. The particle size distribution can be determined by photon correlation spectroscopy (PCS), laser diffraction (LD) and coulter counter multisizer . The PCS method can measure particles in the size range of 3 nm to 3 μm and the LD method has a measuring range of 0.05-80 μm. The coulter counter multisizer gives the absolute number of particles, in contrast to the LD method, which gives only a relative size distribution .

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For IV use, particles should be less than 5 μm , considering that the smallest size of the capillaries is 5-6 μm and hence a higher particle size can lead to capillary blockade and embolism. 2.Zeta potential Surface charge properties of nanosuspension are studied through Zeta potential. Zeta potential is an indication of the stability of the suspension. For a stable suspension stabilized only by electrostatic repulsion, a minimum zeta potential of ±30 mV is required whereas in case of a combined electrostatic and steric stabilizer, a zeta potential of ±20 mV would be sufficient.

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3.Crystal morphology To characterize the polymorphic changes due to the impact of high-pressure homogenization in the crystalline structure of the drug, techniques like X-ray diffraction analysis in combination with differential scanning calorimetry or differential thermal analysis can be utilized. Nanosuspensions can undergo a change in the crystalline structure, which may be to an amorphous form or to other polymorphic forms because of high-pressure homogenization

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4.Dissolution velocity and saturation solubility Nanosuspensions have an important advantage over other techniques, that it can increase the dissolution velocity as well as the saturation solubility. The assessment of saturation solubility and dissolution velocity helps in determining the in vitro behavior of the formulation. Böhm et al. reported an increase in the dissolution velocity with a reduction in the particle size to the nanometer range.

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Size reduction leads to an increase in the dissolution rate. An increase in solubility that occurs with relatively low particle size reduction may be mainly due to a change in the surface tension leading to an increased saturation solubility. Muller explained that the energy introduced during the particle size reduction process leads to an increase in the surface tension and an associated increase in the dissolution rate.

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Stability of Nanosuspensions The high surface energy of nanosized particles induces agglomeration of the drug crystals. The main function of the stabilizer is to wet the drug particles thoroughly to prevent Ostwald ripening and agglomeration of the nanosuspension and form a physically stable formulation by providing a steric or an ionic barrier. Typical examples of stabilizers used in nanosuspensions are cellulosics , poloxamer, polysorbates, lecithin, polyoleate and povidones. Lecithin may be preferred in developing parenteral nanosuspensions.

  Applications of Nanosuspensions:

Applications of Nanosuspensions 1.Bioavailability enhancement The poor oral bioavailability of the drug may be due to poor solubility, poor permeability or poor stability in the gastrointestinal tract (GIT). Nanosuspensions resolve the problem of poor bioavailability by solving the twin problems of poor solubility and poor permeability across the membrane.

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Oral administration of the gonadotrophin inhibitor Danazol as a nanosuspension leads to an absolute bioavailability of 82.3% and the conventional dispersion (Danocrine) only to 5.2%. A nanosuspension of Amphotericin B developed by Kayser et al. showed a significant improvement in its oral absorption in comparison with the conventional commercial formulation. Bioavailability of poorly soluble oleanolic acid , a hepatoprotective agent, was improved using a nanosuspension formulation.

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2.Intravenous administration The parenteral route of administration provides a quick onset of action, rapid targeting and reduced dosage of the drug. It is the preferred route for drugs undergoing first-pass metabolism and those that are not absorbed in the GIT or degraded in the GIT. One of the important applications of nanosuspension technology is the formulation of intravenously administered products.

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IV administration results in several advantages, such as administration of poorly soluble drugs without using a higher concentration of toxic co-solvents improving the therapeutic effect of the drug available as conventional oral formulations

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Peters et al. prepared clofazimine nanosuspensions for IV use and showed that the drug concentrations in the liver, spleen and lungs reached a comparably higher level, well in excess of the minimum inhibitory concentration for most Mycobacterium avium strains. A stable intravenously injectable formulation of omeprazole has been prepared to prevent the degradation of orally administered omeprazole .

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Injectable nanosuspensions of poorly soluble drug tarazepide have been prepared to overcome the limited success achieved using conventional solubilization techniques, such as use of surfactants, cyclodextrins , etc., to improve bioavailability.

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3.Pulmonaryadministration Aqueous nanosuspensions can be nebulized using mechanical or ultrasonic nebulizers for lung delivery. Budenoside drug nanoparticles were successfully nebulized using an ultrasonic nebulizer. The pharmacokinetics of the nebulized nanocrystal budenoside suspension showed better AUC, lower Cmax and lower Tmax .

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Other applications include ocular delivery of the drugs as nanosuspensions to provide a sustained release of drug. Pignatello et al. prepared Eudragit retard nanosuspensions of cloricromene for ocular delivery. They observed that the drug showed a higher availability in rabbit aqueous humor and the formulation appeared to offer a promising means of improving the shelf-life and the bioavailability of this drug after ophthalmic application.

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4.Mucoadhesion of the nanoparticles Nanoparticles orally administered in the form of a suspension diffuse into the liquid media and rapidly encounter the mucosal surface. The particles are immobilized at the intestinal surface by an adhesion mechanism referred to as "bioadhesion.“ From this moment on, the concentrated suspension acts as a reservoir of particles and an adsorption process takes place very rapidly. The direct contact of the particles with the intestinal cells through a bioadhesive phase is the first step before particle absorption.

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The adhesiveness of the nanosuspensions not only helps to improve bioavailability but also improves targeting of the parasites persisting in the GIT , e.g., Cryptosporidium parvum . The bioadhesion can also be improved by including a mucoadhesive polymer in0 the formulation

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Conclusion Nanosuspensions of pure drug offer a method to formulate poorly soluble drug and enhance the bioavailability of several drugs. It has many formulations and therapeutic advantages , such as simple method of preparation less requirement of excipients increased dissolution velocity and saturation solubility improved adhesion increases the bioavailability leading to a decrease in the dose and fast-fed variability and ease of large-scale manufacturing.

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Nanosuspensions can be formulated for various routes of administration, such as oral, parenteral, ocular, topical and pulmonary routes. This technology is gaining significance as the number of molecules with solubility and bioavailability related problems are increasing day by day.

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NANOPARTICLES

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Nanoparticles Nanoparticles are often defined as particles of less than 100nm in diameter. Nanoparticles can be also defined as “particles less than 100nm in diameter that exhibit new or enhanced size-dependent properties compared with larger particles of the same material.” They consist of macromolecular materials in which the active principle is dissolved, entrapped or encapsulated, and/or to which the active principle is absorbed or attached. .

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Various polymers have been used in the formulation of nanoparticles for drug delivery research to increase therapeutic benefit, while minimizing side effects. Depending upon the method of preparation, nanoparticles , nanospheres or nanocapsules can be obtained.

Nanoparticles:

Nanoparticles NANOSPHERES NANOCAPSULES Nanoparticles

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Nanospheres may be defined as solid core spherical particulates, which are nanometric in size. They contain drug embedded within the matrix or adsorbed on to the surface. Nanocapsule are vesicular systems in which drug is essentially encapsulated within the central volume surrounded by an embryogenic continuous polymeric sheath. Here the drug is mainly encapsulated in the solution system.

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The major goals in designing nanoparticles as a delivery system are to control particle size, surface properties and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutically optimal rate and dose regimen.

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The advantages of using nanoparticles as a drug delivery system include the following: 1). Particle size and surface characteristics of nanoparticles can be easily manipulated to achieve both passive and active drug targeting after parenteral administration . 2). Controlled drug release characteristics can be readily modulated by the choice of matrix constituents.

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3). Drug loading is relatively high and drugs can be incorporated into the systems without any chemical reaction; this is an important factor for preserving the drug activity. 4). Site-specific targeting can be achieved by attaching ligand to surface of particles or use of magnetic guidance. 5). The system can be used for various routes of administration including oral, nasal, parenteral , intra-ocular etc.

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Limitations: Their small size and large surface area can lead to particle-particle aggregation , making physical handling of nanoparticles difficult in liquid and dry forms. In addition, small particles size and large surface area readily result in burst release . These practical problems have to be overcome before nanoparticles can be used clinically or made commercially available.

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Preparation of Nanoparticles It involve 3 method (1) Dispersion of preformed polymers (2) Polymerization of monomers (3) Ionic gelation or coacervation of hydrophilic polymers.

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1.Dispersion of preformed polymers : Dispersion of preformed polymers is a common technique used to prepare biodegradable nanoparticles from poly (lactic acid) (PLA); poly (D,L- glycolide ),PLG; poly (D, L- lactide -co- glycolide ) (PLGA) and poly (cyanoacrylate) (PCA). This technique can be used in various ways as described below.

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A.Solvent evaporation method : In this method, the polymer is dissolved in an organic solvent such as dichloromethane, chloroform or ethyl acetate which is also used as the solvent for dissolving the hydrophobic drug. The mixture of polymer and drug solution is then emulsified in an aqueous solution containing a surfactant or emulsifying agent to form an oil in water (o/w) emulsion. After the formation of stable emulsion,the organic solvent is evaporated either by reducing the pressure or by continuous stirring.

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Particle size influenced by the type and concentrations of stabilizer, homogenizer speed and polymer concentration . In order to produce small particle size, often a high-speed homogenization or ultrasonication may be employed.

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B.Production of nanoparticles using supercritical fluid technology Conventional methods such as solvent extraction-evaporation method require the use of organic solvents which are hazardous to the environment as well as to physiological systems. Therefore, the supercritical fluid technology has been investigated as an alternative to prepare biodegradable micro- and nanoparticles because supercritical fluids are environmentally safe.

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A supercritical fluid is a solvent, which shows property of both liquid and gas above critical temperature and critical pressure. Supercritical CO 2 (SC CO 2 ) is the most widely used supercritical fluid because of its mild critical conditions ( Tc = 31.1 °C, Pc = 73.8 bars), nontoxicity, non-flammability, and low price. The most common processing techniques involving supercritical fluids are supercritical anti-solvent (SAS) and rapid expansion of critical solution(RESS).

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The process of SAS employs a liquid solvent, eg. methanol, which is completely miscible with the supercritical fluid (SC CO 2 ) , to dissolve the solute to be micronized; at the process conditions, because the solute is insoluble in the supercritical fluid, the extract of the liquid solvent by supercritical fluid leads to the instantaneous precipitation of the solute, resulting the formation of nanoparticles. Thote and Gupta (2005) reported the use of a modified SAS method for formation of hydrophilic drug dexamethasone phosphate drug nanoparticles for microencapsulation purpose.

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Supercritical fluid technology technique, although environmentally friendly and suitable for mass production, requires specially designed equipment and is more expensive .

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2.Polymerization method In this method, monomers are polymerized to form nanoparticles in an aqueous solution . Drug is incorporated either by being dissolved in the polymerization medium or by adsorption onto the nanoparticles after polymerization completed. The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and re-suspending the particles in an isotonic surfactant-free medium.

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This technique has been reported for making polybutylcyanoacrylate or poly (alkylcyanoacrylate) nanoparticles. Nanocapsule formation and their particle size depends on the concentration of the surfactants and stabilizers used

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3.Coacervation or ionic gelation method Much research has been focused on the preparation of nanoparticles using biodegradable hydrophilic polymers such as chitosan, gelatin and sodium alginate. Calvo and co-workers developed a method for preparing hydrophilic chitosan nanoparticles by ionic gelation. The method involves a mixture of two aqueous phases, of which one is the polymer chitosan , and the other is polyanion sodium tripolyphosphate .

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In this method, positively charged amino group of chitosan interacts with negative charge tripolyphosphate to form coacervates with a size in the range of nanometer. Coacervates are formed as a result of electrostatic interaction between two aqueous phases.

Novel nanoparticulate systems::

Novel nanoparticulate systems: SLNs (Solid Lipid nanoparticles ):- Solid lipid nanoparticles (SLN) are submicron colloidal carriers which are composed of physiological lipid, dispersed in water or in an aqueous surfactant solution.

Advantages of SLNs::

Advantages of SLNs: Small size& narrow size distributiobn leading to better site specific drug delivery Controlled release of active drug over a long period Protection of incorporated drug by chemical degradation Possible to sterilize can be lyophilized or spray dried No toxic metabolites are produced No use of organic solvents, cheaper & stable Ease of industrial scale production by hot dispersion technique incorporation of drug can decrease side effects of the drug

Preparation of SLNs :

Preparation of SLNs Cold homogenization:- Melting of lipid Dissolution of drug in melted lipid Solidification of the drug loaded lipid in liquid Nitrogen or ice Grinding in a powder mill (50-100 µm) Dispersion of the lipid in the cold aqueous dispersion medium SLNs

Hot Homogenization:

Hot Homogenization Melting of the lipid Dissolution of drug in melted lipid Mix preheated dispersion medium & drug lipid melt Coarse pre emulsion High pressure homogenization at temperature higher than Melting Point of lipid o/w nano emulsion Solidification of nanoemulsion to get SLNs

Nanoparticles coated with Antibodies:

Nanoparticles coated with Antibodies The anchoring of target specific antibodies to the nanoparticle surface may facilitate site specific drug delivery. Monoclonal antibodies can be fixed on nanoparticles by direct adsorption or via a spacer molecule or by covalent linkage ( carbodiimide,cynogen bromide& glutaraldehyde reaction) In this way the antibodies are bound to the particles & projecting their antigen specific binding site for target specificity.

Magnetic Nanoparticles:

Magnetic Nanoparticles Nanoparticles are rendered magnetic by incorporating Fe 3 O 4 particles(10-20 nm) simultaneously with the drug during preparation stage. They are then injected through artery supplying to the tumor tissue & guided externally with the help of an external magnet in order to target the nanoparticle carrier & contents.

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Effect of Characteristics of Nanoparticles on Drug Delivery 1.Particle size They determine the in vivo distribution, biological fate, toxicity and the targeting ability of nanoparticle systems. In addition, they can also influence the drug loading, drug release and stability of nanoparticles.

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Generally nanoparticles have relatively higher intracellular uptake compared to bigger size particle. Desai et al found that 100 nm nanoparticles had a 2.5 fold greater uptake than 1 μm microparticles , and 6 fold greater uptake than 10 μm microparticles in a Caco-2 cell line. It was also reported that nanoparticles can across the blood-brain barrier following the opening of tight junctions . It is useful treat diseases like brain tumors .

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Drug release is affected by particle size. smaller particles have larger surface area, therefore, most of the drug associated would be at or near the particle surface, leading to fast drug release. Whereas , larger particles have large cores which allow more drug to be encapsulated. Smaller particles also have greater risk of aggregation of particles during storage and transportation of nanoparticle dispersion.

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2.Surface properties of nanoparticles When nanoparticles are administered intravenously, they are easily recognized by the body immune systems, and are then cleared by phagocytes from the circulation . Apart from the size of nanoparticles, their surface hydrophobicity determines the amount of adsorbed blood components, mainly proteins (opsonins).

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Binding of these opsonins onto the surface of nanoparticles called opsonization acts as a bridge between nanoparticles and phagocytes. once in the blood stream, surface non-modified nanoparticles (conventional nanoparticles) are rapidly opsonized , they cleared by the macrophages of MPS rich organs.

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Hence, to increase the likelihood of the success of nanoparticles, it is necessary to minimize the opsonization and to prolong the circulation of nanoparticles in vivo. This can be achieved by: surface coating of nanoparticles with hydrophilic polymers/surfactants. Surface coating with PEG give hydrophilic enviroment to nanoparticle and thereby shelding them from immune recognition. polyethylene glycol (PEG), polyethylene oxide, polyoxamer , poloxamine and polysorbate 80 ( Tween 80) are used to prevent recognition from immune system.

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Drug loading can be done by two methods: Incorporating at the time of nanoparticles production (incorporation method) 2. Absorbing the drug after formation of nanoparticles (adsorption /absorption technique). 3.DRUG LOADING

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Drug loading very much depend on the drug solubility in matrix material or polymer (solid dissolution or dispersion), the molecular weight, the drug polymer interaction and the presence of endfunctional groups (ester or carboxyl). The macromolecule or protein shows greatest loading efficiency when it is loaded at or near its isoelectric point when it has minimum solubility and maximum adsorption. For small molecules, ionic interaction between the drug and matrix materials can be a very effective way to increase the drug loading.

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5.Drug release: To develop a successful nanoparticulate system , drug release is important consideration factor. In general, drug release rate depends on: ( 1) solubility of Drug (2) desorption of the surface adsorbed drug (3) drug diffusion through the nanoparticle matrix; (4) nanoparticle matrix erosion (5) combination of erosion/diffusion process .

Drug Release from NPs :

Drug Release from NPs

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In nanospheres , the drug release occurs by diffusion or erosion of the matrix under sink conditions. Burst release of drug is mainly seen when drug is bound or adsorbed to the large surface of nanoparticles . If the nanoparticle is coated by polymer, the release is then controlled by diffusion of the drug from the core across the polymeric membrane.

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The membrane coating acts as a barrier to drug release, therefore the solubility and diffusivity of drug in polymer membrane becomes determining factor in drug release. Furthermore release rate can also be affected by ionic interaction between the drug and addition of auxillary ingredients.

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Various methods which can be used to study the in vitro release of the drug are: (1) Side-by-side diffusion cells with artificial or biological memberane . (2) Dialysis bag diffusion technique (3) Reverse dialysis bag technique (4) Agitation followed by ultracentrifugation (5)Ultra-filtration or centrifugal ultra-filtration techniques.

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Usually the release study is carried out by controlled agitation followed by centrifugation. Due to the time-consuming nature and technical difficulties encountered in the separation of nanoparticles from release media, the dialysis technique is generally preferred.

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Applications of Nanoparticulate Delivery Systems 1.Tumor targeting using nanoparticulate delivery systems. The rationale of using nanoparticles for tumor targeting 1) nanoparticles will be able to deliver concentrate dose of drug in the vicinity of the tumor targets via the enhance permeability and retention effect or active targeting by ligands on the surface of Nanoparticles .

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2) nanoparticles will reduce the drug exposure of health tissues by limiting drug distribution to target organ. Verdun et al demonstrated that mice treated with doxorubicine poly( isohexylcyanoacrylate ) nanopsheres show higher concentrations of doxorubicin in the liver, spleen and lungs than in mice treated with free doxorubicin.

2. Delivery of Anticancer Drugs :

2. Delivery of Anticancer Drugs 1)developed by CytImmune company: Targeted chemotherapy that delivers a tumor-killing agent called tumour necrosis factor alpha (TNF) to cancer tumors,attached to a gold nanoparticle along with Thiol-derivatized polyethylene glycol (PEG-THIOL), which hides the TNF bearing nanoparticle from the immune system.

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2) AuroShell™nanoparticles : AuroShell ™ nanoparticles circulate through a patients bloodstream, exiting where the blood vessels are leaking at the site of cancer tumors. Once the nanoparticles accumulate at the tumour the AuroShell ™ nanoparticles are used to concentrate the heat from infrared light to destroy cancer cells with minimal damage to surrounding healthy cells. 3) NBTXR3 nanoparticles : X-ray therapy may be able to destroy cancer tumours using a nanoparticle called NBTXR3 nanoparticles , when activated by x-rays, generate electrons that cause the destruction of cancer tumors to which they have attached themselves. This is intended to be used in place of radiation therapy with much less damage to healthy tissue.

Gold Nanoparticles May Simplify Cancer Detection:

Gold Nanoparticles May Simplify Cancer Detection Gold nanoparticle , is a suspension of sub- micrometre -sized particles of gold in a fluid usually water . The liquid is usually either an intense red colour (for particles less than 100 nm), or a dirty yellowish colour (for larger particles). Preparation of Gold nanoparticle . Generally, gold nanoparticles are produced in a liquid ("liquid chemical methods") by reduction of chloroauric acid (H[AuCl4]), This causes Au3 + ions to be reduced to neutral gold atoms. As more and more of these gold atoms form, the solution becomes supersaturated, and gold gradually starts to precipitate in the form of subnanometer particles.

Cancer detection:

Cancer detection cancer cells have a protein, known as Epidermal Growth Factor Receptor (EGFR) , all over their surface, while healthy cells do not have. Nanoparticles are allow to bind with EGFR antibody. So It is able to get the nanoparticles to attach themselves to the cancer cells. If we add this conjugated nanoparticle solution to healthy cells and cancerous cells and look at the image, we can tell with a simple microscope that the whole cancer cell is shining,”

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“Gold nanoparticles are very good at scattering and absorbing light,” It has scattering property in a living cell to make cancer detection easier. The shapes of the strong absorption spectrum of the gold nanoparticles are also found to distinguish between cancer cells and noncancerous cells. The gold nanoparticles have 600 percent greater affinity for cancer cells than for noncancerous cells.

Anticancer Drugs :

Anticancer Drugs Drug Polymer Doxorubicin Polyisohexylcyanoacrylate Mitoxentrone Polybutylcyanoacrylate Acyclovir Polybutylcyanoacrylate Dexamethasone Polylactideco-glycolide Taxol PVP

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3) Nanoparticles for lymph targeting The major purpose of lymph targeting is to provide an effective anticancer chemotherapy to prevent the metastasis of tumor cells by accumulating the drug in the regional lymph node via subcutaneous administration. It also involved the localization of diagnostic agent to the regional lymph node for the lymphatic vessel visualization before surgery . A wide range of studies are carried out for lymphatic targeting using nanoparticle as carriers: - poly( lactide -co- glycolide ) nanoparticles for the lymphatic delivery of diagnostic agents - polyalkylcynoacrylate nanocapsules bearing markersNanoparticle Diagnostic Imaging Agents for Determining Cancer Status of Lymph Nodes Subcutaneous injection of iodinated nanoparticles for computed tomography imaging Intravenous injection of magnetic nanoparticles for MRI imaging Radiolabeled nanoparticles for sentinel lymph node identification 99m Tc-Colloidal sulfur nanoparticles for sentinel node identification 198 Au-Colloidal gold sa dignostic agent Ultrasound nanobubbles

4)Nanoparticle Formulations in Pulmonary Drug Delivery:

4) Nanoparticle Formulations in Pulmonary Drug Delivery Targeted delivery of nanoparticles to the lungs after intravenous injection ; Nanoparticulate system occur as lung delivery for the treatment of chronic lung infections, lung cancers, tuberculosis and other respiratory pathologies 1) Polysorbate 80-coated nanoparticles which were loaded with doxorubicin (DOX) have been developed to treat lung cancer. Pharmacokinetic of doxorubicin loaded nanoparticles after intravenous injection compared the results with a doxorubicin solution. They showed that the drug concentration in the lungs was higher in animals treated with doxorubicin nanoparticles compared to the doxorubicin solution . The nanoparticles were then incorporated into inhalable carrier particles by a spray freeze-drying technique.

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Targeted delivery of nanoparticles to the lungs through nasal route : For the lung delieevery of drug through nasal route involve two functional parts, the airways ( trachea,bronchi , and bronchioles) and the alveoli (gas exchange areas). The large surface area of the alveoli and the intimate air–blood contact in this region make the alveoli causes more absorption against inhaled substances, such as nanoparticles . The nanoparticulate nature of the drug allows - the rapid diffusion - dissolution of the drug at the site of action. - increased adhesiveness of the drug to mucosal surfaces

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EXAMPLE: The potential work on pulmonary delivery of small molecule taken orally & inhaled are compaired . Itraconazole (ITZ), a poorly water-soluble compound, has displayed low and erratic absorption following oral administration. It has been used for treating invasive fungal infections, in lungs. Two formulations of amorphous nanoparticulate ITZ using polymers and surfactants as excipients were prepared by spray freezing into liquid (SFL) technology,given by different route. The pharmacokinetic profiles of the two formulations were compared with the commercial product Sporanox ® oral solution ( itraconazole /Janssen) after repeated dosing . ITZ-pulmonary achieved significantly greater (more than 10-fold) lung tissue concentrations compared to the Sporanox ® oral solution and ITZ-oral. 2 . Budesonide nanosuspension imply the potential of successful in vivo pulmonary application,found increase concentration in lung for longer time.

5)Nanoparticles for ocular delivery:

5) Nanoparticles for ocular delivery The short elimination half life of aqueous eye drops(due to lachrymal drainage)can be extended from a very short time to long half time. Nanoparticles adhere to the inflammed tissue in a more quantitative manner as compared to the healthy tissue, thus these could be used for targeting of anti-inflammatory durgs to inflamed eyes Pilocarpine and betaxolone loaded polyalkylcyanoacrylate nanoparticles could prolong and maintain the reduced intraoccular pressure in rabits more than 9 hours. Novel approach in that coating of pilocarpine nanoparticles with bioadhesive or viscous polymers. These coated nanoparticles adhere to conjuctival mucin . Thus prolong the residence time of drug loaded particle in the precorneal area. Drug Polymer Amphotericin -B Eudragit RS 100, RL 100 Sparfloxacin PLGA

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( IJPT | Dec-2010 | Vol. 2 | Issue No.4 ) In our present work , levofloxacin encapsulated poly(lactic-co-glycolic acid) nanoparticles were developed and evaluated for various parameters like particle size, zeta potential, in vitro drug release and ex vivo transcorneal permeation. The nanosuspension thus developed was retained for the longer time and drained out from the eye very slowly compared to marketed formulation.

6)Nanoparticles for Brain Delivery:

6) Nanoparticles for Brain Delivery Drug Delivery to the brain using nanoparticles which overcome the problems associated with BBB. It is achieved by 1 .) Solubilisation of endothelial cell membrane lipids by surfactant action of nanoparticles leading to membrane fluidization and enhanced drug permiability 2.) Losening of tight junction between endothelial cells and increased permeability of drug through this channel. 3.) Endocytosis of nanoparticles by the endothelial cells followed by the release of drug intracellularly .

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Coated particles may reach the brain intact and release the drug after endocytosis by the brain blood vessels endothelial cells . The polysorbate 80 used as a coating agent could inhibit the p- glycoprotien efflux pump and thus could increase the brain drug delivery. Researchers showed that hexapeptide dalargin poly ( butylcyanoacrylate ) nanoparticles which were coated with polysorbate 80 cross the BBB . Researchers invastigated the delivery of anticancer drugs using polysorbate 80 coated nanopraticles . High brain concentration of doxorubicin(> 6 µg / gm) were achieved with the nanoparticles coated with polysorbate 80.

7)Nanoparticles for skin targeted delivery:

7) Nanoparticles for skin targeted delivery Nanoparticles can also be delivered to target skin. This system may help in the early diagnosis of a skin disease , which could also be treated with the goal of nanocarriers for drug delivery or targeting of hyperthermia, or magnetofection,as well as in skin wound healing therapies. It was studied that the magnetic properties of these particles might help in directing and localizing these agents in a particular layer of the skin where their action is desired. Targeting one of the layers of the skin (i.e., SC, viable epidermis, dermis) requires overcoming the natural skin barrier and then retaining the delivered agent (i.e., drug, nanoparticle , drug– nanoparticle complex) in one specific skin layer. It is well known that only small (<600 Da ) lipophilic molecules can easily penetrate the skin passively

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SLN have been found to scatter UV light when applied topically, and hence provide a sun-protective effect ,. Nano -scale ZnO & TiO2 particles with broad spectrum of absorption for both UVB & UVA radiation , incorporated in sunscreen lotions for improved protection from sun rays. “UV Pearls” allow absorption of UV light without any contact of the UV filters with the skin by encapsulating active ingredients in highly transparent silica glass matrices or nanospheres .

8.nanoparticles for vaginal delivery:

8.nanoparticles for vaginal delivery Nanotechnology offers a novel approach to formulate microbicides potentially leading to uniform epithelial delivery. Delivery through vaginal mucus may be possible by controlling nanoparticle size and surface characteristics. Drug delivery via vaginal epithelium has suffered from lack of stability due to acidic and enzymatic environments. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.

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pH-sensitive Eudragit nanoparticles for vaginal drug delivery The biocompatible pH-sensitive nanoparticles composed of Eudragit S-100 (ES) were developed to protect loaded compounds sodium fluorescein ( FNa ) or nile red (NR )from being degraded under the rigorous vaginal conditions and achieve their therapeutically effective concentrations in the mucosal epithelium. Study revealed that ES nanoparticles were taken up by vaginal cells, followed by pH-responsive drug release , with no cytotoxic activities & better stability.

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9.Nanoparticles for gene delivery Nanoparticles loaded with plasmid DNA could also serve as an efficient sustained release gene delivery system. Hedley et al.reported that, after their intracellular uptake, nanoparticles could release DNA at a sustained rate resulting in sustained gene expression. This gene delivery strategy could be applied to facilitate bone healing by using PLGA nanoparticles containing therapeutic genes such as bone morphogenic protein

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CONCLUSION The foregoing show that nanoparticulate systems have great potentials, being able to convert poorly soluble, poorly absorbed and labile biologically active substance into promising deliverable drugs. The core of this system can enclose a variety of drugs, enzymes, genes and is characterized by a long circulation time due to the hydrophilic shell which prevents recognition by the reticular-endothelial system. To optimize this drug delivery system, greater understanding of the different mechanisms of biological interactions, and particle engineering, is still required.

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DENDRIMERS

DENDRIMERS:

DENDRIMERS Dendrimers are three dimensional, gloubler , unic architecture, highly branched, mono dispersed, artificial macromolecules, water soluble, controlled surface functionality, versatile carriers. Dendrimer also called arborols , cascade molecule, artificial proteins.

A dendron usually contains a single chemically addressable group called the focal point. The difference between dendrons and dendrimers is illustrated in figure. :

A dendron usually contains a single chemically addressable group called the focal point. The difference between dendrons and dendrimers is illustrated in figure.

Divergent synthesis:

Divergent synthesis Divergent method starts from the centrle core and extends toward the surface by a series of reaction commonly michel reaction. Example: PAMAM , PI dendrimer .

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Fig. Divergent synthesis

Convergent synthesis:

Convergent synthesis In Convergent method, dendrimer synthesised starting from the surface using the convergent approch to produce a dendron unit, that can be as a last step, joined to the multivalent core Ex. Poly( arylether ) dendrimer

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Fig. Convergent synthesis

Hypercore and branched monomers:

Hypercore and branched monomers This method involves the preassembly of oligomeric species which can then be linked together to give dendrimer in fewer steps Ex. Phenyl acetylene dendrimers

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Fig. Hypercore and branched monomers

Types of denerimers:

Types of denerimers Melamine dendrimer PEGylated dendrimer PAMAM dendrimer PI dendrimer Glyco dendrimer Peptide dendrimer Phosphorous dendrimer

Encapsulation of the drugs:

Encapsulation of the drugs

Surface intercation:

Surface intercation

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Applications 1 ) Drug delievery : Targeted and controlled release. Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents,affinity ligands , targeting components, radioligands , imaging agents, or pharmaceutically active compounds. Dendrimers are multivalent systems. In other words, one dendrimer molecule has hundreds of possible sites to couple to an active species. 2) Drug selievery : Solubility enhancement. 3)Gene delievery

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NANOTUBE

Carbon nanotube:

Carbon nanotube Carbon nanotubes are cylindrical hollow macromolecule with variable radii starting at a few nanometer with max. length upto 20cm. 2 types of carbon nanotube Single wall carbon nanotube (SWCNT) Multiplewall carbon nanotube (MWCNT)

SWCNT composed of hexagonal lattice of carbon atoms equivalent to atomic plans of graphite :

SWCNT composed of hexagonal lattice of carbon atoms equivalent to atomic plans of graphite

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MWCNT consist of concentric arragement of simillar graphene sheets, that are spaced by a distance of approx. 3.4A˙ Both single- and multi-walled tubes are capped at their ends by one half of a fullerene-like molecule. However, open-ended tubules have also been reported.

Nanotube application:

Nanotube application Drug delievery peptides, nucleic acids, and various drug molecules can be bonded to the walls and tips of these soluble CNTs. SWNTs translocated easily into the cytoplasm or nucleus of a cell through its cellmembrane , without producing any toxic effects.

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2.Gene Delivery by CNTs CNTs utilized to deliver genes directly into the cell and across the nuclear membrane. DNA molecules not only can attached to the tips and walls of a CNT, it can also be encapsulated inside of the structure. 3. CNT Delivery of Peptides CNTs also use to deliever peptide

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Fullerene

Fullerenes:

Fullerenes Fullerenes are a recently discovered class of carbon allotropes, found in hollow spherical ellipse or tube shapes. The entire class of these closed caged carbon molecules is called fullerenes. The C60 fullerene is commonly referred to as a buckyball .

Fullerene:

Fullerene

Fullerene application:

Fullerene application Fullerenes have potential applications in the treatment of diseases where oxidative stress plays a role in the pathogenesis, such as neurodegenerative diseases. Another possible application of fullerenes is in nuclear medicine, as an alternative to chelating compounds that prevent the direct binding of toxic metal ions to serum components. Water-soluble fullerenes are able to cross the cell membrane , strengthening the proposed use of fullerenes in drug delivery systems and targeting of specific tissues and cell types Metallofullerenes are all-carbon fullerenes that enclose metal ions to deliver radioactive atoms directly to diseased tissues, such as cancer. This has the potential to decrease the side effects of non-targeted radiation treatments,

References:-:

References :- 1) “ Vyas P.S. & Khar K.R.”- Targeted and Controlled Drug Delivery 2) International journal of pharmaceutical science & nanotechnology,vol-3,2010 3) Encyclopedia of Pharmaceutical Technology, Third Edition,vol-2. 4) www.pharmainfo.net 5) www.ijptonline.com 6) International Journal of Pharmaceutics www.elsevier.com /locate/ ijpharm 7) MMG 445 Basic Biotechnology eJournal

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8) Nanotubes , Nanorods , Nanofibers , and Fullerenes for Nanoscale Drug Delivery.... Jessica B. Melanko , Megan E. Pearce, and Aliasger K. Salem , springer . 9) www.scribd.com/doc/63644309/Dendrimers-ppt 10) Minireview : Nanoparticles and the Immune System,endo.endojournals.org /content/151/2/4… 11) Gold Nanoparticles : A new approach for cancer detection, Journal of Chemical and Pharmaceutical Research 12) www.dailymail.co.uk/sciencetech 13) Nanosuspension an approch to enhance solubility of drug- A review article, www.japtar.org

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