Nanotechnology: Nanoparticles

What is Nanotechnology? :

What is Nanotechnology? Nanotechnology is the act of purposefully manipulating matter at the atomic scale, otherwise known as the "nanoscale." In Pharmacy its all about synthesizing, characterizing and screening the particle at Nano range.

Introduction:

Introduction The colloidal carriers based on biodegradable and biocompatible polymeric systems like liposomes, nanoparticles and micro emulsion have largely influenced the controlled and targeted drug delivery concepts Targeted drug delivery implies for selective and effective localization of pharmacologically active moiety at preidentified targets in therapeutic concentration, while restricting its access to non-target normal cellular linings, thus minimizing toxic effects and maximizing therapeutic index

PowerPoint Presentation:

6 Nanoparticle dimensions between 1 nm and 1000 nm Nano derives from the Greek word "nanos", which means dwarf or extremely small . It can be used as a prefix for any unit to mean a billionth of that unit. A nanometer is a billionth of a meter or 10 -9 m. 

Introduction ::

Introduction : Nanoparticles are solid colloidal particles ranging from 1 to 1000 nm in size, they consist of macromolecular materials in which the active ingredients (drug or biologically active material) is dissolved, entrapped, or encapsulated, or adsorbed.

Definition:

Definition Nanocapsules : in which the drug is confined to an aqueous or oily core surrounded by a shell-like wall. Alternatively, the drug can be covalently attached to the surface or into the matrix

PowerPoint Presentation:

Nanoparticles Nanospheres Nanocapsules 9 Matrix type structure in which a drug is dispersed Membrane wall structure with an oil core containing drug 2/28/2013

Nanospheres and Nanocapsules :

Nanospheres and Nanocapsules 

ADVANTAGES::

ADVANTAGES: Nanoparticle drug carriers have higher stabilities Nanoparticles have higher carrier capacity Feasibility of incorporation of both hydrophilic and hydrophobic substances Feasibility of variable routes of administration Nanoparticles are biodegradable, non-toxic and capable of being stored for longer periods. nanoparticles can also be used for controlled delivery of drugs Nanoparticles reduces dosing frequency and have higher bioavailability

Disadvantages of nanoparticles:

Disadvantages of nanoparticles Polymeric nanoparticles posses limited drug-loading capacity On repeated administration, toxic metabolites may be formed during the biotransformation of polymeric carriers. The polymeric nanoparticles are relatively slowly biodegradable which might cause systemic toxicity.

Polymers for nanoparticles:

Polymers for nanoparticles Natural hydrophilic polymers Proteins : - Gelatin, albumin, lectins, legumin. Polysaccharides : - alginate, dextran, chitosan, agarose. Synthetic hydrophobic polymers Pre-polymerized polymers : - Poly (e-caprolactone) (PECL),Poly (Lactic acid)(PLA), Polystyrene Polymerized in process polymers : - Poly (isobutyl cyanoacrylates) (PICA), Poly (butyl cyano acrylates)

Preparation of nanoparticles: :

Preparation of nanoparticles: Nanoparticle Preparation Using Polymerization Based Methods The polymers used in this are poly methyl methacrylate, polyacrylamide, polybutyl cyanoacrylate., etc Two approaches adopted for preparation of nanoparticles using polymerization technique are 1. Methods in which the monomer to be polymerized is emulsified in a non-solvent phase( emulsion polymerization ) 2. Methods in which the monomer is dissolved in a solvent for the resulting polymer ( dispersion polymerization )

Methods used for nanoparticle preparation :

Methods used for nanoparticle preparation Methods used for nanoparticle preparation are Emulsion polymerization Dispersion polymerization Interfacial polymerization Interfacial complexation

1. EMULSION POLYMERIZATION: :

1. EMULSION POLYMERIZATION : The process can be Conventional – continuous phase is aqueous i.e., o/w emulsion Inverse – continuous phase is organic i.e., w/o emulsion. Two mechanisms of emulsion polymerization are A. Micellar nucleation and polymerization B. Homogenous nucleation and polymerization The process can be Conventional – continuous phase is aqueous i.e., o/w emulsion Inverse – continuous phase is organic i.e., w/o emulsion. Two mechanisms of emulsion polymerization are A. Micellar nucleation and polymerization B. Homogenous nucleation and polymerization

A. Micellar nucleation and polymerization :

A. Micellar nucleation and polymerization In this the monomer is emulsified in non-solvent phase using surfactant molecules This leads to the formation of Monomer- swollen micelle ii. Stabilized monomer droplet Monomer swollen micelle have sizes in nanometric range and have much larger surface area compared to monomer droplet Polymerization reaction proceeds through nucleation and propagation stage in presence of chemical or physical initiator .

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Energy provided by initiator creates free monomers in continuous phase, which then collide with surrounding unrelative monomers and initiate polymerization chain reaction. The monomer molecule reaches the micelle by diffusion from the monomer droplets through continuous phase, thus allowing polymerization to progress within micelles. Here monomer droplets act as reservoirs of monomers . CONTINUE……

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20 Monomer droplet Monomer supply Monomer supply for growth Monomer bearing micelle Catalyst Nucleated micelle Stabilized polymeric nanospheres Surfactant Drug Monomer 2/28/2013

B. Homogenous nucleation and polymerization :

B. Homogenous nucleation and polymerization In this method monomer is sufficiently soluble in continuous outer phase. Nucleation and polymerization can directly occur in this phase leading to formation of primary chains called oligomers . In this both micelle and droplets act as monomers reservoir throughout polymer chain length. When oligomers reach certain length, they precipitate and form primary particles and stabilized by surfactant molecules provided by micelle and droplets in which the drug will entrapped to form nanoparticles.

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22 Monomer droplet Stabilized polymeric nanospheres Surfactant Drug Monomer Primary particle Oligomer Activated Monomer 2/28/2013

. DISPERSION POLYMERIZATION :

. DISPERSION POLYMERIZATION In emulsion polymerization, monomer is emulsified in non-solvent phase by means of surfactants. In case of dispersion polymerization, monomer is dissolved on aqueous medium . The nucleation is directly induced in aqueous monomer solution and presence of stabilizer or surfactant is not necessary for formulation of stable nanospheres .

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This method is used to prepare biodegradable polyacrylamide and polymethyl -methacrylate (PMMA) nanoparticles. Being very slowly biodegradable and biocompatible, PMMA nanoparticles have been considered as optimal polymeric systems for vaccination purpose. CONTINUE………

3. INTERFACIAL POLYMERIZATION :

3. INTERFACIAL POLYMERIZATION In this method, a polymer that becomes core of nano - particle and drug molecule to be loaded is dissolved in volatile solvent. Solution is then placed in to a non-solvent for both polymer and core phase Polymer phase is separated at o/w interphase. Resultant mixture instantly turns to milky owing to formulation of nanocapsules .

Preparation of nanoparticles by interfacial polymerization ::

Preparation of nanoparticles by interfacial polymerization : 2/28/2013 26 Core phase + Polymer phase - - - - - - - - - - - - - - - - - - - - - - Non-solvent, which precipitate out polymer from either of phases drug Core dispersed in polymer phase (O/W emulsion) Nanocapsules ( 30-300 nm )

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Size of nanocapsules is 30-300 nm Drug loading depends on drug solubility in core phase Surfactant can be added to stabilize dispersion. Example: encapsulation of proteins, enzymes, antibiotics.etc ., CONTINUE………

PHARMACEUTICAL ASPECTS OF NANOPARTICLES: :

PHARMACEUTICAL ASPECTS OF NANOPARTICLES: From pharmaceutical point of view nanoparticles prepared should be free from toxic impurities, should be easy to store and administer and should be sterile if parenterally used. Three parameters performed before releasing them for clinical trials are Purification Freeze drying Sterilization

Purification of nanoparticles :

Purification of nanoparticles Commonly used methods are Gel filtration Dialysis Ultra-centrifugation Cross flow filtration A new cross – flow filtration method is used for purification of nanoparticles in industrial point of view. In this method nanoparticle suspension is filtered through membranes, with the direction of fluid being tangential to the surface of the membrane. As a result clogging of filters is avoided.

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CONTINUE …….. The suspension is subjected to several filtration cycles, while the filtrate is discarded containing soluble impurities. This leads to the concentration of suspension. After this, water is added to maintain the volume of circulation constant. This is a simple and can be done at a faster rate. Purification of large amounts of nanoparticles can be done without alteration in the sizes.

PowerPoint Presentation:

31 Nanopraticles Impurites Membrane Cross-flow filtration technique: 2/28/2013

Purification of nanoparticles ::

Purification of nanoparticles : 32 Gel filtration : Remark : High molecular weight substances and impurities are difficult to remove Schematic principle Nanoparticle Impurity 2/28/2013

PowerPoint Presentation:

34 Dialysis : Remark : High molecular weight impurities are difficult to remove Time consuming process

Freeze drying of nanoparticles: :

Freeze drying of nanoparticles: This involves freezing of the nanoparticles and subsequent sublimation of its water content under reduced pressure to get a free flowing powdered material. Advantages: Prevention from degradation and solubilization of polymer . Prevention from drug leakage, drug desorption . Easy to handle and store and helps in long term preservation. Readily dispersed in water without modifications in their physicochemical properties. Prevention from drug leakage Disadvantage: Nanocapsules having an oily core surrounded by polymer wall tend to agglomerate. This can be overcome by dessicating in lyoprotective agent ex: glucose, sucrose and trehalose .

Sterilization of nanoparticles: :

Sterilization of nanoparticles: Nanoparticles intended for parenteral use should be sterilized to be pyrogen free before using on animals or humans. Sterilization is achieved by using aseptic technique throughout preparation, processing and formulation or by autoclaving or using γ- irradiation. Autoclaving and γ- irradiation show impact on the physicochemical properties of the particles with modification of particle size stability and drug release characteristics. Sterilization is a critical step and should be systematically investigated during formulation development stage.

Characterization of nanoparticles: :

Characterization of nanoparticles: Size and morphology Specific surface Surface charge and electrophoretic mobility Surface hydrophobicity Density

Size and morphology: :

Size and morphology: Methods used are Photon correlation spectroscopy(PCS) Laser defractometry Transmission electron microscopy(TEM) Scanning electron microscopy(SEM) Atomic force microscopy Mercury porositometry Freeze fracture

PowerPoint Presentation:

PCS and EM are widely used to determine the particle size. Better results are obtained using freeze fracture and photon correlation spectroscopy. Freeze fracture microscopy : In this poly (methyl methacrylate ) is used. Only few particles are analyzed. This method also gives morphology of inner structure of particles.

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Scanning electron microscopy : This measures individual particles. It is a less time taking process. Atomic force microcopy images can be obtained in an aqueous medium so this is an effective technique to investigate nanoparticle behavior in biological environment. CONTINUE….

PowerPoint Presentation:

Field Emission SEM Transmission Electron Microscopy Atomic Force Microscopy Scanning Electron Microscopy

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2. Specific surface : the specific surface area of freeze dried nanoparticles is measured using sorptometer . The residual surfactant reduces the specific surface area. 3. Surface charge and electrophoretic mobility: the nature and intensity of the surface charge of nanoparticles is very important as it determines their interaction with the biological environment. Surface charge measured using laser Doppler anemometry or velocimetry . Surface charge is also measured using electrophoretic mobility in phosphate saline buffer (7.4) and human serum.

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4. Surface hydrophobicity : the hydrophobicity determines the fate of nanoparticles and their contents. The measurement of angle of contact suggests about the hydrophilicity and hydrophobicity of the nanoparticles. Recently X-ray photoelectron spectroscopy is used to identify chemical groups on surface of nanoparticles. 5. Density: the density of nanoparticles is determined with helium or air using a gas Pycnometer .

In vitro release profile of Drugs:

In vitro release profile of Drugs Using standard dialysis or diffusion cell. Double chamber diffusion cell on shaker stand. The donor chamber is filled with nanoparticulate suspension. Receptor chamber with plain buffer. The receptor chamber is assayed at different time intervals using standard procedure.

In vivo fate and biodistribution of Nanoparticles:

In vivo fate and biodistribution of Nanoparticles RES nanoparticles Opsonin adsorption Phagocytosis recognition opsonins adsorb on to the surface of colloidal carriers and render particles recognizable to the “RES” thus they mediate their endocytosis by fixed macrophages of “RES” and circulating monocytes

Surface engineering of Nanoparticles:

Surface engineering of Nanoparticles Nanoparticles are surface engineered for various purposes. They are classified as Magnetically guided nanoparticles Bioadhesive guided nanoparticles Antibody guided nanoparticles

Magnetically guided Nanoparticle:

Magnetically guided Nanoparticle Magnets can be used to deliver forces and energy, and can be sensed remotely Magnetic nanoparticles can be used both in vivo and in vitro, to great effect Endomagnetics has real promise for oncology, hematology, drug delivery, stem cell therapies

PowerPoint Presentation:

Nanoparticles are rendered magnetic by incorporating iron particles (10-20nm) simultaneously with the drug during the preparation stage; the magnetic nanoparticles are then injected through the artery, supplying the tumour tissue and guided externally

Nanoparticles coated with Antibodies:

Nanoparticles coated with Antibodies Target specific antibodies to the nanoparticle surface may facilitate their delivery to specific sites. Monoclonal antibodies can be fixed on nanoparticles by direct adsorption or via a spacer molecule or by covalent linkage, Tumour specific monoclonal antibodies conjugated to super-paramagnetic monocrystalline iron oxide nanoparticles (MION) could be used to yield specific diagnoses with the use of MR imaging

Nanoparticles for Bioadhesion:

Nanoparticles for Bioadhesion Here the drug adhere to the mucosal surface and provide better opportunity for drug absorption in a controlled manner, the fate of nanoparticles follows three different pathways: Bioadhesion, 2) translocation through the mucosa and 3) transit and direct fecal elimination

APPLICATIONS:

APPLICATIONS Application Purpose Cancer therapy Targeting and enhanced uptake of antitumor agents Intracellular targeting Target intracellular infections Prolonged systemic circulation To prolong the drug effect Vaccine adjuvant Enhances immune response Peroral absorption Enhanced bioavailability Ocular delivery Improved retention of drug and reduced washout Other applications Crosses blood-brain barrier Improved absorption Oral delivery of peptides.

Parenteral Administration :

Parenteral Administration Delivery of anticancer drugs Nanoparticles have been found to accumulate in tumors after IV administration Reduction in toxicity of anticancer drugs as drugs are concentrated mainly in liver and spleen Useful in treatment of hepatic metastases

Occular delivery ::

Occular delivery : Material : poly ( alkylcyanoacrylate ) nanoparticles with steroids, anti-inflammatory agents, anti bacterial agents for glaucoma Purpose : improved retention of drug / reduced wash out. 74

PowerPoint Presentation:

Viral infections Nanoparticles represent an interesting for selective transport of antiviral agents displaying poor selectivity and/or short plasma half-life. For ex: nanoparticles loaded with protease inhibitor sesquinvir was shown to be effective in HIV infected human macrophage cultures

Vaccine adjuvant:

Vaccine adjuvant Material : poly ( methylmethacrylate ) nanoparticles with vaccines ( oral and intramuscular immunization ) Purpose : enhances immune response, alternate acceptable adjuvant 56 2/28/2013

Prolonged systemic circulation ::

Prolonged systemic circulation : Material : Polyesters with adsorbed polyethylene glycols or pluronics or derivatized polyesters Purpose : Prolong systemic drug effect, avoid uptake by the reticuloendothelial system 57 2/28/2013

Various forms of nanoparticle systems:

Various forms of nanoparticle systems

COMMERCIAL PRODUCTS:

COMMERCIAL PRODUCTS

Conclusion:

Conclusion Polymeric particulate carrier systems are expected to target the inflamed tissue This new delivery system allows the desired drug to accumulate In the inflamed tissue with high efficiency . The drug is concentrated at its site of action, which reduces possible adverse effects and enhances the effect of the administered dose The sustained drug release allows pharmacological effects to be extended due to the prolonged presence time of the carrier system at the targeted inflamed area.

References:

References Vyas and Khar.Targeted and Controlled Drug Delivery Novel Carrier Systems.First edition,CBS Publishers, New Delhi. healthcare by sensing, moving and heating magnetic nanoparticles in the human body. Quentin Pankhurst, Deputy Director: London Centre for Nanotechnology http://jpet.aspetjournals.org

REFERENCES :

REFERENCES Gilbert s Banker. Modern Pharmaceutics. 4 th edition. N.K. Jain. Controlled and Novel drug delivery. 1 st edition. Y.W. Chien . Novel Drug Delivery Systems. Binghe Wany , Teruna Siahaan , Richard A Soltao . Drug Delivery Principles and Applications. Krishna RSM, Shivakumar HG, Gowda DV and Benerjee S. Nanoparticles: A Novel colloidal drug delivery system. Ind J Pharm Ed Res.2006; 40(1):15-9.