introduction of nanotechnolog grewal

8/7/2019 Introduction of nanotechnolog grewal

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NANOPARTICL

ES

Submitted by: Lakhwinder Singh Submitted to:

Ms. Lotika Bajaj

B-Pharmacy7th semester

Assistant Professor

(8150152018) M. pharm

(pharmaceutics)

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P.C.T.E. Institute of Pharmacy (Jhandey)

Ludhiana.

ACKNOWLEDGEMENT

I owe heartiest thanks to many people who helped and supported me during the

writing of this project. My deepest thanks to Ms. Lotika Bajaj my Guide of the

project for guiding and paying attention and care. She has done a lot to go

through the project and make necessary corrections as and when needed. I

express my thanks to our dean, Dr. B.S. Sekhon, for extending his support. I

would also thank my Institution and my faculty members without whom this

project would have been a distant reality. I also extend my heartfelt thanks to

my family, friends and well wishers.

Lakhwinder Singh Ms. Lotika Bajaj

(8150152018) Assistant Professor

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B-pharma (7th semester) M-Pharma (pharmaceutics)

INDEX

Sr. No. CONTENT Pg. No.

1. NANOTECHNOLOGY 4

2.CURRENT STATUS

5

3.NANOPARTICLES

6

4. HISTORY OF NANOPARTICLES 6-7

5.ADVANTAGES OF NANOPARTICLES

7

6.LIMITATIONS OF NANOPARTICLES

8

7. TYPES OF NANOPARTICLES 8

8.

MATERIALS USED FOR PREPARATION OF

NANOPARTICLES 9-11

9.METHODS OF PREPARATION OF NANOPARTICLES

11-13

10.CHACTERIZATION OF NANOPARTICLES

13-14

11.ZETA POTENTIAL 15

12.BLOOD BRAIN BARRIER

16

13.NANOPARTICLES CROSSES BLOOD BRAIN BARRIER

17

14. APPLICATIONS OF NANOPARTICLES 17-18

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15.DRUG FORMULATIONS OF NANOPARTICLES

18

16. REFERENCES 19-21

NANOTECHNOLOGY

The U.S. National Nanotechnology Initiative defines NT as the understanding and control of

matter at dimensions of roughly 1 to 100 nanometres. Nanotechnology involves imaging,

measuring, modelling, and manipulating matter at this length scale.

The Europeans define it more simply as the technology dealing with applications and

products with engineered structures smaller than 100 nanometres. For comparison, a single

human hair is approximately 80,000 nanometres wide, and a red blood cell is approximately

7,000 nanometres wide [1].

Nanotechnology (NT) is the production and use of materials with purposely engineered

features close to the atomic or molecular scale. NT deals with putting things together atom

by- atom and with structures so small that they are invisible to the naked eye. It provides the

ability to create materials, devices and systems with fundamentally new functions and

properties. The promise of NT is enormous. It has implications for almost every type of

manufacturing process and product. Potential NT applications in the next few decades could

produce huge increases in computer speed and storage capacity, therapies for several

different types of cancer, much more efficient lighting and battery storage, a major reduction

in the cost of desalinating water, clothes that never stain and glass that never needs cleaning.

While the benefits are almost limitless, they will be realized only if the potential adverse

effects of NT are examined and managed. NT is new, but the effort to understand and manage

its effects will be long-term. As the world community tries to reduce the adverse effects of

the technology, our understanding of these effects will steadily increase. At the same time, as

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the technology advances and commercial applications multiply, new challenges and problems

will arise. NT covers a wide variety of processes and materials [2].

Nanotechnology is the study of manipulation or self assembly of individual atoms, molecules

or molecular clusters to create materials and devices with vastly different properties. It also

involves the design, production and application of structures, devices and systems by

controlling the shape and size at the nanometre scale. The first mention of some of the

distinguishing concepts in nanotechnology was given by physicist Richard Feynman on 1959.

He noted the changing magnitude of various physical phenomena: gravity would become less

important, surface tension, etc. This basic idea appears feasible and exponential assembly

enhances it with parallelism to produce a useful quantity of end products [3].

CURRENT STATUS

The present age is characterized by accelerating technological development, and NT is

developing extraordinarily rapidly. The field was not identified until 1959, when Nobel

physicist Richard Feynman called attention to the opportunities in the realm of the

staggeringly small. In 2001, Science magazine named NT the breakthrough of the year.

Currently, there are several hundred different commercial applications of NT. The National

Science Foundation predicts that nano-related goods and services could be a $1 trillion

market by 2015.

The rapid development of NT also means that government managers always will be operating

with outdated information, and that data about NT effects will lag behind commercial

applications. Priorities for research and for regulation will need to shift constantly. We have

moved into a world which is, as David Rejeski states, dominated by rapid improvements in

products, processes, and organizations, all moving at rates that exceed the ability of our

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traditional governing institutions to adapt or shape outcomes. He warns, If you think that

any existing regulatory framework can keep pace with this rate of change, think again [4].

NANOPARTICLES

Nanoparticles are defined as particulate dispersions or solid particles with a size in the range

of 10-1000nm. The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle

matrix [5]. Depending upon the method of preparation, nanoparticles, nanospheres or

nanocapsules can be obtained. Nanocapsules are systems in which the drug is confined to a

cavity surrounded by a unique polymer membrane, while nanospheres are matrix systems in

which the drug is physically and uniformly dispersed [6]. In recent years, biodegradable

polymeric nanoparticles, particularly those coated with hydrophilic polymer such as

polyethylene glycol (PEG) known as long-circulating particles, have been used as potential

drug delivery devices because of their ability to circulate for a prolonged period time target a

particular organ, as carriers of DNA in gene therapy, and their ability to deliver proteins,

peptides and genes [7].

Other names of nanoparticles

Ultra fine particles, clusters, nanocrystals, quantum dots of colloids, aerosols, Hydrosols,

organosols [5].

HISTORY OF NANOPARTICLES

1960s~1970s, preparation of nanoparticles by gas evaporation-condensation method

Quantum confinement (Kubo) effect

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1981-1986 Japan, Ultra-Fine Particle Project under the auspices of the Exploratory

Research for Advanced Technology program (ERATO)

- Preparation, characterization, properties, applications

1981 G.K. Binnig H. Roher (IBM Zurich): invented scanning tunnelling microscope

(1985 Nobel prize)

- allows atomic-scale three-dimensional profiles of surfaces to be obtained

1985 R.Smalley, R.Curl and H.Kroto discovered C60 (Nobel Prize in 1996).

- Officially known as buckminsterfullerene (exactly like a football).

1987 B.J. van Wees and H. van Houten (Netherlands)/D. Wharam and M.Pepper

(Cambridge U.), observed quantization of conductance (step in I-V curve)

- Coulomb blockade, single electron transistor

1991, Iijima made carbon nanotubes (multi-walled), Single-walled(1993)

1999, Self assembly of molecules on metal nanoparticles

1996 NSF et al., assessed current worldwide status of nanoscience and

nanotechnology

2004,Silica nanoshells coated with gold(Rice University and the University of Texas )

- killed cancerous tumours, when exposed to an external source of near infrared light [8].

ADVANTAGES OF NANOPARTICLES

1. Particle size and surface characteristics of nanoparticles can be easily manipulated to

achieve both passive and active drug targeting after parenteral administration.

2. They control and sustain release of the drug during the transportation and at the site of

localization, altering organ distribution of the drug and subsequent clearance of the drug

so as to achieve increase in drug therapeutic efficacy and reduction in side effects.

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3. Controlled release and particle degradation characteristics can be readily modulated by the

choice of matrix constituents. 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 targeting ligands 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. [9].

LIMITATIONS OF NANOPARTICLES

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 limited drug loading and burst

release. These practical problems have to be overcome before nanoparticles can be used

clinically or made commercially available [9].

TYPES OF NANOPARTICLES

Types of Nanoparticles

In Medicine:

Liposome, Dendrimer, Iron oxide nanoparticles, Polymer-drug conjugate,

Polymeric nanoparticle.

a. Other Relevant or Related Items:

Ceramic engineering, Coating, Colloid, Colloid-facilitated transport, Colloidal

crystal, Colloidal gold, Eigencolloid, Gallium selenide, Indium selenide, Liposome,

Magnetic immunoassay, Magnetic nanoparticles, Micromeritics, Nano-

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biotechnology, Nanocrystalline silicon, Nanogeoscience, Nanomaterials,

Nanomedicine,Nanoparticle Tracking Analysis,Nanotechnology, Photonic crystal,

Plasmon, Quantum dot, Silicon, Silver Nano, Sol-gel, Transparent materials[10].

MATERIALS USED FOR PREPARATION

Nanoparticles can be prepared from a variety of materials such as proteins,

polysaccharides and synthetic polymers [11].

1) Protein Based Nanoparticles

Proteins are a class of natural molecules that have applications in both biological as well

as material fields [12].

a. Gelatin

Gelatin is one of the protein materials that can be used for the production of

nanoparticles. It is obtained by controlled hydrolysis of the fibrous, insoluble protein,

collagen, which is widely found as the major component of skin, bones and connective

tissue. Two different gelatins, A and B with different isoelectric points (IEP), are formed

following either acid or base hydrolysis, Characteristic features of gelatin are the high

content of the amino acids glycine, proline and alanine [12].

b. Albumin

Albumin is an attractive macromolecular carrier and widely used to prepare nanospheres

and nanocapsules, due to its availability in pure form and its biodegradability, nontoxicity

and nonimmmunogenicity. Both Bovine Serum Albumin or BSA and Human Serum

Albumin or HSA have been used. On the other hand, albumin nanoparticles are

biodegradable, easy to prepare in defined sizes, and carry reactive groups on their

surfaces that can be used for ligand binding and/or other surface modifications and also

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albumin nanoparticles offer the advantage that ligands can easily be attached by covalent

linkage [12].

c. Gliadin and legumin

For biological applications, vegetal particles have been derived from proteins such as

gliadin extracted fromgluten of wheat and vicillin or legumin extracted from pea seeds.

Gliadin appears to be a suitable polymer for the preparation of mucoadhesive

nanoparticles capable of adhering to the mucus layer. Gliadin nanoparticles (GNP) have

shown a great tropism for the upper gastrointestinal regions. This shows the high capacity

to interaction with the mucosa. In fact, this protein is rich in neutral and lipophilic

residues.

Legumin is also one of the main storage proteins in the pea seeds (Pisum sativum L.)

Legumin is an albuminous substance that resembles casein and functions as the source of

sulfur-containing amino acids in seed meals [12].

2) Polysaccharides Nanoparticles

Ganoderma lucidum (Lentinus edodes) has been reported to be a medicinal

mushroom for the treatment or prevention of many diseases, including AIDS, hepatitis B

and cancer. G. lucidum polysaccharide, a form of bioactive b-glucan, which is extracted

from G. lucidum, is one of efficacious ingredient groups of G. lucidum [13].

3) Synthetic polymer

Class examples

a. Biodegradable polymer

1. Polyester PLA,PGA,PHB

2. Polyanhydrides PCL,PMA,Polydioxanones

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3. Polyamide polysebacic acid, PTA

4. Phosphorous based polyphosphazenes, polyphosphonate,

b. Nonbiodegradable polymer

1. Cellulose derivatives CMC,EC,CA,CAP

2. Silicons PDS, colloidal silica

3. Acrylic polymers PMA,PMMA,PHEMA

4. Others PVP,EVA

The selection of matrix materials is dependent on many factors including:

(a) Size of nanoparticles required

(b) Inherent properties of the drug, e.g., aqueous solubility and stability

(c) Surface characteristics such as charge and permeability

(d) Degree of biodegradability, biocompatibility and toxicity

(e) Drug release profile desired

(f) Antigenicity of the final product [11].

METHODS OF PREPARATION

Nanoparticles have been prepared most frequency by three methods:

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 [14,15,16].

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 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. Particle size was found to be

influenced by the type and concentrations of stabilizer, homogenizer speed and polymer

concentration [17]. In order to produce small particle size, often a high-speed

homogenization or ultrasonication may be employed [18].

b. Spontaneous emulsification or solvent diffusion method:

This is a modified version of solvent evaporation method. In this method, the water

miscible solvent along with a small amount of the water immiscible organic solvent is

used as an oil phase. Due to the spontaneous diffusion of solvents an interfacial

turbulence is created between the two phases leading to the formation of small particles.

As the concentration of water miscible solvent increases, a decrease in the size of particle

can be achieved. Both solvent evaporation and solvent diffusion methods can be used for

hydrophobic or hydrophilic drugs. In the case of hydrophilic drug, a multiple w/o/w

emulsion needs to be formed with the drug dissolved in the internal aqueous phase [19].

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1. 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. 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 [20].

2. Coacervation or ionic gelation method

Much research has been focused on the preparation of nanoparticles using biodegradable

hydrophilic polymers such as chitosan, gelatine 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, a di-block co-polymer ethylene oxide or propylene oxide (PEO-PPO)

and the other is a polyanion sodium tripolyphosphate [21]. In this method, positively

charged amino group of chitosan interacts with negative charged 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, whereas, ionic gelation involves the

material undergoing transition from liquid to gel due to ionic interaction conditions at

room temperature [22].

METHODS OF CHARACTERIZATION OF NANOPARTICLES

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1) Particle size

a) A Photon correlation spectroscopy technique based on dynamic laser light scattering

due to Brownian motion of particles in solution/suspension, suitable for measurement of

particles in the range of 3 nm to 3 mm. The Photon correlation spectroscopy

(hydrodynamic diameters) diameters are based on the amount of light scattered from the

nanoparticles.

b) Transmission electron microscopy uses electron transmitted through the specimen to

determine the overall shape & morphology of the particle.

c) Scanning electron microscopy uses electron transmitted from the specimen to

determine the overall shape & morphology of the particle.

d) Scanned probe microscopes

e) Polarization intensity differertial scattering (PIDS) measures the particle size as 40.

f) Field flow fractionation based on the elution of the small particles when placed on a

parabolic flow profile.All the eluted fractions are analyzed by multi angle light scattering

(MALS) where a photo meter records the scattering signal of the particles & calculates X-

ray diffraction.

2) Molecular weight

a) Gel chromatograpy

b) Static secondary ion mass spectrometer

c) Atomic force microscopy

3) Surface element analysis

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a) X-ray photoelectron spectroscopy

b) Electrophoresis

c) Laser Doppler anaemomometry

d) Amplitude-weighted phase structure

e) X ray diffraction

4) Density

a) Helium compression pychnometry

b) Contact angle mearurement

c) Hydrophobic Interaction chromatography.

ZETA POTENTIAL

The zeta potential of a particle is the overall charge that the particle acquires in a

particular medium and can be measured on a Zetasizer Nano instrument. The magnitude

of the measured zeta potential is an indication of the repulsive force that is present and

can be used to predict the long-term stability of the product. If all the particles in

suspension have a large negative or positive zeta potential then they will tend to repel

each other and there is no tendency for the particles to come together. However, if the

particles have low zeta potential values then there is no force to prevent the particles

coming together and flocculating. The effect of the pH, concentration of an additive or the

ionic strength of the medium on the zeta potential and rheological properties can give

information in formulating the product to give maximum stability. The effect of these

parameters on the stability of particle dispersion can be automatically determined by

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using an autotitrator. The Malvern Multi Purpose Titrator(MPT-2) is a device capable of

performing such titrations in conjunction with the Zetasizer Nano series. In addition, any

one of the Malvern rheometer range can be used for providing complementary

information [25].

Drug loading

Ideally, a successful nanoparticulate system should have a high drug-loading capacity

thereby reduce the quantity of matrix materials for administration. Drug loading can be

done by two methods:

Incorporating at the time of nanoparticles production (incorporation method)

Adsorbing the drug after formation of nanoparticles by incubating the carrier with a

concentrated drug solution.

Drug loading depend on the solid-state drug solubility in matrix material or polymer

(solid dissolution or dispersion), which is related to the polymer composition, the

molecular weight, the drug polymer interaction [26].

Drug release

To develop a successful nanoparticulate system, both drug release and polymer

biodegradation are important consideration factors.

In general, drug release rate depends on:

1) Solubility of drug

2) Desorption of the surface bound/ adsorbed drug

3) Drug diffusion through the nanoparticle matrix

4)Nanoparticle matrix erosion/degradation

5) Combination of erosion/diffusion process

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Thus solubility, diffusion and biodegradation of the matrix materials govern the release

process [27].

BLOOD BRAIN BARRIER

The blood-brain barrier (BBB) is a separation of circulatingbloodandcerebrospinal

fluid (CSF) in the central nervous system (CNS). It occurs along all capillaries and

consists of tight junctions around the capillaries that do not exist in normal

circulation. Endothelial cells restrict the diffusion of microscopic objects (e.g.bacteria)

and large orhydrophilic molecules into the CSF, while allowing the diffusion of

small hydrophobic molecules (O2, hormones, CO2). Cells of the barrier actively

transport metabolic products such as glucose across the barrier with specific proteins [28].

NANOPARTICLES CROSSES THE BLOOD BRAIN BARRIER

Nanotechnology may also help in the transfer of drugs across the BBB. Recently,

researchers have been trying to buildliposomes loaded with nanoparticles to gain access

through the BBB. More research is needed to determine which strategies will be most

effective and how they can be improved for patients withbrain tumors. The potential for

using BBB opening to target specific agents to brain tumors has just begun to be

explored. For example, radiolabeled polyethylene glycol coated hexadecylcyanoacrylate

nanospheres targeted and accumulated in a rat gliosarcoma. Delivering drugs across the

blood-brain barrier is one of the most promising applications of nanotechnology in

clinical neuroscience. Nanoparticles could potentially carry out multiple tasks in a

predefined sequence, which is very important in the delivery of drugs across the blood-

brain barrier.It should be noted that vascular endothelial cells and associatedpericytes are

often abnormal in tumors and that the blood-brain barrier may not always be intact in

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brain tumors. Also, thebasement membraneis sometimes incomplete. Other factors, such

as astrocytes, may contribute to the resistance of brain tumors to therapy [29,30,31].

APPLICATIONS OF NANOPARTICLES

While nanoparticles are important in a diverse set of fields, they can generally be

classified as one of two types: engineered or nonengineered.

Engineered nanoparticles are intentionally designed and created with physical properties

tailored to meet the needs of specific applications.

They can be end products in and of themselves, as in the case of quantum dots or

pharmaceutical drugs, or they can be components later incorporated into separate end

products, such as carbon black in rubber products, Either way, the particles physical

properties are extremely important to their performance and the performance of any

product into which they are ultimately incorporated. Nonengineered nanoparticles, on the

other hand, unintentionally generated or naturally produced, such as atmospheric

nanoparticles created during combustion. With non-engineered nanoparticles, physical

properties also play an important role as they determine whether or not ill effects will

occur as a result of the presence of these particles [32].

DRUGS FORMULATIONS

[33]

Technique Delivery Vehicle Drug Nanoparticle Size

Spray Drying Nanoparticle-

Containing

Microparticles

Prenlukast

Hemihydrate

100-430 nm

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Emulsion/Spray

Drying

Nanoparticle-

Containing

Microparticles

6-Coumarin 259 nm

Nanoparticle

Flocculation

Nanoparticle

Clusters

N/A 300-500 nm

Ionotropic

Ge;ation/Spray

Drying

Nanoparticle-

Containing

Microparticles

Insulin 300-500 nm

Supercritical

Fluid Extraction

Nebulized

Droplets

Indomethacin

or Ketoprofen

10-30 nm

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