Nanoparticles

Nanoparticles

Targeted drug delivery systems

Session objectives

By the end of this session, students will be able to:

•       Explain the importance of nanoparticles

•       Explain the advantages and limitations of nanoparticles

•       Describe different methods used for preparation of nanoparticles

•       Describe the applications of nanoparticles

•       Explain the methods used for the characterization of nanoparticles

Definitions

•       Nanosuspensions :

–      Are colloidal dispersions of nano sized drug particle that are produced by suitable method and stabilized by suitable stabilizer

•       Nanoparticles :

–      They are solid colloidal particles sized from 1-1000  nm

•       Nanospheres :

–      Polymer matrices in which drug is dissolved or dispersed

•       Nanocapsules :

–      Consists of polymer wall entrapping an oily core in which the drug is dissolved

Introduction

•       Nanoparticles are subnanosized colloidal drug delivery  systems ranging in size from 10-1000 nm in diameter

•       They are composed of synthetic or semi-synthetic polymers carrying drugs or proteinaceous substances, i.e.  antigen(s)

•       Drugs are entrapped in the polymer matrix particulates or  solid solutions or may be bound to particle surface by  physical adsorption or in chemical form

Types of nanoparticles

•       Monolithic type

•       Capsule type

Importance of nanoparticles

•      Selective and Effective Localization of pharmacologically  active moiety at preselected target(s) in therapeutic  concentration

•      Restricted access to non-target normal tissues and cells.

•      Nanoparticles are mainly taken by the RES after the  administration and are useful to carry drugs to the liver and  to cells that are phagocytically active

•      By modifying the surface characteristics of the  nanoparticles it is possible to enhance the delivery of drugs  to spleen relative to the liver

•      Distribution of the nanoparticles in the body may be  achieved possibly by : Coating of nanoparticles with  certain Serum components, Attachment of antibodies  or sulfoxide groups and the use of Magnetic  nanoparticles

Advantages

•      Reduction in the frequency of the dosages taken by  the patient

•      More uniform effect of the drug

•      Reduction of drug Side Effects

•      Reduced fluctuation in circulating drug levels

•      Avoids hepatic first pass metabolism

Disadvantages

•      High cost

•      Productivity more difficult

•      Reduced ability to adjust the dose

•      Highly sophisticated technology

•      Requires skills to manufacture

•      Difficult to maintain stability of dosage form

Ideal characteristics

•      It should be biochemical inert, non-toxic and non-immunogenic

•      It should be stable both physically and chemically in In vivo & in vitro conditions

•      Restrict drug distribution to non-target cells or tissues or organs & should have uniform  distribution

•      Controllable & Predicate rate of drug release

•      Drug release should not effect drug action

•      Specific Therapeutic amount  of drug release must be possessed

•      Carriers used must be biodegradable or readily eliminated from the body without any problem

•      The  preparation  of the delivery system should be easy or reasonable

•      Simple, reproducible & cost effective

Polymers used

•      Polymethyl methacrylate copolymers,

•      Polymethyl cyanoacrylate,

•      Polybutyl cyanoacrylate & Polyisobutyl cyanoacrylate,

•      Polyhexyl cyanoacrylate & polyisohexyl cyanoacrylate,

•      Poly(Nα,NÎ-L-lysinedylterephthalamide

•      Polyisobutyl cyanoacrylate

•      Poly-D,L-lactide

•      Serum albumin

•      Gelatin

•      Polyacryl dextran

•      Polyacryl starch

•      Albumin

•      Polylactic acid-poly glycolic acid copolymer

•      Poly(b-hydroxy butyrate)

•      Ethyl cellulose

•      Eudragit RL,RS

Methods of preparation

A. Cross Linking Methods

1)      By Cross-linking of Amphiphilic Macromolecules

2)      By Crosslinking in W/O Emulsion

3)      By Emulsion chemical dehydration

4)      By Phase Separation

5)      By pH lnduced Aggregation 

B. Polymerization Methods

1)      Emulsion polymerization

2)      Dispersion polymerization

1) By Cross-linking of amphiphilic macromolecules

•       Nanoparticles  can be  prepared from Amphiphilic macromolecules, proteins and polysaccharides (which have  affinity for aqueous and lipid solvents)

•       The method involves Aggregation of Amphiphiles followed  by stabilization either by heat denaturation or chemical  cross-linking

2) By Cross linking in W/O emulsion

•       Emulsification of bovine serum albumin (BSA) or human  serum albumin (HSA) or protein aqueous solution in oil  using high-pressure homogenization or high frequency  sonication

•      Emulsification using high-  pressure homogenization or high frequency sonication

W/O emulsion

•      Dilution with preheated oil (100^oC) (Heat cross-linking) or Addition of crosslinking agent (Chemical cross-linking)

•      Centrifugation and isolation of  nanoparticles

3) Emulsion chemical dehydration

•      Stabilization can also be achieved by emulsion chemical  dehydration

•      Hydroxy propylcellulose solution in chloroform is used  as a continuous phase, while a chemical dehydrating  agent,

•      2,2, di-methyl propane is used to disperse into the  internal aqueous phase to form an Emulsion

•      This method avoids coalescence of droplets and could  produce nanoparticles of smaller size (300nm)

4) Phase seperation

•      The protein or polysaccharide from an aqueous phase can  be Desolvated by :

a)      pH change

b)      Change in temperature

c)      Addition of appropriate counter ions e.g. alginate

Aqueous phase (protein aqueous solution)

Heat to 40^o C, subsequent cooling to 4^O C for 24h.  â  Desolvation

Protein aggregates (Coacervates)

â Resolvation

Protein colloidal dispersion

â Cross-linking

Nanoparticles dispersion (External aqueous phase) 200nm

5) pH induced aggregation

•      Gelatin Nanospheres were prepared by :

•      Gelatin & tween 20 were dissolved in aq. phase & pH of the solution was adjusted to optimum value.

•      The clear solution so obtained was heated to 40⁰C followed by its quenching at 4⁰C for 24hrs & subsequently left at ambient temperature for 48hrs.

•      The sequential temperature treatment resulted into a colloidal dispersion of aggregated gelatin. The aggregates were finally cross  linked using glutaraldehyde as cross linking agent the optimum pH  was 5.5- 6.5.values

•      pH below 5.5 produced no aggregation while above 6.5 an  uncontrolled aggregation led to the formation of larger nanospheres

Polymerization based methods

1)      Emulsion polymerization :

It consists of:

a)      Micellar nucleation and polymerization :

Monomer is insoluble in continuous phase-(O/W phase) - Aqueous phase 

b)     Homogenous nucleation and polymerization :

Monomer is soluble in continuous phase- (W/O phase) – Organic phase

2] Dispersion polymerization

(Acrylamide or Methyl methacrylate) Monomer is dissolved in an aqueous medium

â

Further, by chemical initiation (ammonium or potassium per oxo disulphate)

â

Heated to above 65⁰C

â

Oligomers aggregate & precipitates

â

lsolation of nanospheres

Characterization and evaluation of nanoparticles

Parameter	Method
Particle size	- Photon correlation spectroscopy - Laser defractometry - Scanning electron microscopy
Molecular weight	- Gel Chromatography
Charge determination	- Laser Doppler Anemometry - Zeta potentiometer
Density	- Helium pycnometer
Crystallinity	- X-ray diffraction & DSC - Thermogravimetry
Hydrophobicity	- Hydrophobic interaction - Chromatography
Surface element analysis	- X-ray - Photo emission Spectroscopy
Specific Surface Area	Specific surface area( A) = 6/Density x diameter of particle
Invitro Release :	-Diffusion Cell -Modified Ultra Filtration Technique. -Media Used : Phosphate Buffer
Nanoparticle Yield :	% Yield = Actual weight of Product        X 100  Total weight of Drug and Excipients

Applications

1)      Cancer Therapy

2)      In lntracellular Targeting

3)      Used for Prolonged Systemic Circulation

4)      As a Vaccine    Adjuvant

5)      In Case of Ocular delivery

6)      Used in DNA Delivery

7)      It is used in case of Oligonucleotide delivery

8)      Enzyme immunoassays

9)      Radio-imaging

10)  To cross BBB

Application	Purpose	Material
Cancer therapy	Targeting, Reduced toxicity,  enhance uptake of anti-tumor  agent	Polyalkylcyanoacrylate with anticancer agent
Intra cellular targeting	Target reticuloendothelial  system for intracellular  infection	Poly alkyl cyanoarylate
Vaccine adjuvant	Prolong systemic drug effect.  Enhance immune response	Poly methyl metha acrylate  nanoparticles with vaccines
DNA delivery	Enhanced bioavailability and  significantly higher expression  level	DNA gelatin nanoparticles, DNA chitosan nanoparticles
Ocular delivery	Improved retention of the drug and reduced washed out.	Poly alkyl cyanoacrylate  nanoparticles , anti-  inflammatory agent

Summary

1. Nanoparticles  are subnanosized colloidal drug delivery systems  ranging in size from 10-1000 nm in diameter
2. Selective and Effective Localization of drug  to target sites
3. The methods of preparation include 

A. Cross Linking Methods

1)      By Cross-linking of Amphiphilic Macromolecules

2)      By Cross-linking in W/O Emulsion

3)      By Emulsion chemical dehydration

4)      By Phase Separation

5)      By pH lnduced Aggregation 

      B. Polymerization Methods

                   1) Emulsion polymerization

                   2) Dispersion polymerization

4. Nanoparticles can be characterized for their particle size , molecular  weight, surface charge, surface texture, density, crystallinity,  hydrophobicity, surface area, drug release and drug entrapment
5. The polymers used can be synthetic or natural polymers
6. Nanoparticles can be Metal-based, Lipid-based or Polymer-based in nature

7. Carbon nanotubes (CNTs) are allotropes of carbon, made of graphite  and constructed in cylindrical tubes with nanometer in diameter and  several millimeters in length

             Based on the number of layers, structures of CNTs are classified into two types:

             - Single-walled Carbon Nanotubes (SWCNTs)

             - Multi-walled Carbon Nanotubes (MWCNTs)

8. Three main techniques used for SWCNTs and MWCNTs production are

1)      Arc-Discharge method (using arc vaporization of two carbon rods)

2)      Laser Ablation method (using graphite)

3)      Chemical Vapor Deposition (using hydrocarbon sources such as CO,  methane, ethylene, acetylene)

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