NANOPARTICLES
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INTRODUCTION
➢ 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.
➢Eg: liposomes, nanoparticles and micro emulsion.
Nanoparticles is derived from the greek word nano meaning extremely small.
➢ The prefix “ nano” comes from the ancient Greek word “vavoc” through
the latin nanus meaning very small.
➢ Nano particles as a drug delivery vehicle were first developed by Spieser
and co-workers in the late 1960s.
DEFINITION:
“Nanoparticles are subionized colloidal structure composed of synthetic or
semisynthetic polymers”.
➢ It is also defined as solid colloidal particles ranging from 1 to 1000 nm in
size, they consist of macromolecular materials in which the active ingredients
is dissolved , entrapped, encapsulated or adsorbed.
➢ Size range: 10-1000 nm.
➢ The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle
matrix.
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INTRODUCTION
Hydrophilic head
Hydrophobic tail
Nanoparticle is made up of inner hydrophobic tail and outer hydrophilic head
(lipid bilayer).
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TYPES OF NANOPARTICLES
❑ The materials which are used for the preparation of nanoparticles should be
non-toxic, biodegradable , sterilizable, etc.
❑ Based on the method of preparation, nanoparticles are classified into
nanospheres or nanocapsules.
Nanoparticles
Nanoencapsules – membrane wall structure with an oil core containing
drug.
Nanospheres-matrix type structure in which a drug is dispersed.
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NANOPARTICLES
NANOCAPSULES AND NANOSPHERES
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NANOPARTICLES
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BASIC CONCEPT OF NANOPARTICLES
➢ The basic concept involved is:
➢ Selective and effective localization of pharmacologically active moiety at
preselected target(s) in therapeutic concentration.
➢ Provided restriction of it’s access to non-target normal tissues and cells.
➢ Nanoparticles are mainly taken by reticulo endothelial system after the
administration.
➢ Hence are useful to carry drugs to the liver and to cells that are
phagocytically active.
➢ Distribution of the nanoparticles in the body may be achieved by coating
with certain serum components, attachment of antibodies or sulfoxide
groups and use of magnetic nanoparticles.
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IDEAL CHARACTERISTICS OF
NANOPARTICLES
• It should be biochemical inert, non toxic and non-immunogenic.
• It should be stable both physically and chemically in invivo and invitro
conditions.
• Controllable and predicate rate of drug release.
• Restrict drug distribution to non-target cells and have uniform distribution.
• 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 and no carrier induced modulation in disease state.
• The preparation should be easy.
• Simple, reproducible and cost effective.
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ADVANTAGES AND DISADVANTAGES OF
NANOPARTICLES
❑ ADVANTAGES:
• Reduction in the frequency of the dosages taken by the patient.
• More uniform effect of the drug.
• Reduction of drug side effect.
• Reduced fluctuation in circulating drug levels.
• Avoid hepatic first pass metabolism.
❑ DISADVANTAGES:
• High cost
• Productivity more difficult
• Reduced ability to adjust the dose
• High sophisticated technology
• Requires skills to manufacture
• Difficult to maintain stability.
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FORMULATION OF NANOPARTICLES
• Polymers used in Nanoparticles preparation:
Natural Hydrophilic Synthetic Hydrophobic
Proteins Pre-polymerized
Polysaccharides Polymerized in process
In spite of this two, Semi-synthetic polymers are also
available.
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FORMULATION OF NANOPARTICLES
❑ NATURAL HYDROPHILIC POLYMERS:
• Proteins and polysaccharides have been further classified into:
Proteins Polysaccharides
Gelatin alginate
Albumin Dextran
Lectins Chitosan
Legumin Agarose
viciline Pullulan
Disadvantage:
•Batch to batch variations
•Conditional biodegradability
•Antigenicity.
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FORMULATION OF NANOPARTICLES
❑ SEMISYNTHETIC POLYMERS:
• Pseudolatexes. Artificial latexes obtained from dispersion of preformed
polymers.
• Eg: Pseudo latexes of ethylcellulose, Cellulose acetate pthalate, etc.
• These are used for the preparation of nanocapsules.
❑ SYNTHETIC HYDROPHOBIC POLYMER:
PRE-POLYMERIZED POLYMERIZED IN PROCESS
Poly (lactic acid)(PLA) Polyhexylcyanoacrylates (PHCA)
Poly styrene Poly(butylcyanoacrylates)(PBCA)
Poly (epsilon capro lactone)(PECL) Poly(isobutylcyanoacrylates)
Poly (Lactide – co-glycolide)(PLGA) Poly(methacrylate)
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FORMULATION OF NANOPARTICLES
❑ FACTORS DETERMINING THE MATRIX COMPONENTS:
1. Size of the nanoparticles required
2. Inherent properties of the drug eg: aqueous solubility and stability
3. Surface characteristics such as charge and permeability
4. Degree of biodegradability, biocompatibility and toxicity
5. Drug release profile desired
6. Antigenicity of the final product.
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METHOD OF PREPARATION
There are three techniques involved in the preparation of nanoparticles.
❖ Amphiphilic micromolecule cross linking
❖ Polymerization based method
❖ Polymer precipitation method
They are further subdivided into following classes:
❖ Amphiphilic micromolecule cross linking:
1. Heat cross linking
2. Chemical cross linking
❖ Polymerization based technique:
1. Polymerization of monomers in situ
2. Emulsion (micellar) polymerization
3. Dispersion polymerization
4. Interfacial condensation polymerization
5. Interfacial complexation
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METHOD OF PREPARATION
❖ Polymer precipitation methods (Preformed polymer)
1. Solvent evaporation method
2. Solvent displacement method
3. Salting out
4. Solvent diffusion method
5. Dialysis
❖ Super critical fluid technique
❑ AMPHIPHILIC MACROMOLECULE CROSSLINKING:
▪ Nanoparticles can be prepared from amphiphilic macromolecules, proteins
and polysaccharides.
▪ The process involved here is the aggregation of amphiphiles followed by
stabilization either by heat denaturation or chemical cross-linking
▪ Occurs both in biphasic O/W or W/O type of dispersed system.
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METHOD OF PREPARATION
1. HEAT CROSS LINKING:
▪ It is mainly used for the nano-encapsulation of drug.
▪ Involves high pressure homogenization or high frequency sonication.
Aqueous protein + surfactant +oil
O/W emulsion
Addition of cross linking agent and centrifugation
Nanoparticles are obtained
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METHOD OF PREPARATION
2. CHEMICAL CROSSLINKING:
▪ In this method, nanoparticles of size 300 nm are produced.
▪ 2,2 di-methyl propane is used as dehydrating agent used to translate internal
aqueous phase into solid particulate dispersion.
▪ Hydroxypropyl cellulose solution in chloroform used as continuous phase.
❑ POLYMERISATION BASED TECHNIQUES:
▪ Method in which the monomer to be polymerized is emulsified in a non-
solvent phase(emulsion polymerisation)
▪ Methods in which the monomer is dissolved in solvent that is non solvent for
the resulting polymer (Dispersion polymerization)
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METHOD OF PREPARATION
1. EMULSION POLYMERIZATION:
Oil , drug, monomer, stabilizer (lecithin) + Aqueous phase(Polaxomer)
O/W emulsion
magnetic stirring
centrifugation
Isolation of Nanoparticles
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METHOD OF PREPARATION
POLYMERISATION TECHNIQUE
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METHOD OF PREPARATION
2. DISPERSION POLYMERIZATION:
In case of dispersion polymerization, the monomer is dissolved in
an aqueous medium which act as precipitant for subsequently formed
polymer.
3. INTERFACIAL POLYMERISATION:
Core phase + drug + Polymer
O/W emulsion
Addition of non-solvent which precipitate out polymer from either of phases
Nanocapsules(30-300 nm)
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METHOD OF PREPARATION
INTERFACIAL POLYMERISATION
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METHOD OF PREPARATION
4. INTERFACIAL COMPLEXATION METHOD:
Water + Monomer A + Oil phase
high pressure homogenization
W/O emulsion
Monomer B
Nanocapsules
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METHOD OF PREPARATION
❑ POLYMER PRECIPITATION METHOD
❖ SOLVENT EVAPORATION METHOD:
Polymer dissolved in organic solvent(DCM, Chloroform or ethyl acetate)
Drug is dispersed in this solution
Mixture emulsified in an aqueous phase containing surfactant (eg:
polysorbates, poloxamers)
Stirred by mechanical stirrer
Formation of emulsion by evaporation of organic solvent by increasing the
temperature.
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METHOD OF PREPARATION
SOLVENT EVAPORATION METHOD
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METHOD OF PREPARATION
❖ SOLVENT DIFFUSION METHOD
▪ Formation of O/W emulsion between a partially water-miscible solvent
containing the polymer and the drug, and an aqueous solution, containing a
surfactant.
▪ ADVANTAGES:
• In contrast with solvent evaporation, this technique decreases the droplet
size.
• Nanospheres are obtained by this method.
• Nanocapsules are obtained by adding a small amount of oil in the organic
phase.
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METHOD OF PREPARATION
SOLVENT DIFFUSION METHOD
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METHOD OF PREPARATION
❑ DOUBLE EMULSIFICATION METHOD:
Organic phase solvent, drug, polymer +Aqueous phase distilled water,stabilizer
sonication
W/O emulsion
Aqueous phase with stabilizer
W/O/W emulsion
solvent extraction, solvent evaporation
Nanoparticles
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METHOD OF PREPARATION
DOUBLE EMULSIFICATION METHOD
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METHOD OF PREPARATION
❑ EMULSIFICATION- REVERSE SALTING OUT:
▪ The emulsion is formulated from a water miscible polymer solvent like
acetone and an aqueous gel containing the salting out agent.
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METHOD OF PREPARATION
❑ NANOPRECIPITATION METHOD:
▪ Also known as solvent displacement method.
▪ Useful for slightly water soluble drug.
▪ Drug dissolved in organic phase(ethanol/methanol)
emulsified
Aqueous phase
displacement of organic phase
Immediate polymer precipitation because of complete miscibility of both the
phase.
Nanoparticles
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METHOD OF PREPARATION
SOLVENT DISPLACEMENT METHOD
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METHOD OF PREPARATION
❑ DIALYSIS:
▪ Polymer and the drug is dissolved in a organic solvent
▪ This solution is added to dialysis tube and dialysis performed against a non
solvent miscible with the former miscible.
▪ The displacement of the solvent inside the membrane is followed by the
progressive aggregation of polymer due to loss of solubility and formation
of homogenous suspension of nanoparticles.
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METHOD OF PREPARATION
❑ SUPER CRITICAL FLUID TECHNOLOGY:
▪ Advantages:
▪ Formation of dry nanoparticles
▪ Rapid precipitation process.
▪ Contain very low traces of organic solvent.
▪ Involves use of environment friendly solvent like SC carbon dioxide or
nitrogen.
SCF technology
Rapid expansion of super Super critical Anti-solvent (SCA)
Critical solution(RESS)
(For drugs soluble in SCF) (For drugs insoluble in SCF)
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METHOD OF PREPARATION
➢ RAPID EXPANSION OF SUPER CRITICAL SOLUTION:
Drug dissolved in super critical fluid
Solution sprayed into region of low pressure
Solvent power of super critical fluid decreases
Precipitation of nanoparticles
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METHOD OF PREPARATION
➢ SUPER CRITICAL ANTI-SOLVENT(SCA):
Drug + Methanol
Drug is dissolved
Add super critical fluid(miscible with methanol)
Precipitation of drug as fine particles
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METHOD OF PREPARATION
SUPER CRITICAL FLUID TECHNOLOGY
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EVALUATION OF NANOPARTICLES
• EVALUATION OF NANOPARTICLES:
➢ Particle size
➢ Density
➢ Molecular weight
➢ Structure and crystallinity
➢ Specific surface area
➢ Surface charge and electronic mobility
➢ Surface hydrophobicity
➢ Invitro release
➢ Nanoparticles yield
➢ Drug entrapment efficiency
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EVALUATION OF NANOPARTICLES
➢ PARTICLE SIZE:
• Photon correlation spectroscopy(For smaller particles)
• Laser diffractrometry(For larger particles)
• Electron microscopy(For coated materials and dry samples)
• Transmission electron microscopy
• Atomic force microscope, laser force microscope and scanning electron
microscope are used for evaluation of nanoparticles.
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EVALUATION OF NANOPARTICLES
➢ DENSITY:
• Helium or air using a gas pycnometer
• Density gradient centrifugation are used.
➢ MOLECULAR WEIGHT:
• Gel permeation chromatography using refractive index detector .
➢ STRUCTURE AND CRYSTALLINITY:
• X-ray diffraction
• Thermoanalytical methods like Differential scanning calorimetry,
differential thermal analysis and thermogravimetry are used.
➢ SPECIFIC SURFACE AREA:
• Sorptometer used.
• Specific surface area A=6/Density *diameter of particle
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EVALUATION OF NANOPARTICLES
➢ SURFACE CHARGE AND ELECTRONIC MOBILITY:
• By measuring particle velocity in electrical field.
• Laser Doppler Anemometry technique is used.
• Zeta potential can also be obtained by measuring the electronic mobility.
➢ SURFACE HYDROPHOBICITY:
• Hydrophobic interaction chromatography
• Two phase partition
• Contact angle measurement
➢ INVITRO RELEASE:
• Diffusion
• Ultra filtration
• Media used: phosphate buffer
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EVALUATION OF NANOPARTICLES
➢ NANOPARTICLE YIELD:
• % Yield=actual weight of product/total weight of excipient and drug
➢ DRUG ENTRAPMENT EFFICIENCY:
• Drug entrapment % = mass of drug in nanoparticles /mass of drug used in
formulation *100
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BENEFITS OF NANOPARTICLES
• BENEFITS OF NANOPARTICLES:
❑ Improved bioavailability by enhancing the aqueous solubility
❑ Increased resistance time in the body(increasing half life for clearance)
❑ Targeting drug to specific location in the body.
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APPLICATION OF NANOPARTICLES
❑ APPLICATION OF NANOPARTICLES:
• Used in cancer therapy for enhance uptake of anti-tumor agents. Eg:
Polyalkylcyanoacrylate with anticancer agent.
• Used in extra cellular targeting for intracellular infections.
• Used as vaccine adjuvant for enhancing immune response
• Used in DNA delivery for significantly higher expression level.
• Used in ocular delivery.
• Used in gene therapy.
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COMMERCIAL FORMULATIONS IN
THE MARKET
❑ COMMERCIAL FORMULATIONS OF NANOPARTICLES
AVAILABLE:
COMPANY TRADE COMPOSITIO INDICATION ROUTE
NAME N
Novovax Estrasorb Micellular Menopausal Topical
estradiol therapy
Genzyme Renagel Poly(allylamine End stage renal Oral
hydrochloride) disease
Elan,Merck Emend Nanocrystalline Anti emetic Oral
aprepitant
Berna Biotech Epaxal Liposomal IRIV Hepatitis A IM
vacccine
Enzon Abelect Liposomal Fungal infection IV
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REFERENCES
• REFERENCES:
• Mohanraj V.J, Chen Y, Nanoparticles- A Review. Tropical Journal of
Pharmaceutical Research, June 2006; 5(1): 561-573.
• Sovan Lal Pal. Utpal Jana, Mana P.K-Nanoparticle:An Overvview of
preparation and characterization. Journal of Applied Pharmaceutical –
Science 01(06);2011:228-234.
• Konwar Ranjit,Ahmed Abdul Baquee-Nanoparticle:An Overview of
preparation, characterization and application,Int.Res.J.Pharm.2013.
• Nanoparticles-wikipedia.
• Shantanu Tamuly and Aman Kumar-Preparation and Characterisation of
Nanoparticles. Research gate.net-273762796.
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