2. 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.
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.
3. INTRODUCTION
Nanoparticle is made up of inner hydrophobic tail and outer hydrophilic head
(lipid bilayer).
Hydrophilic head
Hydrophobic tail
4. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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)
13. 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.
14. 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
15. 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.
16. 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
17. 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)
20. 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)
22. 4. INTERFACIAL COMPLEXATION METHOD:
Water + Monomer A + Oil phase
high pressure homogenization
W/O emulsion
Monomer B
Nanocapsules
23. 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.
25. 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.
29. 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.
30. 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
32. 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.
33. 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)
34. 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
35. SUPER CRITICAL ANTI-SOLVENT(SCA):
Drug + Methanol
Drug is dissolved
Add super critical fluid(miscible with methanol)
Precipitation of drug as fine particles
37. 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
38. 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.
39. 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
40. 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
41. 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
42. 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.
43. 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.
44. COMMERCIAL FORMULATIONS IN
THE MARKET
COMMERCIAL FORMULATIONS OF NANOPARTICLES
AVAILABLE:
COMPANY TRADE
NAME
COMPOSITIO
N
INDICATION ROUTE
Novovax Estrasorb Micellular
estradiol
Menopausal
therapy
Topical
Genzyme Renagel Poly(allylamine
hydrochloride)
End stage renal
disease
Oral
Elan,Merck Emend Nanocrystalline
aprepitant
Anti emetic Oral
Berna Biotech Epaxal Liposomal IRIV
vacccine
Hepatitis A IM
Enzon Abelect Liposomal
amphotericin B
Fungal infection IV
45. 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.
