2. CONTENTS :
• INTRODUCTION
• IDEAL CHARACTERISTICS
• ADVANTAGES
• DISADVANTAGES
• CARRIER OR MARKERS
• STRATEGIES OF DRUG TARGETING
• TYPES OF TARGETED DRUG DELIVERY SYSTEM 2
3. INTRODUCTION :
• ‘Targeted drug delivery system is a special form of drug
delivery system where the medicament is selectively targeted or
delivered only to its site of action or absorption and
not to the non-target organs or tissues or cells.’
• It is a method of delivering medication to a patient in a manner
that increases the concentration of the medication in some parts
of the body relative to others. 3
4. •Targeted drug delivery seeks to concentrate the
medication in the tissues of interest while
reducing the relative concentration of the
medication in the remaining tissues.
•This improves efficacy and reduce side effects.
4
5. OBJECTIVE
• To achieve a desired pharmacological response at a selected sites
without undesirable interaction at other sites, there by the drug
have a specific action with minimum side effects & better
therapeutic index.
• Ex- In cancer chemotherapy and enzyme replacement therapy.5
6. REASON FOR DRUG TARGETING
• In the treatment or prevention or diseases.
• Pharmaceutical drug instability in conventional dosage form is
Solubility
Biopharmaceutical low absorption,
High membrane bounding,
Biological instability,
Pharmacokinetic/ pharmacodynamic short half life,
Large volume of distribution,
Low therapeutic index.
6
7. IDEAL CHARACTERISTICS
• It should be non-toxic, biocompatible, biodegradable, and physicochemical
stable in-vivo and in-vitro.
• Restrict drug distribution to target cells or tissues or organs and should have
uniform capillary distribution.
• Controllable and predicate rate of drug release.
• Drug release does not effect the drug action. 7
8. • Therapeutic amount of drug release.
• Minimal drug leakage during transit.
• Carriers used must be bio-degradable or readily eliminated from the body
without any problem and no carrier induced modulation of diseased state.
• The preparation of the delivery system should be easy or reasonably
simple, reproductive and cost effective.
8
9. ADVANTAGES
• Drug administration protocols may be simplified.
• Toxicity is reduced by delivering a drug to its target site, there by
reducing harmful systemic effects.
• Drug can be administered in a smaller dose to produce the desire
effect.
9
10. • Avoidance of hepatic first pass metabolism.
• Enhancement of the absorption of target molecules such as
peptides and particulates.
• Dose is less compared to conventional drug delivery system.
• Selective targeting to infections cells that compare to normal
cells.
10
11. DISADVANTAGES
• Rapid clearance of targeted systems.
• Immune reactions against intravenous administered carrier systems.
• Insufficient localization of targeted systems into tumour cells.
• Diffusion and redistribution of released drugs.
• Requires highly sophisticated technology for the formulation.
• Requires skill for manufacturing storage, administration. 11
12. • Drug deposition at the target site may produce toxicity
symptoms.
• Difficult to maintain stability of dosage form. e.g.: Resealed
erythrocytes have to be stored at 4 C.
• Drug loading is usually low. e.g. As in micelles. Therefore
it is difficult to predict /fix the dosage regimen. 12
°
13. TYPES OF TARGETED DRUG DELIVERY SYSTEM
NANO TUBES : They are hollow
Cylinder made of carbon, atoms
Which can be filled and sealed
For potential drug delivery.
Application: Cellular scale
needle for attaching drug
molecule to cancer cells. As
an electrode in thermo cells. 13
14. NANO WIRES : The nanowire pinpoint damage from injury
and stroke, localize the cause of seizures, and detect the presence
of tumours and other brain abnormalities.
Application : Technique has potential as a treatment
for Parkinson's and similar diseases.
14
15. NANO-SHELLS : Nano-shells are hollow silica spheres covered with gold.
Scientists can attach antibodies to their surfaces, enabling the shells to
target certain shells such as cancer cells.
Application : Technique has potential for targeting cancerous drug. 15
16. QUANTUM DOTS : Quantum dots are miniscule semiconductor particles
that can serve as sign posts of certain types of cells or molecules in the
body.
APPLICATION : Technique has potential
for targeting cancerous drug.
16
17. Nano pores : Engineered into particles, they are holes that are
so tiny that DNA molecules can pass through them one strand
at a time, allowing for highly precise and efficient DNA
sequencing.
Application : Potential in genetic
engineering and bio technology.
17
18. GOLD NANO : Particle scientist uses gold nanoparticle to
develop ultrasensitive detection system for dna and protein
markers associated with many forms of cancer, including
breast prostrate cancer.
APPLICATION :
In cancer treatment and
genetic engineering.
18
19. LIPOSOMES
• Liposomes are concentric bi-layered vesicles in which an aqueous core is entirely
enclosed by a membranous lipid bilayer mainly composed of natural or synthetic
phospholipids.
• The size of a liposome ranges from some 20 nm up to several micrometres.
19
20. LIPOSOMES : Liposomes are
simple microscopic vesicles in
which an aqueous volume is
entirely composed by membrane
of lipid molecule various
amphiphilic molecules
have been used to form liposomes.
The drug molecules can either be
encapsulated in aqueous
space or intercalated into
the lipid bilayers.
The extent of location of drug will depend upon its physicochemical characteristics and
composition of lipids.
20
22. • The lipid molecules are usually phospholipids- amphipathic moieties
with a hydrophilic head group and two hydrophobic tails.
• On addition of excess water, such lipid moieties spontaneously
originate to give the most thermodynamically stable conformation.
• In which polar head groups face outwards into the aqueous medium,
and the lipid chains turns inwards to avoid the water phase, giving
rise to double layer or bilayer lamellar structures. 22
24. LAMELLA
• A lamella is a flat plate like structure that appears during the formation
of liposomes.
• The phospholipids bilayer first exists as a lamella before getting
converted into spheres.
• Several lamella of phospholipids bilayers are stacked one on top of the
other during formation of liposomes to form a multilamellar structure.
24
26. STRUCTURAL COMPONENTS OF LIPOSOMES
• The main components of liposomes are :-
1. PHOSPHOLIPIDS
2. CHOLESTEROL
26
27. PHOSPHOLIPIDS
•Phospholipids are the major structural components of
biological membranes such as the cell membrane.
Phosphoglycerides
Two types of phospholipids
along with their hydrolysis(
products)
Two types of phospholipids
(along with their hydrolysis
products)
Sphingolipids 27
28. PHOSPHATIDYLCHOLINE
• Most common phospholipids used is
phosphatidylcholine (PC).
• Phosphatidylcholine is an amphipathic
molecule in which exists:-
– a hydrophilic polar head group,
phosphocholine.
– A glycerol bridge.
– A pair of hydrophobic acyl hydrocarbon chains.
28
30. CHOLESTEROL
• Cholesterol by itself does not form bilayer structure.
• Cholesterol act as fluidity buffer
• After intercalation with phospholipid molecules alter the freedom of motion of carbon
molecules in the acyl chain
• Restricts the transformations of trans to gauche conformations
• Cholesterol incorporation increases the separation between choline head group & eliminates
normal electrostatic & hydrogen bonding interactions
30
31. ADVANTAGES OF LIPOSOMES
• Provides selective passive targeting to tumour tissues.
• Increased efficacy and therapeutic index.
• Increased stability of encapsulated drug.
• Reduction in toxicity of the encapsulated agent.
• Site avoidance effect (avoids non-target tissues).
• Improved pharmacokinetic effects (reduced elimination increased
circulation life times).
• Flexibility to couple with site specific ligands to achieve active targetting.
31
32. DISADVANTAGES
• Physical/ chemical stability
• Very high production cost
• Drug leakage/ entrapment/ drug fusion
• Sterilization
• Short biological activity / t ½
• Oxidation of bilayer phospholipids and low solubility
• Rate of release and altered bio distribution
• Low therapeutic index and dose effectiveness
• Overcoming resistance
• Extensive clinical and laboratory research to a certain long circulating liposomes
• Repeated iv administration problems
32
33. CLASSIFICATION OF LIPOSOMES
MLV
Multilamellar
Large
vesicles
(>0.5 um )
OLV
oligolamellar
vesicles
(>0.1-1.0 um)
UV Unilamellar
Vesicles (all
size ranges)
MVV
Multivesicular
vesicles
)1.0 um(>
MUV Medium Unilamellar
Vesicles
GUV Giant Unilamellar Vesicles
um>1
SUV Small Unilamellar
Vesicles
nm20-100
LUV Large Unilamellar
Vesicles
>100 nm
Based on structural parameters
33
35. PREPARATION OF LIPOSOMES
Methods of liposome
preparation
Passive loading:
Involves loading of
the entrapped agents before or dur
ing the
manufacturing procedure.
Active or remote loading:
Certain types of compounds with
ionisable groups
and those with both manufacturing
procedure lipid and water
solubility can be
introduced into the liposomes
after the
formation of the intact vesicles
35
36. Methods of liposome preparation
Solvent dispersion
methods
Ethanol injection
Ether injection
Double emulsion
vesicles
Stable plurilamellar
Vesicles
Reverse phase
evaporation vesicles
Detergent removal
methods
Passive loading techniques
Detergent(Cholate,
Alkyl glycoside,
Triton X-100) removal
from mixed micelles by
Dialysis
Column
chromatography
Dilution
Reconstituted sendai
virus enveloped
vesicles
Active loading techniques
Lipid film hydration by
hand shaking non-hand
shaking and freeze drying
Micro emulsification
Sonication
French pressure cell
Membrane extrusion
Dried reconstituted
vesicles
Freeze thawed liposomes
Mechanical dispersion
methods
36
37. EVALUATION OF LIPOSOMES
• The liposomes prepared by various techniques are to be evaluated for their
physical properties, has these influence the behaviour of liposomes in vivo.
PHYSICAL PROPERTIES
1. PARTICLE SIZE
Both particle size and particle size distribution of liposomes influence their
physical stability. These can be determined by the following method.
a) Laser light scattering
b) transmission electron microscopy 37
38. 2. SURFACE CHARGE
• The positive, negative or neutral charge on the surface of the
liposomes is due to the composition of the head groups.
• The surface charge of liposomes governs the kinetic and extent of
distribution in vivo, as well as interaction with the target cells.
• The method involved in the measurement of surface charge is
based on free-flow electrophoresis of mlvs. 38
39. It utilizes a cellulose acetate plate dipped in sodium borate buffer of ph 8.8.
About 5n moles of lipid samples are applied on to the plate, which is then
subjected to electrophoresis at 4 ͦ c for 30 mins.
The liposomes get bifurcated depending on their surface charge.
This technique can be used for determining the heterogeneity of charges in
the liposome suspension as well as to detect any impurities such as fatty
acids.
39
40. 3. PERCENT DRUG ENCAPSULATED
• Quantity of drug entrapped in the liposomes helps to estimate the behaviour
of the drug in biological system
• Liposomes are mixture of encapsulated and unencapsulated drug fractions
• The % of drug encapsulation is done by first separating the free drug
fraction from encapsulated drug fraction
• The encapsulated fraction is then made to leak off the liposome into
aqueous solution using suitable detergents
• The methods used to separate the free drug from the sample are:
a. Mini column centrifugation method
b. Protamine aggregated method 40
41. 5. DRUG RELEASE RATE
The rate of drug release from the liposomes can be determined by in vivo
assays which helps to predict the pharmacokinetics and bioavailability of
the drug.
However in vivo studies are found to be more complete. Liposome
encapsulating the tracer [ᵌH] insulin are employed for ᵌ the study.
This [ᵌH] insulin is preferred, as it is released only (ᵌH) in the ECF and
undergoes rapid renal excretion of the face tracer coupled to the
degradation rate constant or the tracer released from the liposomes.
41
42. APPLICATIONS
• Liposomes as drug or protein delivery vehicles.
• Liposome in antimicrobial, antifungal(lung therapeutics) and antiviral (anti
HIV) therapy.
• In tumour therapy.
• In gene therapy.
• In immunology.
• Liposomes as artificial blood surrogates.
• Liposomes as radiopharmaceutical and radio diagnostic carriers.
• Liposomes in cosmetics and dermatology.
42
43. NANOPARTICLES
INTRODUCTION:
• The prefix “nano” comes from the ancient greek vavoc through the
latin nanus meaning very small.
• Nanotechnology defined as design characterization, production and
applications of structures, devices and systems by controlling shape
and size at nanometre scale.
• According to international system of units (si) nanotechnology is
typically measured in nanometres scale of 1 billionth of a meter (1nm
corresponding to 10-9 m) referred as the “tiny science”.
43
44. • Nanoparticles (nps) are defined as particulate dispersions or solid particles
drug carrier that may or may not be biodegradable.
• The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle
matrix.
• The term nanoparticle is a combined name for both nanospheres and nano
capsules.
• Drug is confined to a cavity surrounded by a unique polymer membrane
called nano capsules,
• while nanospheres are matrix systems in which the drug is physically and
uniformly dispersed. Where conventional techniques reaches their limits,
nanotechnology provides opportunities for the medical applications.
44
46. ADVANTAGES OF NANO-PARTICLES
Nanoparticles offers numerous advantage in drug
delivery system. These advantage include, but are not
limited:
• Nanoparticles have many significant advantage over
conventional and traditional drug delivery system.
46
47. • Nanoparticles are control and sustain release form at the site of localization, they
alter organ distribution of drug compound.
• They enhance drug circulation in blood, bioavailability, therapeutic efficacy and
reduce side effects.
• Nanoparticles can be administer by various routes including oral, nasal, parenteral,
intra-ocular etc.
• In the tiny areas of body nanoparticles shows better drug delivery as compare to
other dosage form and target to a particular cell type or receptor. 47
48. • Nanoparticle enhance the aqueous solubility of poorly soluble drug, which improves bioavailability
of drug.
• As a targeted drug carrier nanoparticles reduce drug toxicity and enhance efficient drug
distribution.
• By using polymers drug release form nanoparticles can be modified which makes polymeric
nanoparticle an ideal drug delivery system for cancer therapy, vaccines, contraceptives and
antibiotics.
• Useful to diagnose various diseases
• Enhanced stability of ingredients
• Prolonged shelf life
• Used in dental surgery also as filling the tiny holes in teeth.
• Change the method of drug delivery to improve customer acceptance or reduce manufacturing
costs.
48
49. S.NO TYPES OF NANOPARTICLE MATERIALS UED APPLICATION
1 NANOSUSPENSIONS AND
NANOCRYSTALS Drug powder is disperse d in
surfactant solution
Stable system for
controlled delivery of
poorly soluble drug
2
Solid lipid Nanoparticles
Melted lipid dispersed in Aqueous
surfactant
Least toxic and more stable
Colloidal carrier systems as
alternative materials To
polymers
3
Polymeric nanoparticles Biodegradable polymer
Controlled and targeted
drug delivery
4
Polymeric micelles Amphiphilic block co polymers
Controlled and systemic
Delivery of water insoluble
Drugs
5
Magnetic Nanoparticles
Magnetite Fe2O3,Meghe Mite coated
with dextran
Drug targeting
diagnostics to in
medicine
6
Carbon Nanotubes Metals ,semiconductors Gene and DNA delivery
49
50. POLYMERS USED IN PREPRATION
Natural
Hydrophilic
PROTEINS
POLYSACCHARIDES
Synthetic
Hydrophobic
PRE-
POLYMERIZED
POLYMERIZED IN
PROCESS 50
55. PREPARATION TECHNIQUES
SOLVENT EVAPORATION:
• Solvent evaporation method first developed for preparation of nanoparticles.
• In this method firstly nano-emulsion formulation prepared. Polymer dissolved in organic solvent
(dichloromethane, chloroform or ethyl acetate). Drug is dispersed in this solution. Then this
mixtures emulsified in an aqueous phase containing surfactant (polysorbates, poloxamers
sodium dodecyl sulphates polyvinyl alcohol, gelatine) make an oil in water emulsion by using
mechanical stirring, sonication, or micro fluidization (high-pressure homogenization through
narrow channels).
• After formation of emulsion the organic solvent evaporate by increased the temperature and
reduced pressure with continuous stirring. 55
56. EMULSIONS - DIFFUSION METHOD
• This method patent by leroux et al it is modified form of salting out method.
• Polymer dissolved in water-miscible solvent (propylene carbonate, benzyl alcohol), this
solution saturated with water.
• Polymer-water saturated solvent phase is emulsified in an aqueous solution containing
stabilizer.
• Then solvent removed by evaporation or filtration. Advantages of this method are high
encapsulation efficiencies (generally 70%), no need for homogenization, high batch-to-
batch reproducibility, ease of scaleup, simplicity, and narrow size distribution.
• Some disadvantage of this method is reported high volumes of water to be eliminated from
the suspension and the leakage of water-soluble drug into the saturated aqueous external
phase during emulsification, reducing encapsulation efficiency. 56
57. NANO-PRECIPITATION METHOD
• This is another method which is widely used for nanoparticle preparation
which is also called solvent displacement method.
• In this method precipitation of polymer and drug obtained from organic
solvent and the organic solvent diffused in to the aqueous medium with
or without presence of surfactant.
• Firstly drug was dissolved in water, and then cosolvent (acetone used for
make inner phase more homogeneous) was added into this solution. 57
58. • Then another solution of polymer (ethyl cellulose, eudragit) and propylene
glycol with chloroform prepared, and this solution was dispersed to the
drug solution.
• This dispersion was slowly added to 10 ml of 70% aqueous ethanol
solution. After 5 minutes of mixing, the organic solvents were removed by
evaporation at 35° under normal pressure, nanoparticles were separated by
using cooling centrifuge (10000 rpm for 20 min), supernatant were
removed and nanoparticles washed with water and dried at room
temperature in a desiccator 58
59. EVALUATION PARAMETER OF NANOPARTICLES
YIELD OF NANOPARTICLES:-
Percentage yield = amount of particle (100)
Amount of drug+ polymer
DRUG CONTENT/SURFACE ENTRAPMENT/ DRUG ENTRAPMENT:-
Percentage drug entrapment = W - w (100)
W
PARTICLE SIZE:- Particle size and its distribution is important characteristics in nanoparticles
as they plays major role in distribution, pharmacological activity, toxicity and targeting to specific
sites.
Advanced methods to determine the particle size of nanoparticles is by photon-correlation
spectroscopy or dynamic light scattering, scanning electron microscopy
59
60. PARTICLE SHAPE:- Particle shape of the nano suspensions is determined by
scanning electron microscopy (SEM). In order to form the solid particles these
nano suspensions were subjected to lyophilisation.
ZETA POTENTIAL:- Zeta potential is the potential difference existing between
the surface of a solid particle immersed in a conducting liquid and the bulk of the
liquid. The surface charge of the nanoparticles is usually measured by zeta
potential.
DIFFERENTIAL SCANNING CALORIMERTY (DSC):- It is used to
Determine the nature of crystallinity within nanoparticles through the
measurement of glass and melting point tempertures and their associated
enthalpies. 60
61. ATOMIC FORCE MICROSCOPY (AFM):-
It offers a ultra-high resolution in particle size measurement and is based on
a physical scanning of sample at submicron level using a probe tip of
atomic scale.
AFM provides the most accurate description of size and size distribution
and requires non mathematical treatment.
61
62. DRUG RELEASE AND RELEASE KINETIC
The release of drug from the
particulate system depends
upon three different mechanism:
Release from the surface of
particles.
Diffusion through the swollen
rubbery matrix.
Release due to erosion. 62
63. IN VITRO DRUG RELEASE STUDIES
DISSOLUTION:-
solution from the
USP Type 2
RPM 50
Immersed in 900
ml of phosphate
buffer solution
Temperature37+-
0.02 degree Celsius
Withdraw 5ml
solution from the
medium
Specific time
periods
Same vol. of
dissolution
medium replaced
in the flask
Maintain the
constant volume
Withdrawn
samples analysed
using UV
Spectrophotometer 63
64. STABILITY OF NANOPARTICLES :-
• Nanoparticles
detemination
• Storing
optimized
formulation
degree Celsius4 + 1
degree Celsius & 30
dergree celsius + 2
dergree celsius
• Sample
analyzed
• Stability
chamber for 90
days
,1,2 & 3 month0
time period
• Any changes in
physical
appearance
Their drug
content, drug
release rate
64
65. APPLICATIONS
• Used in targeted drug delivery to brain therapy.
• Used in targeting of nanoparticles to epithelial cells in the gi tract using ligands.
• Nanoparticles for gene delivery.
• Used in bio detection of pathogens.
• Used in detection of stem cell therapy, cancer therapy.
USED IN BIO
65
66. COMMERICAL PRODUCTS OF NANOPRATICLES
COMPANY TRADE
NAME
COMPOSITION INDICATION ROUTES
Astra Zeneca
Pharma
Diprivan Propofol
liposomes/lipid
Anesthetic IV
Teva Pharma Copaxone Copolymeric
mixture of L-
glutamic acid, L-
alanine, L-
tyrosine & L-
lysine
Relapsing
remitting
multiple
sclerosis
subcutaneous
Bio Sante Elestrin Estradiol gel
(0.06%)
Moderate to
severe hot
flashes in
menopausal
women
Transdermal
Abraxis
Bioscience
Abraxane Paclitaxel (Taxol)
bound albumin
nanoparticles
Various cancers IV
66
