3. INTRODUCTION
The therapeutic response of a drug depends upon the interaction of
drug molecules with receptor sites in concentration dependent
manner.
Cytotoxic agents not only demand for controlled drug delivery but needs
to be specified, precise in quantitative level.
Therefore, a delivery system is required to overcome the limitations of
the conventional dosage form which can improve the therapeutic
efficacy of drug.
The concept of designing targeted drug delivery was first given by Paul
Ehrlich in 1902.
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4. Targeted drug delivery system is a special form of drug delivery system
where the pharmacologically active agent or medicament is selectively
targeted or delivered only to its site of action in therapeutic
concentration.
The other organs, tissues and cells remain unaffected with minimized
toxic effects and maximum therapeutic index.
Targeted drug delivery system doesn’t become the part of systemic
circulation and neither do it disturb the extraneous tissue cells.
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5. COMPONENTS OF TARGETED DRUG
DELIVERY
The following components namely Target and Drug carrier are required for the
delivery of drug molecule in this system.
Target : target means an organ or a tissue or a cell which requires treatment.
Drug Carrier : targeted drug delivery system require carrier to deliver drug at
particular receptor. Carriers are molecules responsible for the fruitful
transportation of a drug to the target site. This is possible by means of
encapsulation of drugs such as anticancer, antimicrobials, proteins, vaccines, etc
into carrier molecules.
Other Tissues
Target
High Drug
Concentration
Encapsulated
Drug
Minor Drug Leakage Minor Drug Leakage
6. ADVANTAGES OF TARGETED DRUG
DELIVERY
Drug administration process is simple.
Toxicity of drug is minimum due to delivery of drug at target
receptor.
Lower dose of drug required to get desired therapeutic efficacy
compared to conventional dose.
Bypass the hepatic first pass metabolism and produce improved
bioavailability effect of drug.
Enrichment of the absorption of target molecules such as
peptides.
No peak and Valley plasma concentration.
7. DISADVANTAGES OF TARGETED DRUG
DELIVERY
1. Swift clearance of drug molecule from targeted cells.
2. Immune reactions against intravenous administered carrier systems.
3. Difficult to maintain stability of dosage form.
4. Insufficient localization of targeted systems into tumour cells.
5. Diffusion and redistribution of released drugs.
6. Manufacture of the formulation entails highly sophisticated technology
instruments.
7. Drug deposition at the target site may produce toxicity symptoms.
8. Expensive compared to conventional dosage forms.
8. IDEAL CHARACTERISTICS OF TARGETED
DRUG DELIVERY
Biochemically inert (non-toxic).
Both physically and chemically stable in vivo and in vitro.
Should have uniform capillary distribution.
Controllable and predictable rate of drug release.
Drug release must be in therapeutic amount and should not affect the drug action.
Minimal drug leakage during transit.
Carriers used must be bio-degradable or readily eliminated from the body without
any side effects or carrier induced modulation of diseased state.
Preparation must be simple, easy, reproducible and cost effective.
12. LIPOSOMES
Liposomes are small artificial bilayered vesicles of spherical shape that can be
prepared from cholesterol and natural non-toxic phospholipids.
The size of liposomes ranges from 0.01-5.0µm (10nm–5000nm) in diameter.
Liposomes have a potential advantage of encapsulating hydrophilic as well as
hydrophobic drugs and targeting them to the required diseased site in the body
without getting decomposed.
The properties of liposomes differ considerably with lipid composition, surface
charge, rigidity, fluidity, size and the method of preparation.
Therefore, liposomes are comprehensively used as carriers for numerous molecules
in cosmetic and pharmaceutical preparations.
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13.
14. The choice of bilayer components determines the rigidity, fluidity and the charge
of the bilayer. For example, unsaturated phosphatidylcholine species (egg or
soybean phosphatidylcholine) give much more permeable and less stable bilayers,
whereas, the saturated phospholipids with long acyl chains (di-palmitoyl
phosphatidyl choline) form a rigid, and impermeable bilayer structure.
15.
16. Liposomal encapsulation technology is the newest delivery technique used by medical
investigators to transmit drugs that act as curative promoters to the assured body organs.
This form of delivery system propose targeted the delivery of vital combinations to the
body.
These liposomes form a barrier around their contents, which is resistant to enzymes in the
mouth and stomach, alkaline solutions, digestive juices, bile salts and intestinal flora that
are generated in the human body as well as free radicals.
The contents of the liposomes are therefore, protected from oxidation and degradation.
This protective phospholipid shield or barrier remains undamaged until the contents of the
liposomes are delivered to the exact target gland, organ, or system where the drug will be
utilized.
17. ADVANTAGES OF LIPOSOMES:
Provides selective passive targeting to tumor tissues.
Increased efficacy and therapeutic index.
Increased stability via encapsulation.
Reduction in toxicity of the encapsulated agent.
Biocompatible with chemically & physically well characterized entities.
Improved pharmacokinetic effects.
Used as carriers for controlled and sustained drug delivery.
Variation in sizes can be achieved.
Suitable for delivery of hydrophobic and hydrophilic drugs via various routes.
18. DISADVANTAGES OF LIPOSOMES :
Leakage of encapsulated drug during storage.
Uptake of liposomes by the reticuloendothelial system
(mononuclear phagocyte system).
Difficulty in large scale preparation with batch to batch variation
and sterilization.
Once administered, liposomes can not be removed from the
system.
Less stability and high production cost.
Phospholipids may undergo hydrolysis and oxidation reactions.
19. CLASSIFICATION OF LIPOSOMES
1. CLASSIFICATION BASED ON SIZE :
Multilamellar large vesicles (> 0.5µm) - MLV
Oligolamellar vesicles (> 0.1-1.0µm) - OLV
Unilamellar Vesicles (all size ranges) - ULV
Multivesicular vesicles (> 1.0µm) - MVV
Giant unilamellar vesicles (>1.0µm) -GUV
Small unilamellar vesicles (20-100nm)- SUV
Large unilamellar vesicles (>100nm) -LUV
20.
21.
22. 2. CLASSIFICATION BASED ON METHOD OF PREPARATION :
Vesicles prepared by membrane extrusion method
Vesicles prepared by French press
Vesicles prepared by fusion
Sonication
Micro-emulsification
Vesicles prepared by reverse phase evaporation
Frozen and thawed MLV
Dehydration and rehydration vesicles
Stable plurilamellar vesicles.
23.
24. Preparation of Liposomes
The following materials namely:
1. Phospholipids
2. synthetic phospholipids
3. glycerolipids
4. sphingolipids
5. Glycosphingolipids
6. cholesterol
7. Polymers
charge-inducing lipids, etc are used in the preparation of liposomes. The liposomes
are prepared by active loading or passive loading.
25. Preparation of Liposomes
1. Active/Remote Loading: the liposomes are first generated containing a
transmembrane gradient, i.e. the aqueous phase inside and outside the liposomes
are different.
Subsequently, an amphipathic drug dissolved in the exterior aqueous phase can
penetrate across the phospholipid bilayer followed by interaction with a trapping
agent in the core to lock the drug inside.
1. Passive Loading: involves loading of the drug or entrapped agent before or during
the manufacturing procedure.
34. Detergents can be defined as the particular subgroup of surfactants that are
able to solubilize lipid membranes.
Sufficient amounts of detergents lead to the reorganization of lipid bilayers
to form smaller, soluble detergent–lipid aggregates of various shapes, which
are called mixed micelles (MMs).
The reverse way, that is, when the amount of detergents in MMs is reduced,
leads to a successive enlargement of the MMs. At a critical detergent-to-
lipid ratio membrane bilayers are formed, which spontaneously vesiculate to
form liposomes.
At distinct intermediate phases of detergent–membrane lipid aggregation,
membrane proteins can be reconstituted into the membrane bilayers.
DETERGENT REMOVAL METHOD
37. APPLICATIONS OF LIPOSOMES
1. Site specific targeting delivery of higher concentration of drug to the diseased site.
2. Minimized drug exposure to normal cells without affecting therapeutic efficacy.
3. Sustained release of drugs can be achieved using liposomal drug delivery.
4. Increased delivery even to the cytosol for receptor targeting.
5. Intraperitoneal (IP) administration is useful in treatment of tumor in the IP cavity.
6. Immune response of vaccines can be enhanced by liposomes.
7. Liposomes can be used as protein delivery vehicles.
8. Liposomes can be of great advantage in antimicrobial, antifungal and antiviral
therapy.
9. Liposomes as radiopharmaceutical and radio diagnostic carriers.
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38. NIOSOMES
Niosomes are a novel drug delivery system in which the medicament is
encapsulated in a vesicle composed of a bilayer or non-ionic surface active agents
and hence the name niosome.
Niosomes are synthetic microscopic vesicles of the size ranging from 10-1000nm
consisting of an aqueous core enclosed in a bilayer consisting of cholesterol and
one or more non-ionic surfactants (generally non-irritant, non-immunogenic,
biodegradable and biocompatible in nature).
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39.
40. NIOSOMES
Niosomes are capable of encapsulating both hydrophilic and lipophilic substances.
Hydrophilic drugs are usually in the innermost aqueous core while lipophilic drugs
are entrapped by their partitioning into the lipophilic domain of the bilayers.
Surfactants include sorbitan esters, polyglycerol, crown ether based surfactants.
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41.
42. ADVANTAGES OF NIOSOMES
Reduced dose is required to achieve the desired effect.
Subsequent decrease in side effects.
Therapeutic efficacy of the drugs is improved by reducing the clearance rate.
Encapsulated drug is protected and Targeting to the specific site.
Drug release in sustained/controlled manner.
Niosomes are amphiphilic in nature (both hydrophilic and lipophilic drugs can be
incorporated with wide range of solubility).
Increased bioavailability of poorly soluble drugs.
Drugs are protected even from enzyme metabolism.
Enhance the skin permeability of drugs when applied topically.
Biodegradable, biocompatible and non-immunogenic.
43. DISADVANTAGES
It may decrease their shelf life, and include physical and
chemical instability, aggregation, fusion of vesicles, and
leaking or hydrolysis of the encapsulated drug.
Methods required for preparation of multilamellar vesicles
such as extrusion or sonication are time consuming and may
require specialized equipment for processing.
Inefficient drug loading.
Expensive compared to conventional formulations.
44. COMPOSITION OF NIOSOMES
Two components i.e. cholesterol and non-ionic surfactants are
used in preparation of niosomes.
Cholesterol is a steroid derivative, which is used to provide
rigidity and proper shape and conformation to niosomes.
Non-ionic surfactants such as polyglycerol alkyl ether,
glucosyl dialkyl ethers, crown ethers, esterlinked
surfactants, polyoxyethylene alkyl ether and a series of
spans and tweens are generally used for the preparation of
Niosomes.
45. CLASSIFICATION OF NIOSOMES:
Niosomes are classified as :
Multilamellar vesicles (MLV)
Large unilamellar vesicles (LUV)
Small unilamellar vesicles (SUV)
PREPARATION OF NIOSOMES:
Ether injection for LUV
Hand shaking method for MLV
The Bubble method
Reverse phase evaporation
Sonication
Multiple membrane extrusion method.
Microfluidization method
GENERAL METHOD OF
PREPARATION
Cholesterol + Non-ionic
Surfactant
Dissolve in organic solvent
Solution in organic solvent
Drying
Thin film
Dispersion (Hydration)
Niosomes suspension
47. APPLICATIONS OF NIOSOMES
These are used as drug carriers for delivery of anticancer drugs like
methotrexate. 2,3,8,19,26,40,41,44,51,53,56,58,60
Niosomal system can be used as a diagnostic agents.
Niosomal system can be used for ophthalmic drug delivery.
It is used in studying immune response.
For the delivery of peptides and proteins.
Niosomes are used as carriers for haemoglobin.
Sustained release action of niosomes can be applied for drugs with low
therapeutic index and low water solubility.
Localized drug action can be achieved using niosomes.
48.
49. NANOPARTICLES
1. NPs are tiny materials having size ranges from 1 to
100 nm.
2. They can be classified into different classes based
on their properties, shapes or sizes.
3. The different groups include fullerenes, metal NPs,
ceramic NPs, and polymeric NPs.
4. NPs possess unique physical and chemical properties
due to their high surface area and nanoscale size.
50.
51. •Their reactivity, toughness and other properties
are also dependent on their unique size, shape
and structure.
• Due to these characteristics, they are suitable
candidates for various commercial and domestic
applications, which include
catalysis,
imaging,
medical applications,
energy-based research, and environmental
applications.
52. NANOPARTICLES
Due to the small size, the nanoparticles are easily taken up by cells where the
larger particles would be excluded or cleared from the body.
Nano-particles acts as a vehicle in which a drug is confined to a cavity surrounded
by a polymer membrane where as nanospheres are matrix systems in which the
drug is physically and uniformly dispersed.
Nanoparticles are solid, colloidal particles consisting of macromolecular
substances that vary in size from 10nm to 1000nm in diameter.
The use of nanoparticles allows one to change the pharmacokinetic properties of
the drug without changing the active compound. The nanoparticles can be
metallic, polymeric or lipid based.
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59. APPLICATIONS OF NANOPARTICLES
Nanoparticles improve protein and peptides stability, avoids proteolytic degradation,
as well as sustained release of the incorporated molecules. Important peptides such as
cyclosporin A, Insulin, calcitonin and somatostatin have been incorporated into solid
lipid particles (SLP).
Anticancer drug can be delivered at targeted cells of tumor via the enhanced
permeability and retention effect or active targeting by ligands on the surface of
nanoparticles.
Nanoparticles of topical formulation enhanced the drug efficacy.
Used in various cosmetic products like deodorant, toothpaste, shampoo, hair
conditioner, antiwrinkle creams, etc.
Used in Gene-therapy, ocular and implanatable drug delivery system for prolonged
release of drugs.
60. Nanoparticles as pulmonary drug delivery with better therapeutic efficacy on
bronchial tube.
Nanoparticles as carriers for nasal vaccine delivery.
Nanoparticles in molecular diagnostics (molecular imaging) are used to
characterize and quantify sub-cellular biological processes which include gene
expression, protein-protein interaction, signal transduction and cellular
metabolism.
Nanoparticles as biosensors and bio-labels are employed for determination of
various pathological proteins and physiological-biochemical indicator associated
with disease or disrupted metabolic conditions of body.
61. Preparation of Nanoparticles
Emulsion-solvent evaporation method
Salting out method
Solvent displacement/ precipitation method.
Double emulsion evaporation method
Emulsions diffusion method
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62.
63.
64. heated at high temperatures. This is done to mainly remove
volatile substances and water or oxidise the substance. This
process is also known as the purification process.
66. MONOCLONAL ANTIBODIES
Monoclonal antibodies are laboratory designed proteins
which are used in biomedical research, in diagnosis of
diseases, and in treatment of diseases such as infections
and cancer.
These antibodies are produced by cell lines or animals
that have been immunized with the substance that is
the subject of study.
67. MONOCLONAL ANTIBODIES
Monoclonal antibodies are homogenous (protein)
antibodies used to identify and neutralize foreign
objects like bacteria and viruses recognizing a specific
antigen
68.
69.
70. MONOCLONAL ANTIBODIES
To produce the desired monoclonal antibodies, the cells must
be grown in either of two ways :
1. by tissue culturing in plastic flasks.
2. by injecting into the abdominal cavity of a suitably prepared
mouse.
76. ADVANTAGES OF MONOCLONAL
ANTIBODIES
Hybridoma serves as an immortal source of monoclonal antibodies.
Same quality of antibodies is maintained amongst different production batches.
Highly reproducible and scalable with unlimited production source.
Highly sensitive and specific for Assays.
Antigen or immunogen need not be pure and no need to worry about
maintaining the animals.
Selection helps to identify the right clones against the specific antigens.
77. DISADVANTAGES OF MONOCLONAL
ANTIBODIES
Time consuming (6-9 months for development)
Very expensive and needs considerable efforts to produce them.
Small peptide and fragment antigens may not be good antigens as the
monoclonal antibody may not recognize the original antigen.
Hybridoma culture may subject to contamination.
The system is well developed only for mouse and rat (not for other animals).
More than 99% of the cells do not survive during fusion process-reducing the
range of useful antibodies that can be produced against an antigen.
78. APPLICATIONS OF MONOCLONAL
ANTIBODIES
Protein-protein interaction studies.
Structural analysis such as X-ray .
To identify simple members of protein families.
In cancer diagnosis and treatment.
For prevention of allograft rejection.
In hematopoietic disease therapy.
