Priyanka Shashikant Gavali, M. pharmacy ,first year, Appasaheb birnale collage of pharmacy sangli.

1. The Approach Towards
“Targeted Drug Delivery
System”
1
Presented By :
Gavali Priyanka Shashikant
M . Pharmacy 2st Semister
Department Of Pharmaceutics
Appasaheb Birnale College Of Pharmacy, Sangli .

2. INTRODUCTION
2
 The concept of designing targeted delivery system has been
originated from the Paul Ehrlich.
 Targeted drug delivery system as the name suggests is a
science of specifying the drug moiety to targeted area.
 This type of delivery system is as per with the traditional
drug delivery system as only a targeted area like cancer
cell, kidney, liver etc.
 Targeted drug delivery extensively used for selective and
effective localization of pharmacologically active moiety at
pre-determined target in therapeutic concentration.

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 Products based on such a delivery system are being
prepared by considering the Specific properties of target
cells, Nature of markers or transport carriers or vehicles,
which convey drug to specific receptors.
 Drug delivery and targeting systems under development
aim to minimize drug deprivation and avert harmful side
effects and enhance the availability of the drug at the
disease site.
 Targeted drug delivery means accumulation of
pharmacologically active moiety at desired target in
therapeutic concentration .

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 The drug can be targeted to intracellular sites, virus cells,
bacteria cell and parasites using different scientific
strategies have proven highly effective.
 The minimum distribution of the parent drug to the non
target cells with higher and effective concentration at the
targeted site certainly maximize the benefits of targeted
drug delivery.
 while restricting its access to non-target normal cellular
linings, thus minimizing toxic effects and maximizing
therapeutic index.

5. IDEAL CHARACTERISTICS:
5
Ideally targeted drug delivery system should have
following characteristics:
 Should be biochemically inert (non-toxic).
 Should be non-immunogenic.
 Should be physically and chemically stable in vivo and in
vitro conditions.
 Should have therapeutic amount of drug release.
 Should have minimal drug leakage during transit.
 Predictable and Controllable and rate of drug release.
 Drug release should not influence the drug delivery.
 Therapeutic amount of drug release.

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 Should have restricted drug distribution to target cells or
tissues or organs and should have uniform capillary
distribution.
 Should have Controllable and predictable rate of drug
release and also Drug release should not affect the drug
action.
 Carriers used should be bio-degradable or readily
eliminated from the body without any problem.
 The preparation of the delivery system should be easy or
reasonably simple, reproductive and cost effective.

7. TYPES OF DRUG TARGETING
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As discussed, targeting drug to a specific area not only
increases the therapeutic efficacy of drugs also it aims to
decreases the toxicity associated with drug to allow lower
doses of the drug to be used in therapy.
For the fulfillment of such conditions, Approaches are
used extensively.
(also known as Classification of drug targeting)
1) passive targeting
2) Active targeting

8. 1.PASSIVE TARGETING:
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 It refers to the accumulation of drug or drug-carrier
system at a particular (like in case of anti-cancerous drug)
site whose explanation may be attributed to
physicochemical or pharmacological factors of the disease.
 Hence in case of cancer treatment the size and surface
properties of drug delivery nano-particles must be
controlled specifically to avoid uptake by the
reticuloendothelial system (res), to maximize circulation
times and targeting ability.
 For attaining such conditions the optimal size should be
less than 100 nm in diameter.

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 The surface should be hydrophilic to circumvent
clearance by macrophages (large phagocytic cells of the
RES)2 other examples include targeting of antimalarial
drugs for treatment of leishmiansis, brucellosis, candiadsis.
 Hence Drug delivery systems which are targeted to
systemic circulation are characterized as passive delivery
systems. The ability of some colloid to be taken up by the
reticulo endothelial systems (RES) especially in liver and
spleen made them ideal substrate for passive hepatic
targeting of drugs.

10. 2.ACTIVE TARGETING :
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 Active targeting includes specific modification of a
drug/drug carrier nano systems with active agents having
selective affinity for recognizing and interacting with a
specific cell, tissue or organ in the body .
 In case of cancer, it is achieved by conjugating the
nanoparticle to a targeting component that provides
preferential accumulation of nanoparticles in the tumor-
bearing organ,to tumor, individual cancer cells, intracellular
organelles, or specific molecules in cancer cells.
 Such an approach is based on specific interactions such as
lectin-carbohydrate, ligand-receptor, and antibody antigen.

11. 3.INVERSE TARGETING:
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 In this type of targeting attempts are made to avoid passive
uptake of colloidal carrier by RES and hence the process is
referred to as inverse targeting.
 To achieve inverse targeting, RES normal function is
suppressed by pre injecting large amount of blank colloidal
carriers or macromolecules like dextran sulphate.
 This approach leads to saturation of RES and suppression
of defense mechanism.
 This type of targeting is a effective approach to target
drug(s) to non-RES organs.

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4.Dual Targeting:
In this targeting approach carrier molecule itself have their
own therapeutic activity and thus increase the therapeutic
effect of drug. For example, a carrier molecule having its
own antiviral activity can be loaded with antiviral drug and
the net synergistic effect of drug conjugate was observed.
5.Double Targeting:
When temporal and spatial methodologies are
combined to target a carrier system, then targeting may be
called double targeting. Spatial placement relates to
targeting drugs to specific organs tissues, cells or even subs
cellular compartment whereas temporal delivery refers to
controlling the rate of drug delivery to target site.

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 Target:
Target means specific organ or a cell or group of cells,
which in chronic or acute condition need treatment.
 Drug carrier:
Drug carrier or sometimes also referred to as drug
vectors are the most important entity required for
successful transportation of the loaded drug. Drug vectors
transports and retains the drug and aims deliver it within or
in the vicinity of target. They are made capable of
performing such specific functions which can be attributed
by slight structural modification.

14. Characteristics of an ideal Drug carrier
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 An ideal drug carrier should be able to cross blood brain
barriers and in case of tumour chemotherapy tumour
vasculature.
 It must be recognized by the target cells specifically and
selectively and must maintain the specificity of the surface
ligands.
 The drug ligand complex should be stable in plasma,
interstitial and other biofluids.
 After recognition and internalization, the carrier system
should release the drug moiety inside the target organs,
tissues or cells.

15. Different Type of drug carrier:
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 Drug carrier can be liposome's, monoclonal antibodies and
fragments, modified (plasma) proteins, soluble polymers,
lipoproteins, microspheres and nanoparticles, polymeric
micelles, cellular carriers etc.
 Selection and type of drug carrier depends mainly on the
type of drug, targeted area to which the drug action is
desired and type of disease in which the system is being
used.
 Targeting moieties includes antibodies, lectins and other
proteins, lipoproteins, hormones, charged molecules,
polysaccharides and low molecular-weight ligands.

16. LIPOSOME
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 Liposome's were first described by Bangham in 1965,
while studying the nature of cell membranes.
 The name liposome is derived from two Greek words:
'Lipos‘ meaning fat and 'Soma' meaning body.
 Liposome's are spherical shaped small vesicles that can
produced from cholesterols, non toxic surfactants,
sphingolipids, glycolipids, long chain fatty acids and even
membrane proteins.
 Phospholipids spontaneously form a closed structure when
dissolved in water with internal aqueous environment
bounded by phospholipids bilayer membranes, this vesicular
system is called as liposome.


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 Liposomes are the drug carrier loaded with different
variety of molecules such as small drug molecules,
proteins, nucleotides and even plasmids.

18. Liposome
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 Mechanisms by which Liposomes act are as follows:
 1. Liposome attaches to cellular membrane and appears to
fuse with them, releasing their content into the cell.
 2. They are taken up by the cell and their phospholipids are
incorporated into the cell membrane by which the drug
trapped inside is released.
 3. In case of phagocyte cell, the Liposomes are taken up,
the phospholipids' walls are acted upon by organelles called
lysosomes and the active pharmaceutical ingredients are
released.

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 MECHANISM OF VESICLE FORMATION
 Lipid vesicles are formed when thin lipid films are
hydrated and swelled.
 The hydrated lipid sheets detach during agitation and
form large MLV which prevents the interaction of
water with the hydrocarbon core of the bilayer at the
edges.
 Once the particles formed, it is size reduced by
sonication or by extrusion.

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The liposome's may be classified based on
 1. Structure
 2. Method of preparation
 3. Composition
 4. Conventional liposome
 5. Specialty liposome

21. 1. Classification Based on Structure Vesicle Types
with their Size and Number of Lipid Layer
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Vesicle type Abbreviation Diameter Size No. of Lipid
Layers
Unilamellar UV All size ranges One
Small
Unilamellar
SUV 20-100nm One
Medium
Unilamellar
MUV More than 100nm One
Large
Unilamellar
LUV More than 100nm one
Giant
Unilamellar
GUV More than 1.0 μm One

22. Structural liposome's
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1) Multilamellar vesicle (MLV)
2) Small unilamellar vesicle (SUV)
3) Large unilamellar vesicle (LUV)
Charge on the liposomes, lipid composition and size
(ranging from 20 to 10 000 nm) can be varied and these variations
strongly affect their behaviour in vivo.
Many liposome formulations are rapidly taken up by
macrophages and this can be exploited either for macrophage-
specific delivery of drugs or for passive drug targeting, allowing
slow release of the drug over time from these cells into the general
circulation..

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 A new variety of liposome's known as ‘stealth’liposomes
has recently been developed by incorporating polyethylene
glycol (PEG) which was considered to prevent liposome
recognition by phagocytic cells.
 Such liposome's have longer circulation times and
increased distribution to peripheral tissues in the body.

24. Based on composition and mode of drug delivery
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Conventional liposomes:
 Composed of neutral or negatively charged phospholipids and
cholesterol. Subject to coated pit endocytosis, contents
ultimately delivered to Lysosomes if they do not fuse with the
endosomes, useful for E.E.S targeting; rapid and saturable
uptake by R.E.S; short circulation half life, dose dependent
pharmacokinetics.

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pH sensitive liposomes :
 Composed of phospholipids such as phosphatidyl ethanolamine,
dioleoyl phosphatidyl ethanolamine. Subjected to coated pit
endocytosis at low pH, fuse with cell or endosomes membrane and
release their contents in cytoplasm; suitable for intra cellular
delivery of weak base and macromolecules. Bio distribution and
pharmacokinetics similar to conventional liposomes
Immuno liposomes:
Conventional or stealth liposomes with attached Antibody or
Recognition Sequence. Subject to receptor mediated endocytosis,
cell specific binding (targeting); can release contents extracellularly
near the target tissue and drugs diffuse through plasma membrane to
produce their effects.

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Cationic Liposomes:
 Composed of cationic lipids. Fuse with cell or endosome
membranes; suitable for delivery of negatively charged
macromolecules (DNA, RNA); ease of formation,
structurally unstable; toxic at high dose, mainly restricted
to local administration 2.1.4.
Long circulating or stealth liposomes:
 Composed of neutral high transition temperature lipid,
cholesterol and 5-10% of PEG-DSPE. Hydrophilic
surface coating, low opsonisation and thus low rate of
uptake by RES long circulating half life (40 hrs); Dose
independent Pharmacokinetics 2.1.5.

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Magnetic Liposomes:
 Composed of P.C, cholesterol and small amount of a linear
chain aldehyde and colloidal particles of magnetic Iron oxide.
These are liposomes that indigenously contain binding sites
for attaching other molecules likeantibodies on their exterior
surface. Can be made use by an external vibrating magnetic
field on their deliberate, on site, rapture and immediate release
of their components. 2.1.7.
Temperature (or) heat sensitive liposomes:
 Composed of Dipalmitoyl P.C. These are vesicles showed
maximumrelease at 41o, the phase transition temperature of
Dipalmitoyl P.C. Liposomesrelease the entrapped content at
the targetcell surface upon a brief heating to thephase
transition temperature of theliposome membrane.

28. Components of liposomes
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1) Phospholipids.
2) Cholesterol.
 Phospholipids
 Phospholipids are the major structural components of
biological membranes. The most common phospholipid
used in liposomal preparation is phosphatidylcholine (PC).
 Phosphatidylcholine is an amphipatic molecule containing
-A hydrophilic polar head group, phosphocholine
-A glycerol bridge
- A pair of hydrophobic acyl hydrocarbon chains

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 Molecules of phosphtadityl choline are not soluble in water.
In aqueous media they align themselves closely in planar
bilayer sheets in order to minimize the unfavourable action
between the bulk aqueous phase and the long hydrocarbon
fatty chain. Then the sheets fold on themselves to form
closed sealed vesicles.
 There are several phospholipids that can be used for the
liposome preparation such as Dilauryl phosphotidyl choline
(DLPC), Dimyristoyl phosphotidyl choline (DMPC),
Dipalmitoyl phosphotidyl choline (DPPC), Distearoyl
phosphotidyl choline (DSPC).

30. Cholesterol
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 The role of cholesterol in formulation of liposomes was
given below:8
 Incorporation of sterols in liposome bilayer produces major
changes in the preparation of these membranes.
 Cholesterol itself does not form a bilayer structure.
However, cholesterol acts as a fluidity buffer. It makes the
membrane less ordered and slightly more permeable below
the phase transition and makes the membrane more ordered
and stable above the phase transition. It can be incorporated
into phospholipid membranes in very high concentration up
to 1:1 or even 2:1 molar ratios of cholesterol to
phospholipids.

31. Advantages
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 Biodegradable, biocompatible, flexible, Non ionic
 Can carry both water soluble and lipid soluble drugs
 Increased efficacy.
 Increased stability via encapsulation.
 Reduces toxicity of the encapsulated agents.
 Provide controlled drug delivery
 Drugs can be stabilized from oxidation
 Improve protein stabilization
 Controlled hydration

32. Disadvantages
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 Production cost is high
 Leakage and fusion of encapsulated drug/molecules

33. PREPARATION OF LIPOSOMES
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There are many ways of preparing lipososmes. Some of the
important methods are:
1. Hydration of lipids in presence of solvent
2. Ultrasonication
3. French Pressure cell
4. Solvent injection method
a) Ether injection method
b) Ethanol injection
5. Detergent removal Detergent can be removed by
a) Dialysis

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b) Column chromatography
c) Bio-beads
 6. Reverse phase evaporation technique
 7. High pressure extrusion
 8. Miscellaneous methods
a) Removal of Chaotropic ion
b) Freeze-Thawing

35. Passive loading technique
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1. Mechanical dispersion
 Lipid Hydration Method
 This is the common and most widely used method for the
preparation of MLV. Round bottomed flask can be used for the
preparation.
 The method involves formation of a thin film by drying the
lipid solution and then hydrating the film by adding aqueous
buffer and vortexing the dispersion.
 The hydration step is done at a temperature above the gel
liquid crystalline transition temperature of the lipid or above
the transition temperature of the highest melting component in
the lipid mixture.

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 Depending upon their solubilites the compounds to be
encapsulated are added either to aqueous buffer or to
organic solvent containing lipids.
 The disadvantages of the method include low internal
volume, less encapsulation efficiency and varying size. The
less encapsulation efficiency can be overcome by hydrating
the lipids in presence of immiscible organic solvents like
petroleum ether, diethyl ether.
 Then it is emulsified by sonication. MLVs are formed by
removing organic layer by passing nitrogen.

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 Micro emulsification
 This method is used for preparing small lipid vesicles in
commercial quantities.
 This can be achieved by microemulsifying lipid
compositions using high shearing stress generated from
high pressure homogenizer.
 Microemulsion for biological applications can be produced
by adjusting the speed of rotations from 20 to 200

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 Sonication
 In this method MLVs are sonicated either with a bath type
sonicator or probe sonicator.
 The main drawbacks of this method are
 very low internal volume/encapsulation efficiency,
 degradation of phospholipids,
 exclusion of large molecules,
 metal contamination from probe tip and presence of MLV
along with SUV.

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 French Pressure Cell Method
 The method involves the extrusion of MLV through a small
orifice at 20,000 psi at 4°C.
 The method has several advantages over sonication
method.
 The method is simple, rapid, and reproducible and involves
gentle handling of unstable materials. The resulting
liposomes are larger than sonicated SUVs.
 The disadvantages include difficulty in achieving
temperature and less working volume (about 50 mL
maximum).

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 Membrane extrusion
 In this method, suspension of heterogeneous size liposomes
is passed through a polymer filter having a web-like
construction providing a tortuous-path capillary pore,
network of interconnected, and a membrane thickness of at
least about 100 microns.
 The processed liposomes have a narrow size distribution
and selected average size less than about 0.4 microns.

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 Dried reconstituted vesicles
 In this method the preformed liposomes are added to an aqueous
solution containing drug or mixed with a lyophilized protein,
followed by dehydration of mixture.
 Freeze-Thaw Method
 In this method the SUVs are rapidly frozen, followed by slow
thawing. The sonication disperses aggregated materials to LUV. The
fusion of SUV during the processes of freezing and thawing leads to
the formation of ULV.
 This type of fusion is strongly inhibited by increasing the ionic
strength of the medium and by increasing the phospholipid
concentration. The entrapment efficiencies of 20 to 30% were
obtained by this method.

42. Characterization
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 Particle Size and Surface Charge :
The droplet size and zeta potential of the liposomes was
determined by a Laser Scattering Particle Size Distribution
Analyzer and Zeta Potential Analyzer at room temperature.
One ml of the liposome suspensions was diluted with 14 ml
and 2 ml deionized water, respectively.
 Transmission Electron Microscopy:
Transmission Electron Microscopy (TEM) was used to
visualize the liposomal vesicles. The vesicles were dried on a
copper grid and adsorbed with filter paper. After drying, the
sample was viewed under the microscope at 10–100 k
magnification at an accelerating voltage of 100 kV.

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 4.3. Entrapment Efficiency (%EE) and Loading Efficiency :
 The concentration of MX in the formulation was determined by
HPLC analysis after disruption of the vesicles (liposomes) with
Triton X-100 (0.1% w/v) at a 1:1 volume ratio and appropriate
dilution with PBS (pH 7.4).
 The vesicle/Triton X-100 solutions was centrifuged at 10,000
rpm at C for 10 min. The supernatant was filtered with a 0.45 m
nylon syringe filter.
 The entrapment efficiencies and the loading efficiencies of the
MX-loaded formulation were calculated by (1) and (2),
respectively. (1) Where is the concentration of MX loaded in the
formulation as described in the above methods, and is the initial
concentration of MX added into the formulation.

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 (2) where is the total amount of MX in the formulation and is
the total amount of PC added into the formulation.
 Stability Evaluation of Liposomes:
Liposomes were stored at C and C (room temperature,
RT) for 30 days. Both the physical and the chemical
stability of MX were evaluated. The physical stability was
assessed by visual observation for sedimentation and
particle size determination. The chemical stability was
determined by measuring the MX content by HPLC on
days 0, 1, 7, 14, and 30.

45. Conclusion
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In the development of novel drug delivery system (NDDS),
Liposomes are highly useful for cancer therapy and
vaccination.
 DOXIL, SPI077, Lipoplatin, S-CKD-602 have been approved
or in advance trial of PEGylated liposomal formulations.
 PEG-derivatized liposomes with increased stability can easily
be modified using a wide array of targeting moieties (MAb,
ligands) to deliver the drug specifically to the target tissues
with increasing accuracy.
 The development of liposome delivery to particular
subcellular compartments is a field of great interest in
different fields, such as gene therapy and vaccination.
 .

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 The interaction of stealth liposomes with cell membranes,
and release of the drug in the neighborhood of target tissues
are still under investigation, but some recent studies
indicate that the use of detachable PEG may facilitate cell
penetration and/or intracellular delivery of vesicles.
 PEG-coated liposomes are becoming increasingly
important, giving technological and biological stability to
liposomal systems.

47. APPLICATIONS OF LIPOSOMES
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 Liposomes have great pharmaceutical
applications in oraland transdermal drug delivery
systems. Reduction in the toxic effect and
enhancement of the effectiveness of drugs are
achieved by this drug delivery system. The targeting
of liposome to the site of action takes place by the
attachment of amino acid fragment that target
specific receptors cell. Several modes of drug
delivery application have been proposed for the
liposomal drug delivery system, few of them are as
follows:
 1. Enhancement of solubilisation (Amphotericin-B,
Paclitaxel)

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 2. Protection of sensitive drug molecules (Cytosine
arabinosa, DNA, RNA, Ribozymes)
 3. Enhancement of intracellular uptake (Anticancer,
antiviral and antimicrobial drugs)
 4. Alteration in pharmacokinetics and bio-distribution
(prolonged or SR drugs with short circulatory half
life)

49. A.B.C.P.Sangli.
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50. List of Marketed Liposomal Products
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Sr NO. Product name Drug Manufacturer
1 Abelcet Amphotericin B The liposome
company [USA]
2 Allovecti-711 HLB-B7 plasmid Vical
incorporation[USA]
3 3 AmBisome Amphotericin B NeXatar
pharmaceuticals[US
A]
4 Amphocil Amphotericin B SEQUUS
Pharmaceuticals[US
A]
5 Doxilt Doxorubicin SEQUUS
Pharmaceuticals[US
A]
6 Doxosome Doxorubicin Indian Institute of
chemical
biology[India]

51. Reference
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1. A.Maheswaran1,P.Brindha2,AR.Mullaicharam2,K.Masilamani3
Liposomal Drug Delivery Systems Int. J. Pharm. Sci. Rev. Res., 23(1),
Nov – Dec 2013; nᵒ 55, 295-301.
2. Sarbjeet singh Gujral and Smriti Khatri Basic Concept of Drug Targeting
and Drug Carrier System IJAPBC – Vol. 2(1), Jan- Mar, 2013
1) E.Bhargav, N.Madhuri, K.Ramesh, Anand manne, V. targeted drug
delivery Ravi Volume 3, Issue 1, 150-169.
1. Navneet Kumar Verma1 and Asha Roshan Navneet Kumar Verma and
Asha Roshan2 liposome a targeted drug delivery system.
2. Tarek M. Fahmy, Peter M. Fong, Amit Goyal, and W. Mark Saltzman
targeted drug delivery .

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