CHAPTER 2

LITERATURE REVIEW

2.1 BACKGROUND

Targeted drug delivery system is a process of pharmaceutical compound or some
kind of method for delivering some medication like drugs, only to targeted
organ, tissues or cells, to obtain a therapeutic effect in human or animals
(Punkhardy 2012). Some criteria need to be considered for preparing it, such as
the mature of the transport carriers or vehicles, properties of the target cell and
ligands modulated components. Theres a reason why the drug needs to be
targeted and the reasons are to achieve the wanted therapeutic response and to
avoid the drug from spreading to the other tissues and causes potential toxicity
(Magnani, Rossi et al. 2003) . The advantages of drug targeting are the
concentration of the drug can be increase without effect the non target
compartments and the cost of therapy and drug quantity can be reduced, whereas
the disadvantages of drug targeting is the immunity reaction against the
intravenous administered carrier systems (Punkhardy 2012). Besides, there are
two types of drug targeting, which are active targeting and passive targeting. The
active targeting consists of manipulation of drug carriers to redefine its biofate
and its natural distribution patent is enhanced using chemical, biological and
physical means. While, the passive targeting has the ability of some colloids to
be taken, and offers therapeutic opportunities for delivery of the anti infective
for disease conditions (Barrett, Eglezos et al. 2014).
2.2 DRUG CARRIER

Carrier is important things needed for delivered of the drug that will only deliver
it within the target. It can be either characterize through an inherent or acquired
through the structural modification (Verma 2012). Drug carriers are compounds
that are used to improve the transportation and effectiveness of drug. Its used in
drug delivery system to reduce the toxic effects and can increase the therapeutic
index (PubMed 2012). The water solubility of hydrophobic drugs can be
improved with the presence of drug carrier and can be the most effective use for
drug release (Huang, Song et al. 2014). Besides, the carriers can be categorized
as endogenous and exogenous based on the nature of their origin (Verma 2012).


Table 1: Carriers based on their nature origin
Endogenous Exogenous
o Low density lipoprotein
o High density lipoprotein
o Serum albumin
o Erythrocytes
o Micro particulates
o Soluble polymeric biodegradable
polymeric drug carriers
Source: (Verma 2012)


There are several criteria that are needed for drug carriers in order to be
used in drug delivery system, such as drug carrier should be able to cross
anatomical barriers and tumor vasculature, in case of tumor chemotherapy, and
maintain the specificity and avidity of the surface ligands (Punkhardy 2012).
Also, the drug carrier should be non toxic, non immunogenic and
biodegradable particulate (Punkhardy 2012). Drug carriers come with different
types includes liposomes, niosomes, micelle and lipoproteins.

2.4.1 Liposomes

Liposomes are vesicular systems that can be used as carriers of
amphiphilic and lipophilic drugs. They are spherical vesicles that made
up of phospholipids bilayers (Makeshwar and Wasankar 2013). The
behavior of liposomes in vivo can be affected by variations of charge,
lipid compositions and the size of liposomes (Punkhardy 2012).
Liposomes can help to improve the therapeutic index and rapid
metabolism. But liposomes are lack of stability, have low solubility and
can cause irritation (Verma 2012).












2.4.2 Niosomes

As carriers, niosomes can be said as the best carrier compare to others.
Niosomes are non ionic surfactant vesicles that will enhance the
penetration of drug. They are used for targeting of bioactive agents,
delivery of peptide drugs and transdermal delivery of drug (Verma 2012).
The structure for niosomes is most likely with liposomes, but niosomes
has antibody that attached for drug targeting, and have hydrophilic and
hydrophobic part (Patel 2007).
Figure 1: Liposomes
Hydrophilic Head
Hydrophilic Tail
Source : (Makeshwar and Wasankar
2013)
2.4.3 Polymeric Micelle

Micelle is an aggregate of amphipathic molecules in water, with the non
polar portions in the interior and the polar portions at the exterior surface
that exposed to water. Hydrophobic drugs can be encapsulated or
solubilized into the inner core (Owen, Chan et al. 2012). Polymeric
micelles can be used as drug delivery since drugs have poor solubility in
aqueous solution (Polyscitech 2014).

2.4.4 Lipoproteins

In humans body, lipids are the important molecules, but lipids are non
polar and have poor solubility in water. Therefore, lipoprotein, via the
amphipathic nature of phospholipids can solve the problem. Lipoprotein
is special particles which are used to transport the lipids, while small
amount of fatty acids are transported to blood proteins, called free fatty
acids (Zamora 2014). There are five main classifications of lipoproteins,
High Density Lipoprotein (HDL), Low Density Lipoproteins (LDL),
Chylomicrons, Very Low Density Lipoproteins (VLDL) and Intermediate
Density Lipoproteins (IDL) (Zamora 2014).










Source : (Zamora 2014)
T
T
T
Figure 2: Lipoprotein Structure of
Chylomicrons
2.4.5 Modified (Plasma) Proteins

Plasma consists of water, electrolytes, metabolites, nutrients, proteins and
hormones. The proteins of plasma are a complex mixture that includes
not only simple proteins but also conjugated proteins and various types of
lipoproteins (Namrata 2012). With their properties that are soluble and
have small molecular weight, modified plasma proteins are attractive
carriers, since they can be modified with drugs of interest (Punkhardy
2012).

2.4.6 Monoclonal Antibodies and Fragments

An antibody is a protein used by the immune system to identify and
neutralize foreign objects like bacteria and viruses, and it can recognize
an antigen unique to its target (Muheem 2013). Monoclonal antibodies
are antibodies that are identical because they were produced by one type
of immune cell (Muheem 2013). Antibodies or antibody fragments have
complicated structures that can be used as homing devices for targeting to
liver parenchymal cells (Taylor and Francis 2005).

2.4.7 Soluble Polymers

As for drug targeting delivery system, soluble synthetic polymers have
provided the application and have been widely used. When the drugs are
introduced into the carrier molecule, target moieties also have been
introduced into the carrier molecule. The introduction of drugs into the
polymer may suffice while enhancing permeability retention in tumor
vasculature, for example (Punkhardy 2012).


2.4.8 Microspheres and Nanoparticles

Microspheres are characteristically free flowing powders consisting of
proteins or synthetics polymers which are biodegradable in nature and
ideally having a particle size less than 200 micron (Punkhardy 2012). It is
made up of polymeric, waxy or other protective materials such as gums,
proteins and fats and used as drug carrier matrices for drug delivery. As
for nanoparticles, it has been used as drug delivery since it is
biodegradable, better encapsulation and for the properties, it is less toxic
(Kumari, Yadav et al. 2010). Also, the use of nanoparticles allows one to
change the pharmacokinetic properties of drug without changing the
active compound (Punkhardy 2012). Basically, consider polymeric
nanoparticles as potential carrier due to their applications in drug
targeting to particular organs or tissues.

2.4.9 Resealed Erythrocytes

Erythrocytes have been extensively studied for their potential carrier
capabilities for the delivery of drugs and drug loaded microspheres.
This cell could be used as circulating carriers to disseminate a drug
within a prolonged period of time in circulation or in target or specific
organs, including the liver, spleen and lymph nodes (Verma 2012).

2.4.10 Cellular Carriers

Cellular carriers for drug delivery are used in very different applications
such as cancer therapy, cardiovascular disease and AIDS. The
classifications of biological carriers for drug delivery are based on the use
of cells and cell ghosts (Lanao and Sayalero 2006). Because of their
natural biocompatibility, cellular carriers may have advantages, but they
can easily invoke an immunological response and will encounter
endothelial barriers (Punkhardy 2012).


2.3 NIOSOMES

Niosomes, known as non ionic surfactant vesicles, are synthetic vesicles with
potential technological applications (Hamdy Abdelkader 2014) that are mostly
use as a drug delivery, where the vesicular system used as carriers of hydrophilic
and lipophilic drugs (2010). It has similar structure with liposomes, but made up
by different bilayer. As for niosomes, the bilayer is made up from non ionic
surface active agents (Kshitij B. Makeshwar 2013) and usually stable by adding
cholesterol and small amount of anionic surfactant. By restricting its action to
only target cell, it can improves the therapeutic index of drug and make it less
toxicity. Niosomes are microscopic lamellar structures which are formed on the
admixture of non ionic surfactant of the alkyl or di alkyl polyglycerol ether
class and cholesterol with subsequent hydration in aqueous media (Kr. 2012).

The bilayer vesicles for niosomes can be produce by some surfactants,
even though when interact with water, the surface active agents can produce the
micellar structures (Chandu, Arunachalam et al. 2012). Depending on the method
used for preparation, niosomes can be unilamellar or multilamellar. While the
hydrophobic chains face each other, niosomes is made with its hydrophilic ends
exposed on the outside and inside of the vesicle within the bilayer. Therefore,
within the space that enclosed in the vesicle, the hydrophobic drugs are planted
within the bilayer itself and the hydrophilic drugs are holds by the vesicle (Kr.
2012).









Source : (Patel 2007)

The application of this vesicular systems in cosmetics and for therapeutic
purpose give several advantages, such as niosomes is a water based vesicle
suspension which are better compliance over oil based forms (Chandu,
Arunachalam et al. 2012). Niosomes can fit in with the needs of drug molecule
with wide range of solubilities because of their structure that consists of all
hydrophilic, amphiphilic and lipophilic moieties (Patel 2007). Besides, niosomes
have various types depends on its requirement and controllable, based on its
characteristics such as size, concentration, lamellarity and volume. Since they are
non ionic nature, it can help to reduce the drug toxicity and act as base to
release the drug slowly and controlled (Patel 2007). Niosomes also have the
other advantages and disadvantages, as shown below.

Table 2: Advantages and Disadvantages of Niosomes
Advantages Disadvantages
o Osmotically active and stable
o Increase stability of the entrapped drug
o Increase oral bioavailability of drugs
o Enhance the skin penetration of drugs
o Do not required any special condition
when handling or storage
o Biodegradable, biocompatible and non
immunogenic
o Used for oral, parenteral as well topical
o Time consuming
o Inefficient drug loading
o Physical instability
o Leaking of entrapped drug
o Aggregation
o Fusion
o Hydrolysis of encapsulated drugs
which limiting the shelf life of the
dispersion
Source : (Chandu, Arunachalam et al. 2012)

Hydrophilic Part
Hydrophobic
Antibody
attached drug
for targeting
Figure 3: Niosomes Structure
Niosomes are preparing on hydration of a mixture of a single or double
alkyl chain and non ionic surfactant with cholesterol. It capable of ensnare and
maintain the water soluble solutes to release the ensnared solute slowly (Kr.
2012).

2.3.1 Characteristics of Niosomes

There are three types of niosomes, which are small unilamellar vehicle
(SUV), large unilamellar Vesicles (LUV) and multilamellar vesicle
(MLV). Niosomes can be characterizes based on its size, bilayer
formation, number of lamellae, membrane rigidity and entrapment
efficiency.

2.3.1.1 Size, shape and morphology

Niosomes has similar shape with liposomes, which is spherical in
shape and by using laser light scattering method, the mean
diameter of niosomes can be determined. Besides, the diameter of
niosomes can be determined by using molecular sieve
chromatography, optical microscopy, electron microscopy and
freeze fracture electron microscopy. During the cycle, the
diameter of niosomes can be increase and can attribute to fusion
when the freeze dilution of niosomes occurs (Kazi, Mandal et al.
2010).






2.3.1.2 Bilayer formation, Number of lamellae and membrane rigidity

For bilayer formation, under the light polarization microscopy,
niosomes can be characterized by an X cross formation by
rallying the non ionic surfactant. (Kazi, Mandal et al. 2010).
Whereas, by using nuclear magnetic resonance (NMR)
spectroscopy, small angle X ray scattering and electron
microscopy, the number of lamellae can be determined. And the
membrane rigidity measured through mobility of fluorescence
probe as a function of temperature (Kazi, Mandal et al. 2010).

2.3.1.3 Entrapment efficiency

Unentrapped drug is separated by dialysis, centrifugation or gel
filtration after preparing niosomal dispersion, and the remaining
drug entrapped in niosomes is determined by complete vesicle
disruption and the resultant solution is being analyzed by suitable
method for the drug (Aitha 2012).

2.3.1.4 In vitro release

The use of dialysis tube is one of the methods of in vitro release,
where the vesicle suspension is pipetted into a bag that made up
of the tubing and being sealed. By using a suitable method, the
buffer of the drug content can be analyzed at various time
intervals (Patel 2007).




2.3.2 Compositions of Niosomes

There are two major components in niosomes, non ionic surfactant and
cholesterol, but as basic components needed in niosomes, charge
inducing molecule also must be considered.

2.3.2.1 Non ionic surfactant

The non ionic surfactants orient themselves in bilayer lattices
where the hydrophobic heads align facing aqueous bulk, while the
hydrophobic head align in a way that the interaction with the
aqueous media would be minimized (Shah 2012). In order to
attain thermodynamic stability, every bilayer folds over itself as
continuous membrane so that water interface not exposed. There
are many types of non ionic surfactants are used in the
formation of niosomes such as alkyl ethers, alkyl amides and fatty
acid (Shah 2012).

As for hydrophobic moiety, there is one or two alkyl or
perfluoroalkyl groups or in certain cases a single steroidal group.
A good indicator for a vesicle forming ability of any surfactant is
Hydrophilic Lipophilic Balance (HLB), with the span surfactants
that are compatible with vesicle formation (Rajeshwarrao 2012).


2.3.2.2 Steroids

Steroids are important components of the cell membrane and their
presence in membrane affect the bilayer fluidity and permeability.
Cholesterol is a steroid derivative, which is mainly used for the
formulation of niosomes. Although it may not show any role in
the formation of bilayer, it is important in formation of niosomes
and manipulation of layer characteristics cannot be discarded. The
cholesterol incorporation can affects the properties of niosomes
like membrane permeability, rigidity, encapsulation efficiency
and toxicity. It can prevent the vesicle aggregation by the
inclusion of molecules that stabilize the system against the
formation of aggregates by repulsive steric or electrostatic forces
that leads to the transition from the gel to the liquid phase in
niosomes systems. And then the niosomes becomes less leaky in
nature (Shah 2012).

2.3.2.3 Charge inducers

Some charged molecules are added to niosomes to increase the
stability of niosomes by electrostatic repulsion that can prevents
the aggregation and coalescence. In the niosomal preparations, the
negatively charged molecules used are diacetyl phosphate and
phosphotidic acid, whereas stearylamine and stearyl pyridinium
chloride are used in positively charged molecules (Shah 2012).

2.4 GLYCOSIDES

There are no medicinal plants that containing organic constituents in conjugation
with sugar moiety expect glycosides. They exert therapeutically significant effect
on human and animals. Glycosides are define as organic compound from plants
and animal source, which on enzymatic hydrolysis gives one or more sugar
moieties along with a non sugar moiety. Sugar moiety is called glycon and non
sugar moiety called aglycon (Daniel 2013). The glycine can be attached to the
aglycon in many different ways. The most common bridging atom is oxygen (A
glycoside), but it can also be sulphur (S glycoside), nitrogen (N glycoside)
or carbon (C glycoside). Generally, to distinguish between Glycosides and
Glycosides, it depends on the configuration of the hemiactal hydroxyl group.
The majority of the naturally occurring glycosides are glycosides.


Plants use glycosyltransferases to make a variety of glycoside compounds
that consist of potent chemicals, including medications and poisons. The
glycoside structure renders the chemical inert until the plant must use it. While
animals have to ingest it to use for their own enzymes to sequester it until it can
be eliminated. Diversity in structure makes it difficult to find the general physical
and chemical properties. But some of the properties can be determined, such as:
o Glycosides are water soluble and soluble in alcohols.
o In polar organic solvent, it either insoluble or less soluble
o More sugar units in a glycoside lead to more soluble in polar solvents
o It does not reduce Fehlings solution, but it reduce sugars when
susceptible to hydrolysis, expect for C glycosides.

2.4.1 Classification of Glycosides

Classification of glycosides is according to their therapeutic effects.
a) CHF and cardiac muscles stimulators, such as:
o Digitalis glycosides. For example digoxin, digitoxin and gitoxin
o Ouabain, example strophanthus gratus seeds
o K strophanthin. Example, strophanthus kombe seeds
o Scillaren A, B which isolated from red and white Squill bulbs


b) Laxative group of glycosides
o Sennoside A, B, C, D
o Cascaroside A, B
o Frangulin and glucofrangulin
o Aloin and barbaloin
c) Local irritant group
o Sinigrin
o Sinalbin
d) Anti inflammatory group
o Aloin for acne and peptic ulcer
o Glycyrrhizin

Classification of glycosides according to glycine part
a) Glucose glucoside group like in Sennoside
b) Rhamnose rhamnoside like in frangulin
c) Digitoxose digitoxoside like in digoxin
d) Glucose and rhammnose

Classification of glycosides on the basis of the linkage between glcone
and aglycone part
a) O glycosides the sugar part is linked with alcoholic or phenolic
hydroxyl or carboxyl group
b) S glycosides the sugar attached to a sulfur atom of aglycone such
as in sinigrin
c) N glycosides the sugar linked with nitrogen atom of amino group
of aglycone like nucleosides
d) C glycosides the sugar linked directly to carbon atom of aglycone
like aloin
2.5 VITAMIN E

Vitamin is a group of organic substances that are required in the diet of humans
and animals for normal growth, maintenance of life and normal reproduction.
Vitamins act as catalysts, either the vitamins themselves are coenzymes or they
form integral parts of coenzymes. A substance that functions as a vitamin for one
species does not necessarily function as a vitamin for another species. The
vitamins differ in structure and there is no chemical grouping common to them
all.

Vitamin E, also known as fat soluble vitamin, occurs in at least eight
molecular forms, including tocopherols or tocotrienols. It is a vitamin that
dissolves in fat and can be found in many foods. Vitamin E is an antioxidant
which may protect human cells against the effects of free radicals that produced
when the body breaks down food or by environmental exposures like radiation. It
also plays an important role in immune system and metabolic processes. Besides,
vitamin E supplements may be harmful for people who take blood thinners and
other medicines.











Figure 4: Structure of Vitamin E



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