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. There’s 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. It’s 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 Tail

Hydrophilic Head

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 human’s 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 TT

TT

TC

CC

TT

T T

T TTT

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 stableo Increase stability of the entrapped drugo Increase oral bioavailability of drugso Enhance the skin penetration of drugso Do not required any special condition

when handling or storageo Biodegradable, biocompatible and non

– immunogenico Used for oral, parenteral as well topical

o Time consumingo Inefficient drug loadingo Physical instabilityo Leaking of entrapped drugo Aggregationo Fusiono Hydrolysis of encapsulated drugs

which limiting the shelf life of the dispersion

Source : (Chandu, Arunachalam et al. 2012)

Figure 3: Niosomes Structure

Antibody attached drug for targeting

Hydrophobic

Hydrophilic Part

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 α – Glycosides and

β – Glycosides, it depends on the configuration of the hemiactal hydroxyl group.

The majority of the naturally occurring glycosides are β – 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 Fehling’s 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

(2010) Niosomes. Pharma Change info

Aitha, S. (2012). Liposomes and Niosomes.

Barrett, P., et al. (2014). "Drug Targeting." 2014, from http://www.starpharma.com/drug_delivery/drug_targeting.

Chandu, V. P., et al. (2012). "Niosomes: A novel Drug Delivery System." International Journal of Novel Trends in Pharmaceutical Sciences 2.

Daniel, K. (2013). Glycoside.

Hamdy Abdelkader, A. W. G. A. a. R. G. A. (2014) Drug Delivery; Recent advances in non-ionic surfactant vesicles (niosomes): self-assembly, fabrication, characterization, drug delivery applications and limitations. Informa Healthcare

Huang, L., et al. (2014). "A novel targeting drug carrier to deliver chemical bonded and physical entrapped anti-tumor drugs." International Journal of Pharmaceutics 466(1–2): 52-57.

Kazi, K. M., et al. (2010). "Niosome: A future of targeted drug delivery systems." Journal of Advanced Pharmaceutical Technology and Research.

Kr., G. (2012). "Niosome." Retrieved April, 2014, from http://www.slideshare.net/gaurav11288/niosome-15452751.

Kshitij B. Makeshwar, S. R. W. (2013). "Niosome: A novel Drug Delivery System." Asian Pharma Press: 16-20.

Kumari, A., et al. (2010). "Biodegradable polymeric nanoparticles based drug delivery systems." Colloids and Surfaces B: Biointerfaces 75(1): 1-18.

Lanao, J. M. and M. L. Sayalero (2006). Cells and Cell Ghosts as Drug Carriers. Nanoparticulates as Drug Carrier. V. P. Torchilin. London, Imperial Collage Press: 15.

Magnani, M., et al. (2003). Targeting Drug Loaded Red Blood Cells. Erythrocyte Engineering for Drug Delivery and Targeting. M. Magnani: 29.

Makeshwar, K. B. and S. R. Wasankar (2013). "Niosome: A Novel Drug Delivery System." Asian Pharma Press 3(1): 16 - 20.

Muheem, A. (2013). "Antibodies Drug Delivery System." Retrieved April, 2014, from http://www.slideshare.net/MUHEEM_007/antibodies-drug-delivery-system.

Namrata, C. (2012). "Plasma Proteins - Chemistry, Functions and Clinical Significance." Retrieved April, 2014, from http://www.slideshare.net/namarta28/plasma-proteins.

Owen, S. C., et al. (2012). "Polymeric micelle stability." Nano Today 7(1): 53-65.

Patel, R. P. (2007). "Niosomes: An Unique Drug Delivery System."

Polyscitech (2014). "Polymer Micelles." 2014, from http://polymermicelles.com/.

PubMed (2012). "Reference MD." Drug Carriers. Retrieved April, 2014, from http://www.reference.md/files/D004/mD004337.html.

Punkhardy (2012). DRUG TARGETING: BASIC CONCEPTS AND DRUG CARRIER SYSTEMS A REVIEW. DRUG TARGETING: BASIC CONCEPT

Rajeshwarrao, P. (2012). Niosomes - An Overview.

Shah, S. (2012). Niosome.

Taylor and Francis (2005). Introduction to Advanced Drug Delivery and Targeting. Drug Delivery and Targeting. A. M. Hillery, A. W. Lloyd and J. Swarbrick. London: 114.

Verma, N. (2012). Drug Targeting. H. C. o. Pharmacy.

Zamora, A. (2014). "Lipoproteins: Good cholesterol (HDL), Bad cholesterol (LDL)." Retrieved April, 2014, from http://www.scientificpsychic.com/health/lipoproteins-LDL-HDL.html.