Introduction

1. INTRODUCTION

1.1 Topical Drug delivery system:

Over the years the treatment of illness has been brought

about, mainly, by oral administration of drugs. At the same
time this mode of administration of drugs has been criticized
for various reasons as the varied conditions of absorption, like
pH changes, presence of enzymes, gastric emptying time and
stability of drugs in the acidic medium and issues related to
adverse effects and bioavailability. Topical drug delivery
remains the most favored mode of administration. There is
abundant literature available about the advantages of topical
drug delivery system over other modes of delivery.

A topical medication is applied the body surface suxh as skin

or a mucous membranes to treat ailments. The word topical
derived from an ancient greek topos (meaning place or
location).

Dermal products are developed to minimize the flux of the

drug through the skin while maximizing its retention in the
skin. However, for both, topical (dermal) and transdermal
products, drugs must penetrate across the stratum cormeum,
the outermost layer of the skin.

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1.10.1Basic components of topical drug delivery system [6,7]

Topical gel may include the following components:

(A) Polymer: Polymer is an integral and foremost important

component of topical gel. Different classes of polymeric
materials have been used to achieve rate controlled drug
delivery.

The following criteria should be satisfied for a polymer to be

used in a topical system:

1. Molecular weight, glass transition temperature, chemical

functionality of polymer must follow diffusion and release of
the specific drug.
2. The polymer should permit the incorporation of large amount
of drug.
3. The polymer should not react, physically or chemically with
the drug.
4. The polymer should be easily manufactured and fabricated
into the desired product.
5. Economical

Various techniques have been employed to modify polymer

properties and drug release rates.

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a) Cross- linked polymers.

b) Polymer blends

(B) Drug substance: judicious choice of the drug plays an

important role in the successful development of a topical product.
The important drug properties that effect its diffusion through the
device as well as through skin are as follows-

Physicochemical properties:

Drug should have a molecular weight less than 500 Daltons.

Drug must have adequate lipophilicity.
A saturated aqueous solution of the drug should have a pH
value between 5 and 9.
a) Biological properties:
The drug should not cause direct skin irritation.
The drug should not stimulate an immune reaction in
the skin.
Drugs which degrade un gastrointestinal tract or are
inactivated by hepatic first pass effect are suitable for
topical delivery.
Drugs which have to be administered for a long time or
which cause adverse effects to non- target tissues can
also be formulated for topical delivery.[7][8]

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1.10.2 Advantages of Topical Drug Delivery:

The topical administration of drug in order to achieve

optimum cutaneous and percutaneous drug delivery has
recently gained an importance because of various advantages:

To avoid gastrointestinal drug absorption difficulties caused

by gastrointestinal pH and enzymatic activity and drug
interactions with food and drinks.
To avoid first pass effect the initial passage of drug
substance through the systemic and portal circulation
following gastrointestinal absorption by digestive and liver
enzymes.
Economic
Reduction of doses as compare to oral dosage forms
Localized effect with minimum side effects.

1.10.3Rational approach to topical formulation:

Topical formulations can be used to manipulate the

barrier functions of the skin.
Direct drugs to viable skin tissues without using oral,
systematic or other routes of therapy.
For skin appendage treatment
Deliver drugs for systemic treatment.

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1.8 Skin:

The human body has two systems that protect it from the
harmful organisms existing in the environment. The internal
defense system destroys microorganisms and bacteria that
have already attacked the body. The external defense
system prevents microbial microorganisms to enter the body.
It serves as a mechanical barrier between the inner part of the
body and the external world (Sherwood, 2007).

1.8.1 Physiology of Skin:

The skin is the heaviest single organ of the body, combines

with the mucosal lining of the respiratory, digestive and
urogenital tracts to form a capsule, which separates the
internal body structures from the external environment. The
pH of the skin varies from 4 to 5.6. Sweat and fatty acids
secreted from sebum influence the pH of the skin surface. It is
suggested that acidity of the skin helps in limiting or
preventing the growth of pathogens and other organisms.
(Banker et al, 1979) The skin has several layers. The
overlaying outer layer is called epidermis; the layer below
epidermis is called dermis. The dermis contains a network of
blood vessels, hair follicles, sweat glands and sebaceous
glands. Beneath the dermis are subcutaneous fatty tissues.

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Bulbs of hair project into these fatty tissues. The study of

cross section (Figure 1) of human skin reveals different layers
of skin.

1.8.2 Epidermis:
It is the outermost layer of the skin, which is approximately
150 m thick. Cells from lower layers of the skin travel
upward during their life cycle and become flat dead cells of
the stratum corneum. The epidermis is composed of-
a) Stratum Germinativum: Basal cells are nucleated,
columnar. Cells of this layer have high mitotic index
and constantly renew the epidermis. This
proliferation in healthy skin balances the loss of dead
horny cells from the skin surface.
b) b) Malphigian Layer: The basal cells also include
melanocytes which produce and distribute melanin
granules to the keratinocytes required for
pigmentation, a protective measure against radiation.
c) Stratum Spinosum: The cells flatten and their nuclei
shrink. They are interconnected by fine prickles and
form intercellular bridge, the desmosomes. These
links maintain the integrity of the epidermis.

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Figure 1.3: Skin components and their function

d) Stratum Granulosum: This layer is above the keratinocytes.

These cells manufacture basic staining particle, the
keratinohylline granules.

e) Stratum Lucidum In the palm of the hand and sole of the

foot, the keratogenous zone forms a thin, translucent layer
immediately above the granule layer.

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f) Stratum Corrneum: At the final stage of differentiation,

epidermal cell construct the most superficial layer of
epidermis, stratum corneum. At friction surface of the body
like palms and soles, it is thick and adapted for weight bearing
while membranous stratum corneum over the remainder of the
body is flexible but impermeable.

1.8.3 Dermis:

Non descriptive region lying in between the epidermis and the

subcutaneous fatty region. It consists mainly of the dense
network of structural protein fibre i.e. collagen, reticulum and
elastin, embeddedin the semigel matrix of
mucopolysaccharidic 'ground substance'. The elasticity of skin
is due to the network or gel structure of the cells. Beneath the
dermis the fibrous tissue opens out and merges with the fat
containing subcutaneous tissues.

1.8.4 Subcutaneous tissue:

This layer consists of sheet of fat rich areolar tissue; known as

superficial fascia, attaching the dermis to the underlying
structure.

1.8.5Skin Appendages:

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The skin is interspersed with hair follicle, associated

sebaceous glands and two types of sweat glands .eccrine and
apocrine. Collectively these are referred to as skin
appendages. (Banker et al, 1979)

The human skin, and especially epidermis, constitutes an

efficient barrier for foreign substances to penetrate the skin.
The thickness of the epidermis varies but is in the order of a
few hundred micrometers and consists of stratum corneum,
stratum granulosum, stratum spinosum and the stratum basale.
The stratum corneum (SC) gives the main contribution to the
barrier function against diffusion across the skin. The stratum
corneum consists of corneocytes surrounded by lipids and is
commonly described by the brick-and-mortar model. Stratum
corneum lipids in general are long-chained and have high
chain-melting temperatures (Silvanderet al; 2006). As a result
of the stratum corneum lipid composition, the lipid phase
behaviour is different from that of other biological
membranes. The hydrocarbon chains are arranged into regions
of crystalline, lamellar gel and lamellar liquid crystal phases
thereby creating various domains within the lipid bilayers.
The presence of intrinsic and extrinsic proteins, such as
enzymes, may also affect the lamellar structure of the stratum
corneum. Water is an essential component of the stratum

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corneum, which acts as a plasticizer to prevent cracking of the

stratum corneum and is also involved in the generation of
natural moisturizing Factor (NMF), which helps to maintain
suppleness (Benson et al, 2005). These infections present
different clinical manifestations such as scaling, fissures,
maceration of skin, hyperkeratosis and vesiculation. A typical
change occurs in the skin thickness, further increasing the
barrier effect of the skin and challenging the penetration of
drugs which accounts for the success of the therapy. In such
circumstances vesicular drug delivery systems might be
helpful.

Figure 1.4: Potential targets or site of action for cosmetics

and drugs

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1.9 Permeation through skin:

The major problem associated with the dermal delivery

system is the excellent barrier property of the skin. This
resides in the outermost layer, the stratum corneum. This
unique membrane is only some 20 m thick but has evolved
to provide a layer that prevents us from losing excessive
amounts of water and limits the ingress of chemicals with
which we come into contact. The precise mechanisms by
which drugs permeate the stratum corneum are still under
debate but there is substantial evidence that the route of
permeation is a tortuous one following the intercellular
channels. The diffusional path length is between 300 and 500
m rather than the 20 suggested by the thickness of the
stratum corneum.

Figure 1.5: penetration pathways along with

differentiation in the major routes

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A diffusing drug has to cross, sequentially, repeated bilayers

and therefore encounters a series of lipophilic and hydrophilic
domains.A molecule that is hydrophilic in nature will be held
back by the lipophilic acyl chains of the lipids and conversely,
a lipophilic permeant will not penetrate well through the
hydrophilic head-group regions of the lipids. Furthermore, the
lipids appear to pack together very effectively, creating
regions in the alkyl chains close to the head groups that have a
high micro viscosity. This creates multiple layers in which
diffusion is comparatively slow.[8]

1.11 Physiological Factors in percutaneous Absorption:

Physiological factors are those that involve the properties of

the barrier itself. Some important factors are: Skin integrity,
Hydration, Temperature, Anatomic location, Age, Diseases.

1.12Drug Factors in Percutaneous Absorption:

The drug factors affecting percutaneous absorption are given

as follows: Molecular size, chemical nature of drug, Partition
coefficient, binding to the skin, Metabolism, Thermodynamic
activity of drug in donor.

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1.13 Formulation Factors in Percutaneous Absorption:

The nature of the dosage form is an extremely important factor

in determination of skin penetration characteristics and various
formulation factors such as [7]:

1) Occlusivity
2) Drug concentration
3) pH
4) solubility
5) surfactant
6) penetration enhancer

Figure 1.6: Sites in skin for niosomes delivery.The

niosomess are shown in green and the drug in red.

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1.3 Vesicular Drug Delivery System: [1, 2, 3]

A number of vesicular drug delivery systems like liposomes,

niosomes and ethosomes have been developed. Every new
system show one or more advantages over the older vesicular
systems. These vesicles were first reported in1965 by
Bingham, and were given the name Bingham bodies which
play a major role in modeling biological membranes, and in
transport and targeting of active agents. Vesicular drug
delivery reduces the cost of therapy by improved
bioavailability of medication, especially in case of poorly
water soluble drugs. They can incorporate both hydrophilic
and lipophilic drugs. Vesicular drug delivery system attempts
to either sustain drug action at a predetermined rate, or by
maintaining a relatively constant, effective drug level in the
body with concomitant minimization of undesirable side
effects.

1.2 Advantage of vesicular drug delivery system: [4]

Prolong the existence of the drug in systemic

circulation, and perhaps, reduces the toxicity if
selective uptake can be achieved due to the delivery
of drug directly to the site of infection.

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Improves the bioavailability especially in the case of

poorly water soluble drugs.
Both hydrophilic and lipophilic drugs can be
incorporated.
Delays elimination of rapidly metabolizable drugs and
thus function as sustain release systems.

1.3 Niosomes:

Niosomes are formations of vesicles by hydrating mixture of

cholesterol and nonionic surfactants. They are formed by self
assembly of non-ionic surfactants in aqueous media as
spherical, unilamellar, multilamellar system and polyhedral
structures in addition to inverse structures which appear only
in non-aqueous solvent.

Niosomes are non-ionic surfactant vesicles obtained on

hydration of synthetic non-ionic surfactants, with or without
incorporation of cholesterol or other lipids. The vesicles are
defined to be composed of or relating to small, saclike bodies.
In niosomes the vesicles forming amphiphile is a non-ionic
surfactant which is usually stabilized by addition of
cholesterol and small amount of anionic surfactant such as
decetyl phosphate. Niosomes and liposomes are equiactive in
drug delivery potential and both increase drug efficacy as

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 Introduction

compared with that of free drug. Niosomes are preferred over

liposomes because the former exhibit high chemical stability
and economy. One of the reasons for preparing niosomes is
the assumed higher chemical stability of the surfactants than
that of phospholipids, which are used in the preparation of
liposomes. Due to the presence of ester bond, phospholipids
are easily hydrolyzed. Delivery of different kind of drugs can
be made targeted by incorporating them in niosomes such as
parenteral, ophthalmic and topical, etc.

1.3.1 Structure of the Niosomes: [10]

Niosomes are lamellar structures that are microscopic in size.

They constitute of non ionic surfactant of alkyl or dialkyl
polyglycerol ether class and cholesterol with subsequent
hydration in aqueous media. The surfactant molecules tends to
orient themselves in such a way that the hydrophilic ends of
the non-ionic surfactant point outwards, while the
hydrophobic ends face each other to form the bilayer.
Niosomes are just like liposomes as per as structure is
concerned but the difference lies in the bilayer creation which
is made up of non ionic surfactants in case of niosomes and
phospholipids in case of liposomes. Following figure show
targeting of drug through niosomes.

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Figure 1.1: Structure of Niosomes

1.3.2 Types of Niosomes: [11]

Depending upon the vesicles size, niosomes are classified as:

i. Small Unilamellar Vesicles (SUV, Size=0.025-0.05um)

ii. Multilamellar Vesicles (MLV, Size0.05um)

iii. Large Unilamellar Vesicles (LUV, Size0.10)

1.3.3Advantages associated with Niosomes: [12]

Drug of different solubilities can be accommodated as

niosomes consisting of amphiphile, lipophilic and
hydrophilic moieties together.

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Different route can be opted to deliver niosomes at

targeted site of action, such as oral, parenteral and
topical.
Surfactants dont need any special or essential
condition for handling and storage.
Niosomes can enhance the bioavailability and
permeation of drug which are poorly absorbed from
skin.
Niosomes entrap the drugs with greater efficiency.
By using niosomes systemic clearance of drug is
delayed thus increasing the therapeutic effect.

[13,14,15]
1.3.4Compositions of Niosomes: Following are the
major components used in the formation of niosomes

A) Cholesterol: Cholesterol provides firmness, structure,

shape and confirmation for the proper formation of niosomal
preparations.

B) Non ionic surfactant: Non ionic surfactants contain

hydrophobic tail and hydrophilic head. The hydrophobic tail
consists of one or two alkyl or perfluoro alkyl and in some
conditions single group which is steroidal in nature [9] .

Generally used non ionic surfactants in the preparations of

niosomes are: Span (Span 60, 40, 20, 85, 80), Tweens (Tween

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20, 40, 60, 80), Brijs (brij 30, 35, 52, 58, 72, 76).Sorbitan
monopalmitate, Sorbitan monolaurate, Sorbitan monostearate,
Polyoxyethylene (20) sorbitan monolaurate, Polyoxyethylene
(20)sorbitan monostearate, Polyoxyethylene (10) stearyl ether,
Polyoxyethylene (20) stearyl ether and Polyoxyethylene (2)
stearyl ether.

C.) Other additives: Niosomes are often included with

membrane additives which are charge inducers because they
deprive the formation of the vesicles, flocculation, fusion and
aggregation. Stearyl amine (SA) and dicetyl phosphate (DCP)
can induce positive and negatives charges and are examples of
these kinds of membrane additives.

1.3.5 Method of preparation of niosomes:

Niosomes can be prepared by different methods. Any method

for the preparation of niosomes is opted out according to
desired entrapment efficiency, vesicle membrane
permeability, number of double layer in aqueous phase, size
and distribution.

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(i) Preparation of Small Unilamellar Vesicles:

(a) Sonication:In this typical method an aliquot of solution

containing drug and buffer is added to the mixture of
surfactant/cholesterol in glass vial of 10ml. At 60oC the
mixture is probe sonicated, to give up niosomes, with titanium
probe by using a sonicator. [21]

Figure 1.2: Niosomes after sonication [21]

(b) Micro Fluidization:

Micro fluidization is a recent technique used to prepare

Unilamellar vesicles of defined size distribution. Usually
Unilamellar vesicles are prepared by this technique by
interacting two high velocity streams in an interaction
chamber containing defined micro channels. Energy of the
system remains restricted to area of niosomes formation along

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a common front. In this technique niosomes formed are of

smaller size, high degree of reproducibility (Khandare et al.,
1994).and uniformity. [22]
(ii) Preparation of Multilamellar Vesicles:

(a) Hand Shaking Method (Thin Film Hydration

Technique):

A mixture of vesicle forming agents and cholesterol is

dissolved in diethyl ether, chloroform or any other organic
volatile solvent in a round bottom flask. At room temperature
organic solvent is removed by using rotary evaporator and a
thin layer is formed on the walls of flask. Multilamellar
niosomes are produced when dried film is rehydrated with an
aqueous phase by gentle shaking. [21]

(b)Transmembrane pH Gradient Drug Uptake Process(

Remote Loading):

Solution of surfactant and cholesterol is formed in

chloroform. Pressure is kept low to evaporate the solvent and
form a thin layer on the wall of round bottom flask which is
hydrated with citric acid by using vortex mixing to get
multilamellar vesicles. Theses vesicles are then are treated
with three freeze thaw cycles and sonicated. Solution of the
drug is added and pH is increased to 7.0-7.2 using 1 molar

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 Introduction

disodium phosphate. Mixture is heated for 10 minutes at 60oC

to obtain niosomes.

(iii) Preparation of Large Unilamellar Vesicles:

(a) Reverse Phase Evaporation Technique (REV):

Solution of surfactant and cholesterol is formed. Aqueous

phase containing drug is added to this mixture and sonicated
at 4-5oC to form a clear gel. Phosphate buffer solution (PBS) is
added and more sonication is done. Temperature is raised to
40oC and pressure is decreased for removing organic phase. A
thick suspension is formed which is further diluted with PBS.
Additional heating is done in the water bath at 60oC for 10
minutes to obtain niosomes.

(b) Ether Injection Technique:

A solution of surfactant and diethyl ether is formed. An

injection needle (14 gauges) is used to add the solution in
aqueous medium containing the drug. Vesicle formation takes
place after the evaporation of organic solvent. Vaporization of
the ether leads to the formation of single layered vesicles. The
particle size of the niosomes formed depend on the conditions
used, and can range anywhere between 50-1000 m.[23]

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1.7 Applications of Niosomes:

1.7.1 Niosomes as Drug Carriers:

Niosomes can be used to carry haemoglobin and iobitridol.

[25,26]
Iobitridol has its role in diagnosis and is used in X ray
imaging technique. Topically niosomes are used as
penetration enhancer and a local reservoir for the release of
compounds having activity for skin.[27]

1.7.2Drug Targeting:

Drugs to be targeted to reticuloendothelial system are

delivered through niosomes. Opsonins (serum factor) are
responsible for the niosomal uptake. This localization is
exploited to treat liver parasitic infection and tumors.[28]
Niosomes can also attach other carrier systems including
antibodies for specific organ targeting because lipid surfaces
can attach immunoglobulins quickly.[29]

1.7.3 Anti-neoplastic treatment:

Administering the drug through niosomes also show the

[30]
benefit of less proliferation rate of sarcoma. Drugs, like
methotrexate entrapped in niosomes, show greater half life,
slower elimination and altered metabolism.[31,32]Some of the

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anti cancer agents which have been studied to deliver through

niosomes include daunorubicin hydrochloride, doxorubicin,
Methotrexate, Bleomycin and Vincristine, etc.[33]

1.7.4. Delivery of Peptide Drugs:

Entrapment in the niosomes can increase the stability of
peptides as studied by Yoshida et al in investigating oral
niosomal delivery of vasopressin and arginine in an invitro
intestinal loop design.[35]
1.7.6 Transdermal Delivery of Drugs through Niosomes:
Drawback of lesser penetration of drugs in skin trough
transdermal route can be overcome by incorporating the drugs
in niosomes. Toxicity studies of nonionic surfactant vesicles
revealed that if chain length of alkyl group is increased it
results in decreased toxicity for topical administration.[36]
1.7.7 Sustained Release:
Niosomal entrapment of the drugs having low therapeutic
index and water solubility is helpful in maintaining
bioavailability in systemic circulation. Sustained release of
paclitaxel (PCT) encapsulated with niosomes was observed
after its oral administration in Wistar rats.[37]

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Table 1.1: Gel forming polymers

Natural Proteins Collagen

polymers Gelatin
Polysaccharides Agar
Alginic acid
Carrageenan
Tragacanth
Pectin
Guar gum
Xanthin
Gellun gum
Gum acassia
Semi- Cellulose derivative Carboxymtheyl
synthetic cellulose
polymers Methylcellulose
Hydroxylpropyl
cellulose
Hydroxylpropyl
methyl cellulose
Hydroxyethyl
cellulose
Synthetic Carbomer Carbopol 934
polymers Carbopol 940
Carbopol 941
Poloxamer Polyacrylamide
Polyvinyl alcohol
Polyethylene and it
co polymer

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