Chapter 1 Introduction

Introduction

Semecarpus Anacardium Linn.

Plants are the basis of life on earth and are central to people’s livelihood. The people generally
depends upon nearby forest areas to supply their needs such as medicine, timber, fuel-wood,
wood, wild vegetables and many more. For thousands of years, cultures around the world
have used herbs and plants to treat illness and maintain health. The Indian
knowledge of herbal medicines is gaining widespread acceptance globally. In Ayurveda,
almost all medicinal preparations are derived from plants. Herbs and plants are valuable not
only for their active ingredients but also for their minerals, vitamins, volatile oils,glycosides,
alkaloids, acids, alcohols, estersetc. Higher plants, as sources of medicinal
compounds continue to play a dominant role in maintenance of human health since
antiquities. Over 50% of all modern clinical drugs are naturally originated1 and natural
products play an important role in drug development programmes of the pharmaceutical
industry. According to Edwards 3, about two thirds of 50, 000medicinal plants in use are still
harvested from the natural habitat

Semecarpus Anacardium Linn” can be considered to be a best, versatile and most commonly
used herb as a household remedy. The word “Semecarpus “is derived from a Greek word
called “simeion” meaning marking or tracing and “carpus” meaning nut. “Anacardium” refers
to cardium that means heart shaped. This plant is well known for its medicinal value in
Ayurveda and Siddha system of medicine. It is also called as marking nut as in the past it was
used by washer men to mark cloth, as it tends to impart a water insoluble mark to the cloth. In
India,it is mostly distributed and found in sub-Himalayan regions, Tropical region, Bihar,
Bengal, Orissa and central parts of India. It is also found in Western peninsula of East
Archipelago, Northern Australia. It is sweet and astringent in taste. It is extremely heat
generating substance. It can be used externally as well as internally. But before using, it
should undergo purification as it may cause toxic effects. The most common method used for
purification is “shodhansanskara or shodhana”. The fruits, seeds and oil of Semecarpus
Anacardium have great medicinal value and are used to treat a wide range of diseases. The
chemical constituents present in Semecarpus Anacardium are Bhilawanol (Alkaloid), phenolic

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compounds, biflavonoids, sterols and glycosides. It is used traditionally for hair care, hair
growth and hair dyeing. It also shows Anti-Cancer activity, Neuroprotective Activity, Anti-
inflammatory activity, Anti-oxidant activity, Anti-microbial activity, Anti-spermatogenic
activity, Anti-atherogenic activity and hypoglycemic activity.

 Synonyms for semecarpus anacardium:

Hindi : Bhilwa, Billar, Bhelwa, Bhilawa

Sanskrit : Bhallataka, Antahsattva,
Arusharah, Aruskara, Arzohita,
Bhallata, Viravrksa, Vishasya,
Bhallatakah
English : Marking Nut Tree, Marsh Nut,
Oriental Cashew Nut
Tamil : Erimugi (Erimuki)
Telugu : Nallajeedi, Bhallatamu
Gujarati : Bhilamu, Bhilamo
Marathi : Bibba, Bhillava
Oriya : Bhollataki, Bonebhalia, Amberi
Urdu : Baladur, billar, bhilavan
Assamese : Bhala
Nepali : Bhalaayo

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Fig. 1:- Plant of Semecarpus anacardium Linn.

 CLASSIFICATION:

Kingdom:Plantae

Sub-kingdom: Tracheobionta

Super division: Spermatophyta

Division: Magnoliophyta

Class: Magnoliopsida

Subclass: Rosidae

Order: Sapindales

Family: Anacardiaceae

Genus: Semecarpus

Species: Anacardium

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Fig 2: seed, nut or fruit of bhilawa.

L
(3) (4)

Fig: (3) Leaf and (4) Stem.

 Plant Morphology/ Botanical Description

It is a medium sized deciduous tree, growing up to 10-15 metres in height. The plant grows
naturally in tropical and dry climate. Bark is grey in colour and exudes an irritant secretion
on incising. The leaves are simple alternate, 30-60 cm long and 12-30 cm broad. They are
glabrous above and pubescent beneath. The flowers are greenish white, in panicles. Fruits
are ripe between December to March and are 2-3 cm broad, ovoid and smooth with a
lustrous black. Flowering occurs in June and then onwards the plant bears fruits. It has got

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no specific soil affinity and Easily recognized by large leaves and the red blaze exuding resin,
which blackens on exposure

 Microscopic structure
Fruit - Pericarp differentiated into epicarp, mesocarp and endocarp; in longitudinal
section pericarp shows outer epicarp consisting of single layer of epidermal cells
which are elongated radially and lignified. Characteristic glands are found in pericarp
which exude oil globules and arise as small protuberances in epicarp. Due to pressure
exerted by cells of mesocarp, some of epidermal cells and cuticle rupture and oil globules
exude from oil glands; mesocarp has a very broad zone, 30-40 layers thick, composed mostly
of parenchymatous cells having lysigenous cavities and fibro-vascular bundles, below
epidermis a few outer cells of parenchyma smaller as compared to rest; rosette crystals of
calcium oxalate found scattered in parenchymatous cells, some cells get dissolved and form
lysigenous cavities which increase in size with maturity of fruit, cavities do not have any
special lining and contain an acrid and irritant yellowish oily secretion; 19 endocarp consists
of two distinct layers, innermost prismatic having very much
elongated radial walls, being highly thickened, the outer layer is shorter and thinner than
prismatic layer but the cells similar to the former; number of mesocarp parenchyma
contain rosette crystals of calcium oxalate and oil drops in oil glands; lysigenous cavities of
mesocarp contain oily vesicating substance, insoluble in water and soluble in alcohol, ether,
chloroform.

 Pharmacology
Number of drugs are derived from Semicarpus anacardium plant which are available in
market against several disease like skin disease, tumors, malignant growth, fungal
disease, excessive menstruation, vaginal discharge, fever, haemoptysis, constipation
and intestinal parasites. Anti-inflammatory, antiarthritic, antioxidant
activity, hypolipidemic, hypoglycaemic, antiatherogenic, anti-inflammatory, antifertility,
neuro-protective activities of Semecarpus anacardium nut with different solvents are also
reported on experimental animal and cell lines.

 Properties
Bhallataka is sweet and astringent in taste. It is extremely heat generating.

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 Traditional Uses
Bhallataka is used for hair care in traditionalsystem of medicines. It is used for dyeing, and
promoting hair growth in folk medicine. It was used by washermen to mark cloth before
washing, as it imparted a water insoluble markto the cloth.

 Active Principles/ Phytochemistry

The most significant components of the S. anacardium Linn. are bhilwanols, phenolic
compounds, 4,5 biflavonoids,6 sterols and glycosides. 4,7 alkaloid, Bhilawanol has
been isolated from oil and seeds. Bhilwanol from fruits was shown to be a mixture of cis
and Trans isomers of ursuhenol. Oil from nuts, bhilavinol, contains a mixture of phenolic
compounds mainly of 1,2-dihydroxy-3 (pentadecadienyl-8, 11) benzene and 1,2-
dihydroxy-3 (pentadecadienyl-8', 11’)- benzene8. On exposure to air, phenolic
compounds get oxidized to Quinones. The oxidation process can be prevented by
keeping the oil under nitrogen. Nut shells contain the biflavonoids: biflavones A, C, A1, A2,
tetrahydrorobustaflavone, B (tetrahydromentoflavone) 9, jeediflavanone, semecarpuflavan
12,13 and gulluflavone Other components isolated are anacardic acid,
cardol, catechol, fixed oil, semecarpetin, anacardol, anacardoside and semecarpol. The
kernel oil contains oleic acid- 60.6%; linoleic acid- 17.1%; palmitic acid- 16%; stearic acid-
3.8%; arachidic acid- 1.4%.

 Kalpaamruthaa
(KA), an indigenous-modified Siddha formulation, consists of SA nut milk
extract and fresh dried powder of Emblica officinalis (EO) fruit along with honey.
Kalpaamrutha was found to be nontoxic up to the dose level of 2000 mg/kg.

 Folk medicine
Semecarpus anacardium is a one of most popular medicinal valuable plant in world of
Ayurveda. Charak, Sushrut and Vagbhatt, the main three treatises of Ayurveda have
described the medicinal properties of Semecarpus anacardium and it’s formulation.
Bhallataka is used both, internally as well as externally. The fruits, their oil and the seeds
have great medicinal value, and are used to treat the wide range of diseases. Detoxified
nut of SA were used in Ayurveda for skin diseases, tumors, malignant growths, fevers,

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haemoptysis, excessive menstruation, vaginal discharge, deficient lactation, constipations,

intestinal parasites. (Charaka, Sushruta), Before using Semecarpus anacardium for
medicinal purpose, it’s necessary to detoxifying it because it is highly toxic for body
if not use properly. Number of detoxification methods have been recorded the most
common detoxification method involves rubbing of Semecarpus anacardium seeds
with brick powder and then washing the seeds with warm water. The second common
recommended method is to tie the seeds in muslin cloth and suspended it in a vessel
containing coconut water, then heated for about 3 hrs continuously. The seeds oil is
mainly used for medicinal purpose. Seeds are generally boiled in milk and the milk is
consumed. The seeds oil is used in minimum possible quantity, typically mixed with food
items or mustard oil. Externally, the oil is applied on wounds to prevent pus formation
and better healing of wounds, It works well, when medicated with garlic, onion and
ajavayana in sesame oil. In glandular swellings and filariasis, the application of its oil
facilitates to drain out the discharges of pus and fluids
and eases the conditions. It is also use as a brain tonic, blood purifier
and haematinic tonic. The combination, Semecarpus anacardium, Terminalia chebula,
Sesamum indicum L. seeds powders with jaggery, has excellent results in chronic
rheumatic disorders. In dysmenorrheal (painful menstruation) and oligomenorrhea (scanty
menstruation), the medicated milk or its oil is salubrious. It reduces the urinary output,
hence beneficial in diabetes of kapha type, Bhallataka is the best rejuvenative (rasayana)
for skin ailments, vata disorders and as a preventive measure to increase the body resistance.
Winter is the best season for its usage.

 Dose - 1.2 g. of the drug in Ksirapaka form.

 Powder - Dark-brown; shows rosette crystals of calcium oxalate and oil globules.

 Identity, purity and strength

Contain Percent

Foreign matter 1%

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Acid-insoluble ash 0.5 %

Total Ash 4%

Water-soluble extractive 5%

Alcohol-soluble extractive 11 %

 Table no. 1: Identity, purity and strength of bhilawa.

 Current status

Due to the toxic activities, large size, allergic effect are loss of traditional knowledge
generation by generation, most of the peoples don’t know the importance and proper use of
Semecarpus anacardium, that’s why now a day’s peoples are avoiding to gardening it in
surrounding area. now Semecarpus anacardium plant has become a wild plant, it
found only in forest area. Day by day the quantity of this plant is decreasing, it is need to
aware it's importance to society otherwise it will be become rare and we will loss one of
important plant from the dictionary of Indian medicinal plants.

Inflammation

Inflammation (from Latin: inflammatio) is part of the complex biological response of body
tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective
response involving immune cells, blood vessels, and molecular mediators. The function of
inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues
damaged from the original insult and the inflammatory process, and initiate tissue repair.

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Fig: Major inflammation spots in human body

The five classical signs of inflammation are heat, pain, redness, swelling, and loss of function.
Inflammation is a generic response, and therefore it is considered as a mechanism of innate
immunity, as compared to adaptive immunity, which is specific for each pathogen. Too little
inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g.
bacteria) and compromise the survival of the organism. In contrast, chronic inflammation may
lead to a host of diseases, such as hay fever, periodontitis, atherosclerosis, rheumatoid
arthritis, and even cancer (e.g., gallbladder carcinoma). Inflammation is therefore normally
closely regulated by the body.

Inflammation can be classified as either acute or chronic. Acute inflammation is the initial
response of the body to harmful stimuli and is achieved by the increased movement of plasma
and leukocytes (especially granulocytes) from the blood into the injured tissues. A series of
biochemical events propagates and matures the inflammatory response, involving the local
vascular system, the immune system, and various cells within the injured tissue. Prolonged
inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells
present at the site of inflammation, such as mononuclear cells, and is characterized by
simultaneous destruction and healing of the tissue from the inflammatory process.

Inflammation is not a synonym for infection. Infection describes the interaction between the
action of microbial invasion and the reaction of the body's inflammatory response — the two

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components are considered together when discussing an infection, and the word is used to
imply a microbial invasive cause for the observed inflammatory reaction. Inflammation on the
other hand describes purely the body's immunovascular response, whatever the cause may be.
But because of how often the two are correlated, words ending in the suffix -itis (which refers
to inflammation) are sometimes informally described as referring to infection. For example,
the word urethritis strictly means only "urethral inflammation", but clinical health care
providers usually discuss urethritis as a urethral infection because urethral microbial invasion
is the most common cause of urethritis.

It is useful to differentiate inflammation and infection as there are many pathological

situations where inflammation is not driven by microbial invasion – for example,
atherosclerosis, type III hypersensitivity, trauma, and ischemia. There are also pathological
situations where microbial invasion does not result in classic inflammatory response—for
example, parasitosis, eosinophilia.

 Some general characteristics of inflammation are as follows:

1. The inflammatory process is redundant and complex. This makes it a challenging
subject to study. You will see that many mediators of inflammation have the same
functions and many mediators have multiple functions. Also, the same mediator may
have different effects on different tissues.
2. The process is continuous over a period of time. Peracute, acute, subacute, and
chronic are terms used to describe different stages of inflammation.
3. Inflammation is caused by a stimulus and removal of the stimulus should result in
abatement of inflammation. If it doesn’t get fixed in the acute period, it becomes
chronic.
4. Blood is the primary delivery system for inflammatory components.
5. Inflammation is on a continuum with the healing process.

The four principal effects of inflammation (rubor, tumor, calor et dolor) were described nearly
2,000 years ago by the Roman Aulus Cornelius Celsus, more commonly known as Celsus.

o Redness (rubor)

An acutely inflamed tissue appears red, due to dilatation of small blood vessels within the
damaged area (hyperemia).

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o Swelling (tumor)

Swelling results from edema, the accumulation of fluid in the extravascular space as part of
the inflammatory fluid exudate, and to a much lesser extent, from the physical mass of the
inflammatory cells migrating into the area.

o Heat (calor)

Increase in temperature is readily detected in the skin. It is due to increased blood flow
through the region, resulting in vascular dilation and the delivery of warm blood to the area.

o Pain (dolor)

Pain results partly from the stretching and distortion of tissues due to inflammatory edema
and, in part from some of the chemical mediators of acute inflammation, especially
bradykinin and some of the prostaglandins.

o Loss of function

Loss of function, a well-known consequence of inflammation, was added by Virchow (1821-

1902) to the list of features described in Celsus’ written work. Movement of an inflamed area
is inhibited by pain, either consciously or by reflexes, while severe swelling may physically
immobilize the affected area.

 Causes of Inflammation

o Microbial infections

One of the most common causes of inflammation is microbial infection. Microbes include
viruses, bacteria, protozoa, fungi and various parasites. Viruses lead to death of individual
cells by intracellular multiplication, and either cause the cell to stop functioning and die, or
cause explosion of the cell (cytolytic), in which case it also dies. Bacteria release specific
toxins – either exotoxins or endotoxins. What’s the difference? Exotoxins are produced
specifically for export (like anthrax toxins or tetanus toxins) whereas endotoxins are just part
of the cell walls of Gram negative bacteria and they do terrible things to the body too but they
aren’t as specific in their actions as the exotoxins.

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o Hypersensitivity reactions

A hypersensitivity reaction occurs when an altered state of immunologic responsiveness

causes an inappropriate or excessive immune reaction that damages the tissues. The types of
reaction will be discussed in more detail later (In the lesson on Immune Mediated
Inflammation).

o Physical agents, irritant and corrosive chemicals

Tissue damage leading to inflammation may occur through physical trauma, ultraviolet or
other ionizing radiation, burns or excessive cooling ('frostbite'). Corrosive chemicals (acids,
alkalis, oxidizing agents) provoke inflammation through direct tissue damage. These chemical
irritants cause tissue damage that leads directly to inflammation.

o Tissue necrosis

Death of tissues from lack of oxygen or nutrients resulting from inadequate blood flow
(infarction) is a potent inflammatory stimulus. The edge of a recent infarct often shows an
acute inflammatory response.

 Effects of Inflammation

The effects of inflammation can be both local and systemic. The systemic effects of acute
inflammation include fever, malaise, and leukocytosis. The local effects are usually clearly
beneficial, for example the destruction of invading microorganisms, but at other times they
appear to serve no obvious function, or may even be harmful.

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Beneficial effects of inflammation Harmful effects of inflammation

Dilution of toxins Persistent cytokine release

Entry of antibodies Destruction of normal tissues
Fibrin formation Swelling
Delivery of nutrients and oxygen Inappropriate inflammatory response
Stimulation of immune response

Table: Effects of inflammation

 Systemic Effects of Inflammation

Both acute and chronic inflammation, even if well localized, can have effects on the whole
body. The main ones are:

1. Leukocytosis

Leukocytosis is a common feature of inflammatory reactions. Leukocytosis means that there

is an abnormally high number of circulating white blood cells. A general rule is that increased
neutrophils indicate a bacterial infection whereas increased lymphocytes are most likely to
occur in viral infections. This is one reason why we often do a CBC when an animal is sick –
gives us more clues.

2. Fever

Fever is a common systemic response to inflammation. Fever is most often associated with
inflammation that has an infectious cause, although there are some non-infectious febrile
diseases. Fever is coordinated by the hypothalamus and involves a wide range of factors. Here
are some of the contributors to fever:

3. Endotoxemia

Sepsis is the term used for disease due to toxic bacterial products circulating in the blood.
Endotoxemia specifically refers to circulating gram-negative bacterial toxic products (LPS).
There are some cell wall products released from gram-positive bacteria that can have a similar
toxic effect.

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 Acute inflammation

In the early stages of inflammation, the affected tissue becomes reddened, due to increased
blood flow, and swollen, due to edema fluid. These changes are the result of vascular response
to inflammation. The vascular events of the acute inflammatory response involve three main
processes:

1. changes in vessel caliber and, consequently, blood flow (hemodynamics)

2. increased vascular permeability and
3. formation of the fluid exudates.

 Chronic Inflammation

Chronic inflammation, like its acute cousin, is a host response to an inciting stimulus. There
are, however, some distinct differences. First and foremost is the time factor. Chronic
inflammation is considered to be inflammation of prolonged duration - weeks to months.
Second, rather than being just exudative, chronic inflammation usually is productive or
proliferative. Chronic inflammation is rarely gooey. Cells in the chronic inflammatory process
tend to produce substances that add new tissue, such as collagen and new blood vessels. Many
of these changes also represent the repair process and there is a blurry continuum between
chronic inflammation and the whole repair process. In general, chronic inflammation is
characterized by inflammation, tissue destruction, and attempts at repair all happening at
once.

Grossly, chronic inflammation does not have as much rubor (redness) or calor (heat) as in the
acute reaction. Also, exudates aren’t so grossly apparent as they are in acute inflammation.
Because of the fibroplasia and neovascularization, areas affected by chronic inflammation
tend to be slightly swollen and firm. If fibrosis is extensive the lesions can be large and
disfiguring. Fibrosis (granulation tissue) is the best indicator that the inflammatory response is
chronic.

Chronic inflammation tends to occur under the following conditions:

o Infections by organisms which are resistant to killing and clearing by the body tend to
cause chronic inflammation. Such persistent organisms include some of the higher
bacteria (including mycobacteria), fungi, and quite a few metazoan parasites.

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o Repeated bouts of acute inflammation can result in a chronic reaction.

o Prolonged exposure to toxins can cause chronic inflammation.
o Chronic inflammation is a common component in many of the autoimmune diseases.
Because the reaction is against a host epitope, which is always present, the
inflammation is by definition chronic and persistent.
o Because chronic inflammation doesn’t ooze, rather its exudates tends to be kind of
solid and white or greyish and it looks the same no matter what the cell types, the only
way to add an exudative moniker is to see the histology.

Anti-inflammatory

Historical developments

The anti-inflammatory analgesic drugs have their origins in the use of extracts of salicylate-
containing plants, especially the bark of the willow tree (Salix alba and other members of the
Salix species), in the treatment of fever, pain and inflammatory conditions (Rainsford, 2004a).
These treatments date from early Chinese, Indian, African and American eras and were
initially described in some detail by Roman and Greek medical authorities. During the 17th–
19th centuries, the popularity of these plant extracts became evident following the publication
by the Reverend Edward Stone in the 17th century of probably what were the first clinical
trials of willow bark extract for the treatment of agues or fever. Isolation of the
principallyactive salicylate components followed in the early 19th century and with advances
in chemistry in Europe and developments in the German chemical industry in the mid-late
19th century, there followed the synthesis or salicylic and acetylsalicylic acids, the latter being
highly successfully commercialised by Bayer AG as Aspirin™ over 100 years ago. The
historical aspects of the origins and development of aspirin and other salicylates are told in
detail elsewhere (Rainsford, 2004a). During the period of the exploitation of the by-products
of the coal tar industry in Germany in the 19th century came also the development of
antipyretic/analgesic agents, antipyrine, aminopyrine, phenacetin and later following
recognition of paracetamol (acetaminophen) as the active metabolite of phenacetin, this was
eventually commercially developed for use as an analgesic/antipyretic agent in the 1950’s
(Prescott, 2001).

Nanogel

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The term ‘nanogels’ defined as the nanosized particles formed by physically or chemically
crosslinked polymer networks that is swell in a good solvent. The term “nanogel”
(NanoGel™) was first introduced to define cross-linked bifunctional networks of a polyion
and a nonionic polymer for delivery of polynucleotides (cross-linked polyethyleneimine (PEI)
and poly (ethylene glycol) (PEG) or PEG-cl-PEI) (Kabanov and
Vinogradov, 2008). Sudden outbreak in the field of nanotechnology have introduced the need
for developing nanogel
systems which proven their potential to deliver drugs in controlled, sustained and targetable
manner. With the emerging field of polymer sciences it has now become inevitable to prepare
smart
nano-systems which can prove effective for treatment as well as clinical trials progress.

 Nanogels are superior drug delivery system than others because

1. The particle size and surface properties can be manipulated to
avoid rapid clearance by Phagocytic cells, allowing both
passive and active drug targeting.

2. Controlled and sustained drug release at the target site,

improving the therapeutic efficacy and reducing side effects.
Drug loading is relatively high and may be achieved without
chemical reactions; this is an important factor for preserving
the drug activity.

3. Ability to reach the smallest capillary vessels, due to their tiny

volume, and to penetrate the tissues either through the
paracellular or the transcellular pathways (Gonçalves et al.,
2010).

4. Highly biocompatible and biodegradable. A model of drug

release from nanogel is given in figure 1.

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Fig no. 6: Drug release model from nanogel.

ROUTES OF ADMINISTRATION

 Oral,
 pulmonary
 nasal
 parenteral
 intra-ocular
 topical

 PROPERTIES OF NANOGELS

o Biocompatibility and degradability

Nanogel based drug delivery system is highly
biocompatible and biodegradable due to this characteristics it is
highly promising field now a days.

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o Swelling property in aqueous media

The most beneficial feature of Nanogels is their rapid
swelling/de-swelling characteristics.

o Higher drug loading capacity

The properties of higher drug loading capacity of
nanogels depend on the functional group present in the polymeric
unit. These functional groups have a tremendous effect on drugcarrying
and drug-releasing properties, and some functional groups
have the potential to conjugate with drugs/antibodies for targeting
applications.
These pendent functional groups of polymeric chains
contribute toward establishing hydrogen bonding or van der Waals
forces of interactions within the gel network and thus facilitate the
drug-carrying efficiency. Moreover, the presence of functional
groups at interface with drug/protein molecules is also responsible
for higher loading.

o Particle size
Nanogels typically range in size of 20–200 nm in
diameter and hence are effective in avoiding the rapid renal
exclusion but are small enough to avoid the uptake by the
reticuloendothelial system.
Good permeation capabilities due to extreme
small size. More specifically, it can cross the blood brain barrier
(BBB).

o Solubility
Nanogels are able to solubilize hydrophobic drugs and
diagnostic agents in their core or networks of gel.

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o Electromobility
Nanogels could be prepared without employing energy or
harsh conditions such as sonication or homogenization, which is
critical for encapsulating biomacromolecules.

o Colloidal stability
Nanogels or polymeric micellar nanogel
systems have better stability over the surfactant
micelles and exhibit lower critical micelle concentrations,
slower rates of dissociation, and longer retention of loaded drugs.

o Non-immunologic response
This type of drug delivery system usually does not
produce any immunological responses.

o Others
Both type of drugs (hydrophillic and hydrophobic drugs
and charged solutes) can be given through nanogel.
Such properties of nanogel are significantly influenced by
temperature, presence of hydrophilic/ hydrophobic groups in the
polymeric networks, the cross-linking density of the gels,
surfactant concentration, and type of cross-links present in the
polymer networks.

 Drug Release Mechanism of the Nanogels

There are multiple mechanisms to which the release of the
drug or the biomolecule is attributed to including: simple
diffusion, degradation of nanogel structure, pH and temperature
changes, counterion displacement or induced due to external
energy source. Figure displays the main mechanisms of
nanogel release:

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o pH responsive mechanism
As the name indicates, drug
release responds to pH changes in the surrounding environment.
In other words, the release of drug can take place in different
physiological environments that acquire different pH values. The
most release will take place in the appropriate pH which means
that the release is mainly achieved in a targeted area of the
body that possesses that pH. This mechanism is based on the
fact that polymers employed in the synthesis of a nanogel
contain pH sensitive functional groups that deionize in the
polymeric network. The deprotonation results in increase in
osmotic pressure, swelling and porosity of the polymer which
triggers the release of the electrostatically bound molecules.

o Thermosensitive and volume transition mechanism

Some nanogels are reactive to a specific temperature known as
volume phase transition temperature (VPTT) which means they
display a change in volume according to the temperature. If the
surrounding medium is below VPTT, the polymer becomes
quenched and hydrated which makes it swell and release the
drug loaded. Above VPTT the opposite occurs and the nanogel
shrinks abruptly and the content flows out. Previously, the
thermoresponsive nanogels used to rupture cellular network
when they expand and increase in volume. So, some alterations
were applied on thermosensitive drug-containing nanogels like
changing the polymers ratio to achieve lower critical solution
temperature. A good example is the biocompatible magnetic
field targetibility of poly (N-isopropylacrylamide) and chitosan
nanogel which is quiet employed in hyperthermic cancer
treatment.

o Photochemical internalization and photoisomerization

Photoisomerization refers to a process in which a bond of

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restricted rotation undergoes some conformational changes due

to exposure to light. Double bond containing molecules are good
example; they isomerize usually from a trans orientation to cis
orientation upon light irradiation. When photosensitizers
loaded nanogel are excited, they produce two species of oxygen
(singlet and reactive) which can result in oxidation in the cellular
compartment walls that highly influence the release of
therapeutic agents into the cytoplasm. Azodextran nanogel
loaded with aspirin was a subject of release studies. The
observations showed that Cis-trans isomerization of azobenzene
by photoregulation causes the formation of E-configuration of
azo group. This results in better release profile of aspirin
compared to the previous Z-configuration

 Classification of Nanogels
Nanogels are classified according to two basis
o Non-responsive nanogels: When non-responsive nanogels
come in contact with water, they absorb it, resulting in swelling
of the nanogel.
o Stimuli-responsive nanogels: Environmental conditions, such
as temperature, pH, magnetic field, and ionic strength, control
whether swelling will occur or not and the extent of swelling or
deswelling of the nanogels. Any changes in any of these
environmental factors, which act as stimuli, will lead to
alteration in the behavior of the nanogels as a response, hence
the term stimuli-responsive nanogels.
Nanogels that are responsive to more than one environmental
stimulus are termed as multi-responsive nanogels.
*Nanogels that are responsive to more than one environmental
stimulus are termed as multi-responsive nanogels.

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o Physically cross-linked nanogels: Physically cross-linked

nanogels, which are also called pseudo gels, depend greatly on
the characteristics of the polymer used in their production
including polymer composition, temperature, concentration of
the polymer, type of cross-linking agent, and the ionic strength
of the medium. Weak linkages like van der Waals forces,
hydrogen bonding or hydrophobic, electrostatic interactions
are the forces that form this type of nanogels. Physical crosslinked
nanogels can be produced within a short time via a
number of simple methods. These methods involve a variety of
processes such as association of amphiphilic blocks, selfassembly
aggregation of polymeric chains as well as
complexation of oppositely charged polymeric chains.

o Chemically cross-linked nanogels: Where physically crosslinked

nanogels are linked by weak forces, chemically cross-linked
nanogels are formed by networks of strong covalent
bonds and other permanent chemical linkages. The strength of
the linkage is highly dependent on the type of functional groups
present in the molecules of the nanogel network.

 Advantages of Nanogels
Nanogels are considered advantageous over other drug
delivery systems for a number of reasons, including:
1. High biocompatibility, which makes nanogels a very
promising approach to drug delivery systems.
2. High biodegradability, which is crucial to avoid
accumulation of nanogel material in the bodily organs,
thereby leading to toxicity and adverse effects.
3. Nanogels are inert in the blood stream and the internal
aqueous environment, meaning that they do not induce
any immunological responses in the body.

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4. Extremely small size, which induces a number of effects

such as:
• Enhanced permeation capability.
• Avoidance of rapid renal exclusion. Escaping renal clearance
leads to prolonged serum half-life.
• Avoidance of clearance by phagocytic cells and the uptake by
reticuloendothelial system, which permits both passive and
active drug targeting.
• Capability to cross the Blood Brain Barrier.
• Enhanced penetration of endothelium in pathological sites
like solid tumors, inflammation tissue and infracted areas.
Since Tumor tissues have a high capillary permeability, more
nanoparticles permeate into the tumor tissue and
accumulate there, which increases the amount of drug
delivered and the selectivity of the drug delivery.
• Improved ability to access areas that is not accessible by
hydrogels, upon intravenous administration.
• Safe delivery of drug carrying nanogel particles into the
cytoplasm of target cells, therefore making them ideal for
intracellular drug delivery.
• Rapid responsiveness to environmental changes such as pH
and temperature.

 Disadvantages of nanogels
a) Expensive technique to completely remove the solvent
sand surfactants at the end of preparation process.
b) Surfactant or monomer traces may remain and can impart
toxicity.

 Application of nanogels

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o Nanogel-based drug delivery formulations improve the

effectiveness and safety of certain anti-cancer drugs, and many
other drugs, due to their chemical composition, which have been
confirmed from in vivo study in animal models. There is still some
work to do before these products are ready for human trials.

o Cancer
Cancer treatment involves targeted delivery of drugs with
expected low toxicities to surrounding tissues and high therapeutic
efficacy. Nanogels technology assures all these advantages as
listed below:

o Autoimmune disease
Nanogels were fabricated by remotely loading liposomes
with mycophenolic acid (MPA) solubilized within cyclodextrin,
oligomers of lactic acid-poly(ethylene glycol) that were terminated
with an acrylate end group, and Irgacure 2959 photoinitiator.
Particles were then exposed to ultraviolet light to induce
photopolymerization of the PEG oligomers.
The Nanogels are attractive because of their intrinsic
abilities to enable greater systemic accumulations of
their cargo and to bind more immune cells in vivo than free
fluorescent tracer, which, we reason, permits high, localized
concentrations of MPA. This new drug delivery system increases
the longevity of the patient and delays, the onset of
kidney damage, a common complication of lupus (Michael et al.,
2013).

o Opthalmic

pH-sensitive polyvinyl pyrrolidone-poly (acrylic acid) (PVP/PAAc) nanogels prepared by γ

radiationinduced polymerization of acrylic acid (AAc) in an
aqueous solution of polyvinyl pyrrolidone (PVP) as a

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template polymer were used to encapsulate pilocarpine in

order to maintain an adequate concentration of the pilocarpine at
the site of action for prolonged period of time.

o In stopping bleeding
A nanogel composed of protein molecules in solution has
been used to stop bleeding, even in severe gashes. The proteins
self-assemble on the nanoscale into a biodegradable gel.

o Diabetics
“An Injectable Nano-Network that Responds to Glucose
and Releases Insulin”has been developed. It contains a mixture of
oppositely charged nanoparticles that attract each other. This keeps
the gel together and stops the nanoparticles drifting away once in
the body. To make the nanogel respond to increased acidity
dextran, a modified polysaccharide, was used. Each nanoparticle
in the gel holds spheres of dextran loaded with insulin and an
enzyme that converts glucose into gluconic acid.
Glucose molecules can easily enter and diffuse through the gel.
Thus when levels are high, lots of glucose passes through the gel
and triggers release of the enzyme that converts it to gluconic acid.
This increases acidity, which triggers the release of the insulin.
There is still some work to do before the gel is ready for human
Trials.

o Neurodegenerative
Nanogel is a promising system for delivery of ODN to
the brain. A novel system for oligonucleotides delivery to the brain
based on nanoscale network of cross-linked poly (ethylene glycol)
and polyethylenimine ("nanogel") is used for the treatment of
neuro- degenerative diseases. Nanogels bound or encapsulated
with spontaneously negatively charged ODN results in formationof

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stable aqueous dispersion of polyelectrolyte complex with

particle sizes less than 100 nm which can effectively transported
across the BBB. The transport efficacy is further increased when
the surface of the nanogel is modified with transferrin or insulin
(Vinogradov.

o Anti-inflammatory action
Poly-(lactide-co-glycolic acid) and chitosan were used to
prepare bilayered nanoparticles and the surface was modified with
oleic acid. Hydroxypropyl methyl cellulose (HPMC) and Carbopol
with the desired viscosity were utilized to prepare the nanogels.
Two anti-inflammatory drugs, spantide II and ketoprofen drugs
which are effective against allergic contact dermatitis and psoriatic
plaque were applied topically along with nanogel. The result
shows that nanogel inncreases potential for the percutaneous
delivery of spantide II and ketoprofen to the deeper skin layers for
treatment of various skin inflammatory disorders.

WHY NANOGEL

Transdermal delivery in the form of nanogel is a promising and challenging task that enables
the delivery of drug into the deep layers of skin by providing maximum penetration and
making the formulation more effective. The entry of drug through the stratum conium may
follow the intercellular, transcellular. The intercellular route is more common pathway of the
drug permeation through the skin. Transdermal route has proven to be more effective route of
administration then injectables and oral route and provides more convenience thus increasing
patient compliance and avoiding first pass metabolism respectively. Transdermal delivery
provides controlled, constant administration of the drug; it allows continuous input of drugs
with short biological half-lives and reduces the undesirable side effects.

Nanogels based drug delivery system is highly biocompatible and biodegradable due to this
characteristic it is highly promising field now a days. Other properties of nanogel include high
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drug loading capacity, good permeation capabilities due to extreme small size, can cross blood
brain barrier, nanogels are able to solubilize hydrophobic drugs and diagnostic agents in their
core or networks of gel. Nanogel or polymeric nanogel systems have better stability over the
surfactant micelles and exhibit lower critical micelle concentrations, slower rates of
dissociation and longer retention of loaded drugs and this type of delivery system usually does
not produce any immunological responses. The most important character of nanogel is that it
can load both hydrophilic and hydrophobic type of drugs and also charged solutes.

Limitations of Nanogels
The only limitations to using nanogels include:
 It is expensive to remove the surfactant and the solvent at the end of the preparation
process although the manufacturing process itself is not very pricey.
 Adverse effects may occur if any traces of polymers or
surfactant remain in the body.

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