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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 Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 1

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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, Antiinflammatory activity, Anti-oxidant activity, Anti-microbial activity, Anti-spermatogenic activity, Anti-atherogenic activity and hypoglycemic activity.

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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.

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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 Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 4

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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.

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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.

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Properties Bhallataka is sweet and astringent in taste. It is extremely heat generating. Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 5

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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.

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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 1,2dihydroxy-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 acid3.8%; arachidic acid- 1.4%.

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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.

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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, Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 6

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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.

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

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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 Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 9

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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). Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 10

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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 (18211902) 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.

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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. Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 11

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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. Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 13

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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.

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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. Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 14

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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 salicylatecontaining 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).

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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

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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. Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 17

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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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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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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 Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 20

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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

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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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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. Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 22

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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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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 Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 24

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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 Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 25

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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 Formulation and evaluation of anti-inflammatory nano gel using bhilawa (semecarpus anacardium linn). Page 26

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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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