INTRODUCTION:

Skin being the largest organ of the body is the most important route for systemic, regional and topical action for the drug delivering to the target site. It is a biochemical and protective barrier to prevent water loss from the body and provides protection against foreign infectious agents and toxic chemicals from entering into the body^1. The outermost layer consisting of corneocytes, which are surrounded by lipid bilayer, is the stratum corneum. This bilayer of lipids prevents water loss from the body as well as stop the entry of drugs which are topically applied rather than low molecular weight and lipid soluble drugs².

Corneocytes may be referred to as bricks which are entrenched in the lipid layer consisting of cholesterol, fatty acids, sulfates of cholesterol and ceramides³. As this layer is continuous, the target substance should interact with stratum corneum layer. Therefore, for the passage of substance through the stratum corneum special transdermal permeation enhancers have been developed⁴.

ANATOMICAL CHARACTERISTICS OF SKIN

The skin is largest organ of the body, that covers almost whole of the body as a protective barrier. It is known to have four different layers which are described Figure-1.

Figure 1: Human Skin layers

1. STRATUM CORNEUM:

Often referred to as non-viable epidermis. It is the outermost layer of the skin. It contains keratin filled flat dead cells⁵. It provides protective barrier against light and heat. It contains protein, lipids, phospholips and cholestrol sulfate. This layer consists of flat plate like structure with surface area 750 -1200 micrometer⁶.

2.VIABLE EPIDERMIS:

This layer lies between non viable epidermis (stratum corneum) and dermis, held by tonofibrils.The layer is physiochemically almost similar to living cells or tissues with a thickness of 50-100 micrometer⁷.

3.VIABLE DERMIS:

This layer is composed of connective tissues including elastic fibres and collagen. It also contains macrophages (engulfment), adipocytes (fat cells) and fibroblasts. They are thick in soles, palms and thin in scrotum and penis with thickness ranging from 2000-3000 micrometer. Various nerves, blood vessels and hair follicles have been embeded in the dermis layer. It also contains finger like projections called as dermal papillae which generally increase the surface area^6,8.

4. HYPODERMIS:

It is a subcutaneous layer of connective tissue though not a true part. It is a white fibrous tissue containg lymph, blood vessels, cutaneous nerves and secretory pores for sweat⁹.

TRANSDERMAL DRUG DELIVERY SYSTEM

Transdermal drug delivery system may be defined as the system in which medications are being applied topically over the skin and which delivers the applied drug via skin in a controlled manner. This drug delivery system has many advantages over oral route. In the oral route proper drug concentration needs to be maintained at finite interval of time and also the drug needs to be passed through first pass metabolism and it needs to be monitored for preventing overdosing. Therefore to avoid these disadvantages new drug products are developed for the transdermal route for safe and effective target delivery of the drug to the targeted site^10-11. The prime objective of TDDS is to provide safety and increase the efficiency of the given drug with more patient compliance⁷. Various advantages and disadvantages offered by TDDS are:

ADVANTAGES OF TDDS:

1. Modifications of the properties of biological barriers for absorption

2. Avoidance of first pass metabolism

3. Discontinuation of drug administration

4. Longer period of time to control the drug delivery^12,13.

DISADVANTAGES OF TDDS:

1. On the site of application irritation may be developed

2. High drug level could not be achieved in the blood.

3. Drug molecules with effective 800-1000daltons molecular sieve can be used for effective absorption

4. For each drug concentration varies for effective response ¹⁴.

PENETRATION ENHANCERS

Penetration enhancers may be defined as chemicals which patronize drug flux and interaction of drug with constituents of skin. This increases the skin permeation. They are often known as absorption or promoter enhancers as they increase the absorption of the drug or substance via skin. They also increase the skin permeability. Ideal penetration enhancers should impart following properties:

1. Must be stable chemically and non toxic

2. Must be non irritant, inert as well as non allergic

3. Should not impart pharmacological activity inside the body

4. Must be odorless, colorless and inexpensive

5. Should be accepted cosmetically

6. Rapid onset of action¹⁵

Chemical penetration enhancers directly insert themselves between the lipid tails which are mainly hydrophobic and causes changes in lipid layer, which results in increase in permeation of drug¹⁶. Chemical enhancers mainly act by three mechanism i.e. by

(1) Interaction with intercellular proteins

(2) By improved partition of drug and

(3) By disruption of highly ordered structure of lipid of stratum corneum ¹⁷.

The chemical enhancer act by altering one of these pathways. They cause conformational change in protein or solvent swelling during the pathway. The fluidity of the lipid portion is increased by fatty acid enhancers of the stratum corneum. While some absorbers act on polar as well as non polar pathway for the penetration and increase the diffusion of drugs via skin proteins. This aspect of action depends on the type of enhancer employed¹⁸.

ADVANTAGES OF PENETRATION ENHANCERS:

1. Posses no harmful effect on skin.

2. Non toxic.

3. Absorption of topical preparation gets improved.

4. Can be used for unabsorbable drugs.

5. High therapeutic efficiency.

6. Acts as limiting factor¹⁹.

DISADVANTAGES OF PENETRATION ENHANCERS:

1. Concentration varies largely from drug to drug

2. May posses side effects in the body due to physiochemical properties²⁰.

FUNCTION OF PENETRATION ENHANCER:

1. PROTEIN MODIFICATION:

Many particles such as DMSO, ionic surfactants combine or interact with kertain of corneocytes and cause conformation in the structure of protein, thus making more permeable.

2. PARITIONING PROMOTION:

The solution properties of the horny layer is changed, thereby increasing the partitioning of the drug. Example: Penetration of nitro glycerin and estradiol is increased by ethanol by stratum corneum.

3. DISRUPTION OF LIPID LAYER:

The stratum corneum structure is distorted by the enhancers, thus making it more permeable to the drugs. Example: fatty acids, azones, alocohols etc²¹.

Penetration enhancers or absorbents may be used to decrease the time of TDDS and increase the delivery time of drugs which are ionizable such as timolol maleate. Delievering of impermeable drugs such as heparin and maintenance of blood levels are the uses of penetration enhancers^22-23. Hence there are many aspects of penetration enhancers, though they are used in combination to obtain required properties.

PENETRATION ENHANCERS MODE OF ACTION

Permeation of drug is enhanced by the penetration enhancers by several mechanism.These enhacers may be used induvidually or in combination to exert different effects. One of the major mechanism of the chemical penetration enhancers are:

1. Intercellular protein interaction

2. Improved partition of drug through stratum corneum

3. Lipid layer disruption

The first mechanism is the intercellular protein interaction. The enhancers interact with the proteins and through corneocyte layer they promote permeation of various drugs. The second proposed mechanism is the solvent action causing improved partiton of drug through SC . They generally solubilize the components of skin-tissuse. The third proposed mechanism is the disruption of lipid layer by the permeation enhancers. According to Lipid-protein-partitioning propsed by Barry, there are three active sites in the intercellular region where the enhacer acts to enhance the permeation of drugs. Polar head group of lipds, lipid region of hydrophobic tails and lipid head group which is the aqueous region are the three active sites. The polar head of the keratin interact with penetration enhancers like aprotic solvents and surfactants in the intracellular region, which result in conformational chamges in the protein structure by reducing the binding forces between molecules of proteins²⁴. Another mechanism proposed by Guy and Hadgraft (1989) by which partitoning of drug is promoted by solvent nature of dermal tissue²⁵.

CLASSIFICATION OF CHEMICAL PENETRATION ENHANCERS:

Chemical enhancers have the ability to promote penetration into the skin by reducing the barrier of stratum corneum.Various chemical penetration enhancers are used such as alcohols, urea, terpenes, essential oils. They enhance the skin permeation. Permeation activity can be expressed as:

Drug permeabilty coefficient after enhancement

ER= -----------------------------------------------------------

Drug permeabilty coefficient before enhancement

Various chemical enhancers are as follows:

• Sulphoxides: DMSO, DMF.

• Essential oils: terpenes and terpenoids, sesquiterpene, L-menthol

• Azones: 1-dodecylazacycloheptan-2-one

• Oxazolidinones: 4-decyloxazolidin-2-on

• Fatty acids: lauric acid, myristic acid and capric acid

• Nonic surfactant: polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether

• Glycol: diethylene glycol and tetraethylene glycol

• Pyrrolidones: N-methyl-2-pyrolidone^6,25

SULPHOXIDES:

The effective penetration enhancer, which promotes permeation by reducing the skin to drug molecules and by promoting drug partitioning from the dosage form, is Dimethylsulfoxide (DMSO). DMSO denatures the intercellular structural proteins of stratum corneum. Due to various disadvantages such as scaling, burning, erythema and stinging, DMSO is not a better choice²⁶.

ESSENTIAL OILS:

The major components of volatile oils are terpenes and terpenoids. It mainly consists of repeating isoprene structures to classify terpenes. Two isoprene units make up monoterpenes (C10), three isoprene units make sesquiterpenes (C15) and diterpenes consists of four isoprene units. Also another classification of terpenes can be linear, monocyclic and bicyclic. They are generally used as fragrance or flavoring agents. Essential oils such as eucalyptus and chenopodium oils are used for 5- fluorouracil penetration into the skin as penetration enhancer ²⁷.

AZONES:

The first specially designed molecule as skin enhancer is azone which is chemically 1- dodecylazacycloheptan-2-one or laurocapram. This is a odourless, colourless liquid with -7 degree melting point. It is soluble in most of organic solvents and is generally lipophillic. It promotes transport of drug through the skin including antibiotics, antiviral and steroids. They are more effective at low concentrations. They work on a mechanism of partition of lipid layer and disrupting the struture.They exist in separate domains in the bilayer or as dispersed phase in barrier lipoid ^28,29.

FATTY ACIDS:

One of the mono –unsaturated fatty acid which is used to increase the penetration of drug via skin is oleic acid and acts by transdermal pathway³¹.They permeate within the stratum corneum lipid for the barrier skin function. They are long chain ceramides. Consist of cholestrol esters, fatty acids and cholestrol which make it different from other biological membranes³¹.

OXAZOLIDINONES :

These are chemical agents which are generally used in personal and cosmetic products as have localized administration within the skin layers, leading to low penetration. They closely resemble ceramide lipids or sphingosine. 4-decyloxazolidin 2- one one of the oxazolidinones, localize many ingredients such as diclofenac in the skin layer³².

NON – IONIC SURFACTANTS:

These agents promote absorption of active substance applied to the skin by interacting with the one of the layers of the skin, the sratum corneum. For its quantitative studies various measures are applied for its effects in the skin . Generally the surfactant changes the structure by deposition on the stratum corneum layer. As a result the water soluble or lipid substances present on the surface of SC are removed or becomes solubilised. And the active substance is moved to the layer³³.

Out of the cationic, anionic and non ionic surfactants, anionic surfactans are more effective for the penetration of the drug into the layer of skin for better absorption. The molecules of anionic surfactant interact with the lipids and kertain of the startum corneum, while in the cationic surfactant the cornified cellls interact with the surfactant resulting in the disruption of cell-lipid layer or matrix. The third type of surfactant, the non ionic surfactant promotes fluidization of lipids of stratum cormeum layer, thereby enhancing absorption. As reported by Scheuplein and Ross with the presence of sodium dodecanoate as well as sodium dodecyl sulfate the membrane bound capapcity is reduced by the stratum corneum. Thought it is wholly reversible by removing these substances. Therefore anionic surfactants act on the helical filaments of the SC, causing uncoiling as well as extension of keratin filaments for the production of keratin, thus increasing the permeability³⁴. Scannin and calorimetery anaylsis have shown that the SLS distort both lipid as well as proteins. The extent of penetration depends on the critical micelle concentration (CMC) and monomer activity. Micelles are formed in the solution above CMC when surfactant is added. Also the barriers extent of distortion and penetration depends on structure of surfactant i.e alkyl chain length. It is shown that alkyl chain having 12 carbons causes more disruption and allows more penetration of the drugs than alkyl chain having less carbons, though it is not explained completely ³³.

PYRROLIDONES:

Pyrrolidones are used as penetration enhancers which include lipophillic (hydrocortisone and progesterone) and hydrophillic (5-fluorouracil and mannitol). Permeation enhancer for captopril was N- methyl -2- pyrrolidone into matrix –type transdermal patches³⁵. They act by mechanism of partition into stratum corneum of the tissue and alter the solvent nature of the layer. They are known to generate reservoirs with the layer which offers sustained release of hydrophillic and lipophillic permeants from the stratum corneum layer³⁶. Due to skin irritation, erythema and other adverse reactions, use of pyrrolidone was precluded clinically^37-38.

GLYCOLS:

One of the most common co-solvent is propylene glycol^39-41.When used in topical formulations pyrrolidones show penetration enhancement and opposite effect⁴². They are based on the mechanism of solvation of the keratin filaments which interact with water of hydrogen bonding sites and polar head groups of the bilayer lipid layer⁴³. It has been found quantitatevly that propylene glycol for the permeation of acyclovir is based on the concentration of alcohol⁴⁴.

UREA:

By facilitating hydration of stratum corneum and hydrophillic diffusion channels urea promotes transdermal permeation. To synthesize potent enhancing moieties urea has been attempted and has marginal penetration enhancing activity. Wong and his co- workers found that azone is more potent for promoting indomethacin around hairless mouse skin. These are non toxic and biodegradable molecules which contain long chain alkyl ester group and polar parent moiety. Therefore urea permeation enhancer is used for hydrophilic activity and lipid disruption mechanism⁴⁵.

CYCLODEXTRINS:

They form inclusion complexes with lipophillic drugs and are biocompatible substances. As a result there is increase in solubility in aqeous solutions. They are determined as effective enhancers with propylene glycol and fatty acids⁴⁶.

PHOSPHOLIPIDS:

Phosoplipids are generally used as penetration enhancers in the form of miscellar sytem, vesicles and micro emulsions. They donot have the ability to interact with stratum corneum. Therefore they fuse with lipid layer and enhance the partitioning of the drug and disrupt the bilayer structure. This leads to collapsation of poorly soluble drug into the solvent thereby enhancing the drug delivery process^47-48.

ALKANES:

These long chain carbon chain increases the permeabiltiy of skin by alteration of startum corneum barrier⁴⁹. Nonane is investigated as enhancer because of solubilization and biochemical extraction by lipophillic solvents⁵⁰.

EUGENOL:

One of the member of allylbenzene class is eugenol. Generally it a yellow oily liquid which is extracted from certain oils like nutmeg, cinnamon and clove oils. They are soluble in organic liquids and slightly soluble in water. They are aromatic dried buds belonging to family Myrtaceae. They react to the pain by reducing pain such as prilocane or lidocaine. They increase the permeability because of lipid extraction and also increase the partition coefficient⁵¹.

DIMETHYLACETAMIDE AND DIMETHYLFORMAMIDE:

These enhancers are alternatives to DMSO and are less potent chemical enhancers. It result in the partitioning of keratin regions at low concentration to enhance its activity. Lipid fluidity is increaed at higher concentrations by distortion of lipids . this disruption leads to formation of solvation shell around polar heads⁵².

ESTERS:

Isopropylpalmitate, ispropyl-n-butyrate, ethylacetate and butylacteate are one of the mostly used skin penetration enhancer. The mostly penetration enchancer used is ethyl acetate as a transdermal delivery of levonorgestrel⁵³. 5-aminolevulinic acid and protophorphyrin IX are enhanced by glycerol monoleate in presence of propylene glycol⁵⁴.

Table 1: Reported Transdermal Chemical Penetration Enhancers

Sr. No.	Chemical penetration enhancer	Drug	References
1.	Cyclodextrins	Itraconazole	55
2.	Alcohols	Buprenorphine	56
3.	Alcohols	Tizanidine hydrochloride	57
4.	Terpenes	Valsartan	58
5.	Terpenes	Zaltoprofen	59
6.	Terpenes	Minoxidil	60
7.	Terpenes	Verapamil hydrochloride	61
8.	Surfactant	bisoprolol tartrate	62
9.	Surfactant	Buprenorphine	56
10.	Azone	Sod. salicylate	63
11.	Azone	Flurbiprofen	64
12.	Fatty acids	Diolein	65
13.	Fatty acids	Buprenorphine	56
14.	Fatty acids	flurbiprofen	66
15.	Fatty acids	Daphnetin	67
16.	Urea	Leuprolide	68
17.	Urea	Haloperidol	69
18.	Pyrrolidones	Bupranolol	70
19.	Pyrrolidones	Acyclovir	71
20.	Pyrrolidones	Lidocaine	72

PENETRATION REDUCERS:

Skin penetration reducers inhibits the compounds such as xenobiotics for reaching into the circulation. They inhibit the transdermal or dermal route activity. This has originated the basis for designing compounds opposite than penetration enhancers. Though the exact mehcanism is still unknown⁷³. Fatty acids can be used as enhancer as well as retarder based on the vehicles used and structure⁷⁴.

TOXICITY CAUSED DUE TO ENHANCERS:

The Permeabilty is increased by the chemical penetration enhancers which damage the horny layer (stratum corneum). They alter the structure and components of the cell membrane. Various chemical penetration enhancers used may produce skin irritation, side effects, sometimes leading to adverse drug reactions. Various solubility parameters are used for determining the drug interactions⁷⁵.

CONCLUSION:

Various chemical penetration enhancers have been used for the transdermal drug delievery so that drug penetrates into the skin. They have an important role for introducing transdermal patches because of its efficiency and bioavailabitlty⁷⁶. Skin Enhancement technology has shown rapid increase significantly in the recent years. Skin being the largest organ has been used widely for the permeation. Recent experimentation has shown that chemical penetration enhancer have great advantages to be used for the penetration of the medicament .Various chemical enhancers have been described with its uses to be used in transdermal drug delievery. These chemical enhancers produce systemic effects for various illness. Chemical enhancers should be prepared with desired uses and its interaction with the skin thus changing its conformation . Hence there is a need to sythesize more enhancers for efficient transdermal drug delivery process.

ACKNOWLEDGEMENT:

The authors are grateful to Dr. Madhu Chitkara, Vice Chancellor, Chitkara University, Rajpura, Patiala, India, Ashok Chitkara, Chancellor, Chitkara University, Rajpura, Patiala, India and Dr. Sandeep Arora, Director, Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India for support and institutional facilities.

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Received on 24.12.2016 Modified on 18.03.2017

Research J. Pharm. and Tech. 2017; 10(6): 1809-1815.

DOI: 10.5958/0974-360X.2017.00319.5