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ragupathyrenganathan
Chemical Penetration Enhancers For Transdermal Drug Delivery Systems
Formulation Discussion
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About Authors:
Himanshi Tanwar*, Ruchika Sachdeva, Manish Garg
Lord Shiva College of Pharmacy,
Sirsa, Haryana
tanwarhimanshi@gmail.com

Abstract
Delivery of the drug via skin would provide a useful alternative to oral route and important site of drug application for local and systemic effects with minimum undesirable side effects. Skin penetration techniques have been developed to improve bioavailability and enhance the range of drugs for which transdermal delivery is a viable option. The permeation of drug through skin can be enhanced by chemical penetration enhancers. The present review article includes the classification of permeation enhancers and their mechanism of action; thus it will help in the selection of suitable penetration enhancer for improving the permeation of poorly absorbed drugs via transdermal route.

REFERENCE ID: PHARMATUTOR-ART-2026

Transdermal drug delivery system
During the past few years, interest in the development of novel drug delivery systems for existing drug molecules has been renewed. The development of a novel delivery system for existing drug molecules not only improves the drug’s performance in terms of efficacy and safety but also improves patient compliance and overall therapeutic benefit to a significant extent.

When properly designed and developed for a particular drug, novel drug delivery system can overcome specific hurdles associated with conventional methods of delivery, e.g., drugs that undergo partial or complete degradation before reaching the site of action could be effectively delivered with improved bioavailability by using the novel concepts of timed or pulsatile release, targeted release, or gastro-resistant delivery.

With the advent of new era of pharmaceutical dosage forms, advances in drug formulations and innovative routes of administration have been made. Our understandingof drug transport across tissues has increased. While topical or drug delivery systems have been used for centuries for the treatment of local skin disorders, the use of the skin as a route for systemic drug delivery is of relatively recent origin. The administration of drugsby transdermal route offers the advantage ofbeing relatively painless. The appeal of using the skin as a portal of drug entry lies in ease of access, its huge surface area, and systemic access through underlying circulatory and lymphatic networks and the noninvasive nature of drug delivery. These changeshave often resulted in improved patient adherence to the therapeuticregimen and pharmacologic response.

Merits of transdermal drug delivery system

*  Provide utilization of drugs with short biological half lives, narrow therapeutic window

*  Avoid fluctuations in plasma drug levels

*  Maintain plasma concentration of potent drugs

*  Avoid hepatic first pass metabolism

*  Avoid gastro-intestinal side effects

*  Improve physiological and pharmacological response

*  Provide sustained delivery for a prolonged period of time

*  Elimination of local infections associated with subcutaneous, intramuscular or intravenous injections

*  Greater patient compliance due to elimination of multiple dosing profiles

*  Termination of therapy is easy at any point of time

*  Ability to deliver the drug to a specific target site

Limitations of transdermal drug delivery system
1) Only relatively potent drugs are suitable candidates for transdermal delivery because of the natural limits of drug entry imposed by the skin’s  impermeability

2) Some patients develop contact dermatitis at the site of application from one or more of the system components, necessitating discontinuation

Basic Principal of Transdermal permeation
Transdermal permeation is based on passive diffusion1. Skin is the most intensive and readily accessible organ of the body as only a fraction of millimeter of tissue separates its surface from the underlying capillary  network.7 The release of a therapeutic agent from a formulation applied  to the skin surface and its transport to the systemic circulation is a multistep process1,which includes
1) Diffusion of drug from drug to the rate controlling membrane.
2) Dissolution within and release from the formulation.
3) Sorption by stratum corneum and penetration through viable epidermis.
4) Uptake of drug by capillary network in the dermal papillary layer.
5) Effect on the target organ.
6) Partitioning into the skin’s outermost layer, the stratum corneum.
7) Diffusion through the stratum corneum, principal via a lipidic intercellular pathway.

Methods of enhancing transdermal delivery
It is very important to enhance the transdermal delivery so that drug can easily and quickly reach the systemic circulation and shows its effect. Following approaches are used to enhance the drug permeation through skin.

Ideal characteristics of chemical penetration enhancers
Ideally, penetration enhancers reversibly reduce the barrier resistance of the stratum corneum without damaging viable cells. Some of the more desirable properties for penetration enhancers acting within the skin have been given as:

• They should be non-toxic, non-irritating and non-allergenic

• They would ideally work rapidly; the activity and duration of effect should be both predictable and reproducible.

They should have no pharmacological activity within the body.

• The penetration enhancers should work unidirectionally, i.e., they should allow therapeutic agents into the body whilst preventing the loss of endogenous materials from the body.

• When removed from the skin, barrier properties should return both rapidly and fully to normal.

• They should be cosmetically acceptable with an appropriate skin feel.

Chemical approaches
Chemical substances temporarily diminishing the barrier of the skin and known as accelerants or sorption promoters can enhance drug flux.

Chemical penetration enhancers may act by one or more of three main mechanisms
1. Disruption of the highly ordered structure of stratum corneum lipid.
2. Interaction with intercellular protein.
3. Improved partition of the drug, co enhancer or solvent into the stratum corneum.

The commonly used chemical penetration enhancers are described below

Sulphoxides and similar chemicals
Dimethyl sulphoxide is the most important compound belonging to the category of sulphoxides, enhances the transdermal permeation of a variety of drugs. It is a powerful aportic solvent which hydrogen bonds with itself rather than with water. It is colourless, odourless and is hydroscopic and is often used in many areas of pharmaceutical sciences as a “universal Solvent”. The mechanism of the sulphoxide penetration enhancers is widely used to denature protein and, on application to human skin, has been shown to change the intercellular keratin conformation, from ? helical to β sheet. DMSO alone has also been applied topically to treat systemic inflammation, although currently it is used only to treat animals.

Azones
Azone (1-dodecylazacycloheptan-2-one or laurocapran) was the first molecule specifically designed as a skin penetration enhancer Azone enhances the skin transport of a wide variety of drugs including steroids, antibiotics and antiviral agents. Azone is most effective at low concentrations, being employed typically between 0.1- 5% but more often between 1- 3% Azone molecules may exist dispersed within the barrier lipoid or separate domains within the bilayer.16

Pyrrolidones
Pyrrolidones have been used as permeation enhancers for numerous molecules including hydrophilic (e.g. mannitol and 5-flurouracil) and lipophilic (progesterone and hydrocortisone) permeants. N-methyl-2- pyrrolidone was employed with limited success as a penetration enhancer for captopril when formulated in a matrix-type transdermal patch. The pyrrolidones partition well into human stratum corneum within the tissue and they may act by altering the solvent nature of the membrane. Pyrrolidones have been used to generate reservoirs within the skin membrane. Such a reservoir effect offers a potential for sustained release of a permeant from the stratum corneum over extended time period.

Fatty acids
Percutaneous drug absorption has been increased by a wide variety of long-chain fatty acids, the most popular of which is oleic acid. It is of interest to note that many penetration enhancers such as azone contain saturated or unsaturated hydrocarbon chains. Oleic acid greatly increased the flux of many drugs such as increasing the flux of salicylic acid 28-fold and 5-flurouracil flux 56-fold through human skin membrane invitro. The enhancer interacts with and modifies the lipid domains of the stratum corneum as would be expected for a long chain fatty acid with cis configuration.

Urea
Urea promotes transdermal permeation by facilitating hydration of the stratum corneum and by the formation of hydrophilic diffusion channels within the barrier. Cyclic urea permeation enhancers are biodegradable and non-toxic molecules consisting of a polar parent moiety and a long chain alkyl ester group. As a result, enhancement mechanism may be a consequence of both hydrophilic activity and lipid disruption mechanism.

Oxazolidones
Oxazolidinones are a new class of chemical agents which have the potential for use in many cosmetic and personal care product formulations. This is due to their ability to localize co-administered drug in skin layers, resulting in low systemic permeation. The structural features of these permeation enhancers are closely related to sphingosine and ceramide lipids which are naturally found in the upper skin layers. Oxazolidinones such as 4-decyloxazolidin-2-one has been reported to localize the delivery of many active ingredients such as retinoic acid and diclofenac sodium in skin layers. This compound has a higher molecular weight and lipophilicity than other solvent-type enhancers, physical characteristics that may be beneficial in terms of a reduction in local toxicity because of the lack of effective absorption of these enhancers into the lower skin layers where irritation is likely to be occur.

Conclusion
Skin permeation enhancement technology is a rapidly developing field which would significantly increase the number of drugs suitable for transdermal drug delivery, with the result that skin will become one of major route of drug administration in next era. Chemical penetration enhancers are not only specific towards stratum corneum; also penetrate into the deeper layers of the skin to viable epidermis cells. A better understanding of the interaction of enhancers with stratum corneum and the development of structure activity relationship for enhancers will aid in the design of optimal characteristics and minimal toxicity.

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