PRESENT REVIEW- TRANSDERMAL DRUG DELIVERY SYSTEM

About Author:
Akshay Rajgaria
Kanak Manjari Institute of Pharmaceutical Sciences
akshaykrish2007@gmail.com

ABSTRACT
Transdermal drug delivery system (TDDS) provides a means to sustain drug release as well as reduce the intensity of action and thus reduce the side effects associated with its oral therapy. Transdermal drugs are self contained, discrete dosage form. Transdermal Drug Delivery System is the system in which the delivery of the active ingredients of the drug occurs by the means of skin. Skin is an effective medium from which absorption of the drug takes place and enters the circulatory system. Various types of transdermal patches are used to incorporate the active ingredients into the circulatory system via skin. The patches have been proved effective because of its large advantages over other controlled drug delivery systems.

REFERENCE ID: PHARMATUTOR-ART-1818

INTRODUCTION
At present, the most common form of delivery of drugs is the oral route. While this has the notable advantage of easy administration, it also has significant drawbacks -- namely poor bioavailabiltity due to hepatic metabolism (first pass) and the tendency to produce rapid blood level spikes (both high and low), leading to a need for high and/or frequent dosing, which can be both cost prohibitive and inconvenient.

To overcome these difficulties there is a need for the development of new drug delivery system; which will improve the therapeutic efficacy and safety of drugs by more precise (i.e site specific), spatial and temporal placement within the body thereby reducing both the size and number of doses. New drug delivery system are also essential for the delivery of novel, genetically engineered pharmaceuticals (ie peptides, proteins) to their site of action, withouincurring significant immunogenicity or biological inactivation. Apart from these advantages the pharmaceutical companies recognize the possibility of repattening successful drugs by Appling the concepts and techniques of controlled drug delivery system coupled with the increased expense in bringing new drug moiety to the market. One of the methods most often utilized has been transdermal delivery - meaning transport of therapeutic substances through the skin for systemic effect. Closely related is percutaneous delivery, which is transport into target tissues, with an attempt to AVOID systemic effects.

There are two important layers in skin: the dermis and the epidermis. 
The outermost layer, the epidermis, is approximately 100 to 150 micrometers thick, has no blood flow and includes a layer within it known as the stratum corneum.  This is the layer most important to transdermal delivery as its composition allows it to keep water within the body and foreign substances out. Beneath the epidermis, the dermis contains the system of capillaries that transport blood throughout the body. If the drug is able to penetrate the stratum corneum, it can enter the blood stream. A process known as passive diffusion, which occurs too slowly for practical use, is the only means to transfer normal drugs across this layer.  The method to circumvent this is to engineer the drugs be both water-soluble and lipid soluble.  The best mixture is about fifty percent of the drug being each. This is because “Lipid-soluble substances readily pass through the intercellular lipid bi-layers of the cell membranes whereas water-soluble drugs are able to pass through the skin because of hydrated intracellular proteins”. Using drugs engineered in this manner, much more rapid and useful drug delivery is possible.

The stratum corneum develops a thin, tough, relatively impermeable membrane which usually provides the rate limiting step in transdermal drug delivery system. Sweat ducts and hair follicles are also paths of entry, but they are considered rather insignificant.

TRANSDERMAL DRUG DELIVERY SYSTEM
Transdermal drug delivery system are topicaly administered medicaments
in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate.

A transdermal drug delivery device, which may be of an active or a passive design, is a device which provides an alternative route for administering medication. These devices allow for pharmaceuticals to be delivered across the skin barrier . In theory, transdermal patches work very simply. A drug is applied in a relatively high dosage to the inside of a patch, which is worn on the skin for an extended period of time. Through a diffusion process, the drug enters the bloodstream directly through the skin. Since there is high concentration on the patch and low concentration in the blood, the drug will keep diffusing into the blood for a long period of time, maintaining the constant concentration of drug in the blood flow.

This approach to drug delivery offers many advantages over traditional methods. As a substitute for the oral route, transdermal drug delivery enables the avoidance of gastrointestinal absorption, with its associated pitfalls of enzymatic and pH associated deactivation. This method also allows for reduced pharmacological dosaging due to the shortened metabolization pathway of the transdermal route versus the gastrointestinal pathway. The patch also permits constant dosing rather than the peaks and valleys in medication level associated with orally administered medications. Multi-day therapy with a single application, rapid notification of medication in the event of emergency, as well as the capacity to terminate drug effects rapidly via patch removal, are all further advantages of this route.

However this system has its own limitations in which the drug that require high blood levels cannot be administered and may even cause irritation or sensitization of the skin.the adhesives may not adhere well to all types of skin and may be uncomfortable wear. Along with these limitations the high cost of the product is also a major drawback for the wide acceptance of this product.

PROPERTIES THAT INFLUENCE TRANSDERMAL DELIVERY
Release of the medicament from the vehicle.
Penetration through the skin barrier.
Activation of the pharmacological response

Basic Components of Transdermal Drug Delivery Systems

The components of transdermal devices include:
1. Polymer matrix or matrices.
2.  The drug
3.  Permeation enhancers
4. Other excipients

1.Polymer Matrix
The Polymer controls the release of the drug from the device.

Possible useful polymers for transdermal devices are:
a)Natural Polymers:
e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc.

b) Synthetic Elastomers:
e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc.

c)Synthetic Polymers:
e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone, Polymethylmethacrylate, Epoxy etc.

2. Drug
For successfully developing a transdermal drug delivery system,
the drug should be chosen with great care. The following are some of the desirable properties of a drug for transdermal delivery.

Physicochemical properties
1. The drug should have a molecular weight less than approximately 1000 daltons.

2. The drug should have affinity for both – lipophilic and hydrophilic phases. Extreme partitioning characteristics are not conducive to successful drug delivery via the skin.

3. The drug should have low melting point.
Along with these propertiesthe drug should be potent, having short half life and be non irritating.

3.Permeation Enhancers
These are compounds which promote skin permeability by altering
the skin as a barrier to the flux of a desired penetrant.

These may conveniently be classified under the following main headings:
a) Solvents
These compounds increase penetration possibly by swallowing the polar pathway and/or by fluidizing lipids. Examples include water alcohols – methanol and ethanol; alkyl methyl sulfoxides – dimethyl sulfoxide, alkyl homologs of methyl sulfoxide dimethyl acetamide and dimethyl formamide; pyrrolidones – 2 pyrrolidone, N-methyl, 2-purrolidone; laurocapram (Azone), miscellaneous solvents – propylene glycol, glycerol, silicone fluids, isopropyl palmitate.

b) Surfactants
These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs.The ability of a surfactant to alter penetration is a function of the polar head group and the hydrocarbon chain length.

Anionic Surfactants: e.g. Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethylsulphoxide etc.

Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc

Bile Salts: e.g. Sodium ms taurocholate, Sodium deoxycholate, Sodium tauroglycocholate.

Biary system: These systems apparently open up the heterogeneous multilaminate pathway as well as the continuous pathways.e.g. Propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid.

c) Miscellaneous chemicals
These include urea, a hydrating and keratolytic agent; N, N-dimethyl-m-toluamide; calcium thioglycolate; anticholinergic agents.

Some potential permeation enhancers have recently been described but the available data on their effectiveness sparse. These include eucalyptol, di-o-methyl-ß-cyclodextrin and soyabean casein.

4.Other Excipients

a) Adhesives:
The fastening of all transdermal devices to the skin has so far been done by using a pressure sensitive adhesive which can be positioned on the face of the device or in the back of the device and extending peripherally. Both adhesive systems should fulfill the following criteria
(i)Should adhere to the skin aggressively, should be easily removed.
(ii)Should not leave an unwashable residue on the skin.
(iii) Should not irritate or sensitize the skin.

The face adhesive system should also fulfill the following criteria.
(i) Physical and chemical compatibility with the drug, excipients and enhancers of the device of which it is a part.
(ii) Permeation of drug should not be affected.
(iii) The delivery of simple or blended permeation enhancers should not
be affected.

b) Backing membrane:
Backing membranes are flexible and they provide a good bond to the drug reservoir, prevent drug from leaving the dosage form through the top, and accept printing. It is impermeable  substance that protects the product during use on the skin e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc.

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Desirable features for transdermal patches

• Composition relatively invariant in use.
• System size reasonable.
• Defined site for application.
• Application technique highly reproducible.
• Delivery is (typically) zero order.
• Delivery is efficient.

TYPES OF TRANSDERMAL PATCHES

Four Major Transdermal Systems

1. Single-layer Drug-in-Adhesive

The Single-layer Drug-in-Adhesive system is characterized by the inclusion of the drug directly within the skin-contacting adhesive. In this transdermal system design, the adhesive not only serves to affix the system to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. The rate of release of drug from this type of system is dependent on the diffusion across the skin.

 2.  Multi-layer Drug-in-Adhesive

The Multi-layer Drug-in-Adhesive is similar to the Single-layer Drug-in-Adhesive in that the drug is incorporated directly into the adhesive. However, the multi-layer encompasses either the addition of a membrane between two distinct drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single backing film.

3. Drug Reservoir-in-Adhesive

The Reservoir transdermal system design is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of the product responsible for skin adhesion can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane.

4. Drug Matrix-in-Adhesive

The Matrix system design is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

Transdermal Market
The market for transdermal products has been in a significant upward trend that is likely to continue for the foreseeable future. An increasing number of TDD products continue to deliver real therapeutic benefit to patients aroundthe world. More than 35 TDD products have now been approved for sale in the US, and approximately 16 active ingredients are approved for use in TDD products globally. The table 1 gives detail information of the different drugs which are administered by this route and the common names by which they are marketed; it also gives the conditions for which the individual system is used..   

TABLE - 1

The pie diagram given below shows that Fentanyl and nitroglycerine are the drugs most popularly marketed using transdermal patches.

ADVANCE DEVELOPMENT IN TDDS

Drug in adhesive technology has become the preferred system for passive transdermal delivery, two areas of formulation research are focused on adhesives and excipients. Adhesive research focuses on customizing the adhesive to improve skin adhesion over the wear period, improve drug stability and solubility, reduce lag time, and increase the rate of delivery. Because a one-size-fits-all adhesive does not exist that can accommodate all drug and formulation chemistries, customizing the adhesive chemistry allows the transdermal formulator to optimize the performance of the transdermal patch.

A rich area of research over the past 10 to 15 years has been focused on developing transdermal technologies that utilize mechanical energy to increase the drug flux across the skin by either altering the skin barrier (primarily the stratum corneum) or increasing the energy of the drug molecules. These so-called “active” transdermal technologies include iontophoresis (which uses low voltage electrical current to drive charged drugs through the skin), electroporation (which uses short electrical pulses of high voltage to create transient aqueous pores in the skin), sonophoresis (which uses low frequency ultrasonic energy to disrupt the stratum corneum), and thermal energy (which uses heat to make the skin more permeable and to increase the energy of drug molecules). Even magnetic energy, coined magnetophoresis, has been investigated as a means to increase drug flux across the skin.

CONCLUSION
A lot of progress has been done in the field of Transdermal Patches. Due to large advantages of the Transdermal Drug Delivery System, this system interests a lot of researchers. Many new researches are going on in the present day to incorporate newer drugs via this system. Various devices which help in increasing the rate of absorption and penetration of the drug are also being studied. However, in the present time due to certain disadvantages like large drug molecules cannot be delivered, large dose cannot be given, the rate of absorption of the drug is less, skin irritation, and etc. the use of the Transdermal Drug Delivery System has been limited. But, with the invention of the new devices and new drugs which can be incorporated via this system, it used is increasing rapidly in the present time.

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