DEVELOPMENT & EVALUATION OF TRANSDERMAL DRUG DELIVERY

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ABOUT AUTHOR:
Rakesh Kumar Sati
M.Pharm D.I.T Faculty of Pharmacy
Dehradun Uttarakhand
rakeshsatiq.a@gmail.com

ABSTRACT
Transdermal administration of drugs is an another way of administration that can significantly deliver larger molecules in potent quantities that overcome the problem with the oral administration such as poor bioavailability due to first pass metabolism and sometimes responsible for rapid blood level. Drugs that are given by transdermal route may enhance the potency as well as safety of drugs. One such advance has been the development of transdermal patch delivery systems. Transdermal drug technology specialists are continuing to search for new methods that can effectively and painlessly deliver larger molecules in therapeutic quantities to overcome the difficulties associated with the oral route. 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. New transdermal drug delivery system (TDDS) technologies now have been developed that is considered to be helpful in rate controlled delivery of drug that is difficult to administer.

REFERENCE ID: PHARMATUTOR-ART-2034

1.1 INTRODUCTION
Transdermal drug delivery systems (TDDS) are defined as self contained, discrete dosage forms which, when applied to intact skin, deliver the drug(s), through the skin, at a controlled rate to systemic circulation. The Transdermal route of administration is recognized as one of the potential route for the local and systemic delivery of drugs. In comparison to conventional pharmaceutical dosage forms.

TDDS offer many advantages, such as elimination of first pass metabolism, sustained drug delivery, reduced frequency of administration, reduced side effects and improved patient compliance.

Transdermal delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation, which often causes undesirable side effects. Thus various forms of Novel drug delivery system such as Transdermal drug delivery systems, Controlled release systems, Transmucosal delivery systems etc. emerged. Several important advantages of transdermal drug delivery are limitation of hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. The first Transdermal system, Transderm-SCOP was approved by FDA in 1979 for the prevention of nausea and vomiting associated with ravel, particularly by sea. The evidence of percutaneous drug absorption may be found through measurable blood levels of the drug, detectable excretion of the drug and its metabolites in the urine and through the clinical response of the patient to the administered drug therapy.2 the common ingredients which are used for the preparation of TDDS are as follows.

DRUG DELIVERY ROUTES ACROSS HUMAN SKIN

Drug molecules in contact with the skin surface can penetrate by three potential pathways: through the sweat ducts, via the hair follicles and sebaceous glands (collectively called the shunt or appendageal route), or directly across the stratum corneum (Fig. 1). The relative importance of the shunt or appendageal route versus

transport across the stratum corneum has been debated by scientists over the years (eg. [5-7]) and is further complicated by the lack of a suitable experimental model to permit separation of the three pathways. In vitro experiments tend to involve the use of hydrated skin or epidermal membranes so that appendages are closed by the swelling associated with hydration. Scheuplein and colleagues [8, 9] proposed that a follicular shunt route was responsible for the presteady-state permeation of polar molecules and flux of large polar molecules or ions that have difficulty diffusing

across the intact stratum corneum. However it is generally accepted that as the appendages comprise a fractional area for permeation of approximately 0.1% [10], their contribution to steady state flux of most drugs is minimal. This assumption has resulted in the majority of skin penetration enhancement techniques being focused on increasing transport across the stratum corneum rather than via the appendages. Exceptions are iontophoretic drug delivery which uses an electrical charge to drive molecules into the skin primarily via the shunt routes as they provide less electrical resistance, and vesicular delivery.

The stratum corneum consists of 10-15 layers of corneocytes and varies in thickness from approximately 10-15 μm in the dry state to 40 μm when hydrated [12-14]. It comprises a multi-layered “brick and mortar” like structure of keratin-rich corneocytes (bricks) in an intercellular matrix (mortar) composed primarily of long chain ceramides, free fatty acids, triglycerides, cholesterol, cholesterol sulfate and sterol/wax esters [15]. However it is important to view this model in the context that the corneocytes are not brick shaped but are polygonal, elongated and flat (0.2-1.5 μm thick, 34-46 μm in diameter). The intercellular lipid matrix is generated by keratinocytes in the mid to upper part of the stratum granulosum discharging their lamellar contents into the intercellular space. In the initial layers of the stratum corneum this extruded material rearranges to form broad intercellular lipid lamellae [16], which then associate into lipid bilayers [17, 18], with the hydrocarbon chains aligned and polar head groups dissolved in an aqueous layer (Fig. 2). As a result of the stratum corneum lipid composition, the lipid phase behaviour is different from that of other biological membranes. The hydrocarbon chains are arranged into regions of crystalline, lamellar gel and lamellar liquid crystal phases thereby creating various domains within the lipid bilayers [19]. The presence of intrinsic and extrinsic proteins, such as enzymes, may also affect the lamellar structure of the stratum corneum. Water is an essential component of the stratum corneum, which acts as a plasticizer to prevent cracking of the stratum corneum and is also involved in the generation of natural moisturizing factor (NMF), which helps to maintain suppleness. In order to understand how the physicochemical properties of the diffusing drug and vehicle influence permeation across the stratum corneum and thereby optimise delivery, it is essential to determine the predominant route ofdrug permeation within the stratum corneum. Traditionally it was thought that hydrophilic chemicals diffuse within the aqueous regions near the outer surface of intracellular keratin filaments (intracellular or transcellular route) whilst lipophilic chemicals diffuse through the lipid matrix between the filaments (intercellular route) [9] (see Fig. 2). However, this is an oversimplification of the situation as each route cannot be viewed in isolation. A molecule traversing via the transcellular route must partition into and diffuse through the keratinocyte, but in order to move to the next keratinocyte, the molecule must partition into and diffuse through the estimated 4-20 lipid lamellae between each keratinocyte. This series of partitioning into and diffusing across multiple hydrophilic and hydrophobic domains is unfavourable for most drugs. Consequently, based on more recent data (for example [16, 20-23]) the intercellular route is now considered to be the major pathway for permeation of most drugs across the stratum corneum. As a result, the majority of techniques to optimise permeation of drugs across the skin are directed towards manipulation of solubility in the lipid domain or alteration of the ordered structure of this region

To overcome these difficulties there is need for development of new drug delivery system; which will improve therapeutic efficacy and safety of drugs by more precise (i.e. site specific), spatial and temporal placement within the body there by reducing both the size and number of doses. New drug delivery system are also essential for the delivery of novel, genetically  engineered pharmaceuticals (i.e. peptides, proteins) to their site of action, without incurring significant immunogenicity or biological inactivation. Apart from these advantages the pharmaceutical companies recognize the possibility of repattening successful drugs by applying the concepts and techniques of controlled drug delivery system coupled with the increased expense in bringing new drug moiety to the market. (1) 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 AVOID systemic effects. (2)

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 mean to transfer normal drugs across this layer. The method to circumvent this is to engineer the drugs to be water-soluble and lipid soluble. The best mixture is about fifty percent of the drug being each. This is because “Lipid-soluble substance readily pas through the intercellular lipid bi-layers of the cell membranes where as 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. (3)

Transdermal drug delivery system was first introduced more than 20 years ago. The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s. By the mid to late 1990s, the trend of Transdermal drug delivery system companies merging into larger organizations. Transdermal drug deliveries in the text of research articles grow continuously in the transdermal drug delivery 1980s, and have remained constant throughout the past decade. (3)

Innovations in technologies continue to occur at a positive rate, making the technology a fertile and vibrant are a of innovation, research and product development. In the present study, various new development in the field of TDDS are included to improve the release rate and other parameters on need base system and most suitable to the patient. The conventional passive means of applying drugs to skin include the use of vehicles such as ointments, creams, gels and patch technology. More recently, such dosage forms have been developed and/or modified in order to enhance the driving force of drug diffusion (thermodynamic activity) and/or increase the permeability of the skin. These approaches include the use of penetration enhancers, supersaturated systems, hyaluronic acid, prodrugs, liposome’s and other vesicles.

However, the amount of drug that can be delivered using these methods is still limited since the barrier properties of the skin are not fundamentally changed and as such, with the exception of patches, the majority are used to treat localized skin diseases where systemic absorption is not required. Thus, while new passive technologies typically offer an improvement in dose control, patient acceptance and compliance compared to more traditional semisolid formulations, they do not have the potential to widen the applicability of Transdermal drug delivery unlike active Transdermal drug delivery technologies.

Transdermal drug technology specialists are continuing to search for new methods that can effectively and painlessly deliver larger molecules in therapeutic quantities to overcome the difficulties associated with the oral route. 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. This review article covers a brief outline of various components of Transdermal patch, applications of Transdermal patch, their advantages, disadvantages, when the Transdermal patch are used and when their use should be avoid and some of the recent development in the field along with the latest patents in this field.

Association of Pharmaceutical Scientists. Even though scientists and engineers with high interest continue to this day to publish Transdermal related scientific papers in great numbers, it is intriguing to find such continued interest while only 10 or so new drugs utilizing Transdermal technology have been introduced during these past 20 years.

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 pharmaceuticals to be delivered across 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 blood stream directly through the skin. Since there is high concentration on the patch and low concentration in the blood, the drug keep diffusing in to the blood for a long period of time, maintaining the constant concentration of drug in blood flow.

Today drugs administered through skin patches include scopolamine (for motion sickness), estrogen (for menopause and to prevent osteoporosis after menopause), nitroglycerin (for angina), and lidocaine to relieve the pain of shingles (herpes zoster). Non-medicated patches include thermal and cold patches, weight loss patches, nutrient patches, skin care patches (therapeutic and cosmetic), and aroma patches, and patches that measure sunlight exposure.

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