Transdermal drug delivery system is an alternative and safe route for drugs to reach in systemic circulation via skin than oral route in novel drug delivery system. It give sustained release and minimize the side effects in comparison to conventional dosages forms. More than 20 drug molecules are in market with 40 products in present time. Stratum corneum acts as barrier for transdermal products to reach drug into the blood circulation. Different approaches are carried out to defeat skin as barrier in this system. With the innovation of technology, there are various techniques are used in TDDS system to improve efficacy and compliance of patients. In this review article, we try to discussed various techniques based on TDDS like iontophoresis, sonophoresis, microneedles, magnetophoresis, liposomes and niosomes
Transdermal drug delivery system through particular dose of drug across the skin reach into the bloodstream. Sustained drug release can be achieved by transdermal drug delivery systems (TDDS) which can deliver the drug through the skin in blood circulation at a predetermined rate over a long time period(1). Moreover, it improve the therapeutic efficacy and reduced side effect such as first pass metabolism,. TDDS reduces the load as compared to oral route and increase the patient compliance. This delivery system offer much to those drug molecules having narrow therapeutic window, short half-life and undergo first pass metabolism(2).
Advantages of TDDS:
' longer duration of action resulting in a reduction in dosing frequency.
' Increased convenience to administer drugs
' Frequent dosing not required
' Improved bioavailability and uniform plasma levels
' Reduced side effects and improved therapy due to maintenance of plasma levels up to the end of the dosing interval.
' Drug and other exipients may be caused itching, edema and erythema.
' High cost of treatment.
' Dose dumping may occur drug in skin
' Skin irritation may occur at application site in some cases.
Skin as a barrier
Skin is the most accessible organ of body receiving for about one third of the body's blood circulation. Anatomically skin contain three different layers: epidermis, dermis and hypodermis. The epidermis outer layer of skin wihich is directly exposed to environment and has no blood flow (100 to 150 ??m thick approximate) . It also contain a layer that known as the stratum corneum lipid layer (15-20 ??m thick) consists of dead cells (corneocytes) (3,4). The dead nature of the SC, solute pass through this layer by passive diffusion in accordance with Fick's Law (5). It possesses of keratinized and flattened remnants diving epidermal cells.
The dermis is a the thickest layer of skin consist of hair follicles, sweat glands, nerve endings and acts as site for the systemic absorption. The intracellular space is long chain ceramides, rich in lipid, cholesterol and free fatty acid. To overcome the skin barriers in transdermal drug delivery methods are divided broadly in two category which are active and passive transport. alternative depends on many factors which consists of permeation time, physiochemical properties of drug such as molecular weight, solubility, pKa, stability , partition coefficient, binding affinity, thickness of stratum corneum, metabolism, hydration of skin, follicular and sweat gland density. Stratum corneum is a highly lipophilic membrane and resistance to drug penetration. Delivery of drugs via passive diffusion provides the greatest resistance to penetration of drugs lipophilicity and molecular weight<500 Da. The drug pass through the skin with different ways:
a. the sweat ducts
b. follicular regions
c. stratum corneum
Recent methods to enhance the transdermal drug delivery:
Advantages of recent techniques over the conventional dosages form: Conventional dosages form use vehicle to increase permeability such as ointment, gel, lotions and creams are applied on particular site for therapeutic use of drug . Various approaches are done to facilitate the skin barrier. Topical dosages are applied twice a day and accurate dosing is not possible in comparison to recent techniques. Parenteral dosages are given through needle induce pain in body and solid dosages like tablets and capsules problem in swallowing, first pass effect of drug molecules, which increase patient non-compliance. In case of recent techniques, accurate and sustained release of drug at particular dose is possible. Although new techniques are expensive and highly technical but used frequently in transdermal drug delivery system(6,7)
Factors Affecting Transdermal Bioavaibility:
Two major factors affect the bioavaibility of the drug by transdermal routes:
' Physiological factors
' Formulation factors
Physiological factors include:
(a) Age of the patient (b) Application site of the skin (c) ) Skin metabolism (d) Disease and skin condition (e) Race
Formulation factors include:
(a) ) Device (b) Method of application (c) Penetration enhancers (d)Vehicles and membrane(8, 32)
The permeation of therapeutic agent is increase in this method with the use of electric current (a few milliamperes) either directly with skin or indirectly via dosages form ( few square centimeters of skin) through the electrode. Due to enhancement in permeation of drug, this method can be allotted to either one or combination of mechanisms such as electro osmosis, electrorepulsion and electropertubation. The iontophoretic skin delivery system can be altered by following parameters that affect design; pH of the system, current intensity, electrode type, permeant type and competitive ion effect. To improve the patient non compliance, utilization of efficient, portable and patient- friendly iontophoretic systems necessary. The improved system consists of E-TRANS and Vyteris iontophoretic devices. The work reported previously concluded that combination of electroporation and iontophoresis is much better than single technique employed for drug molecules through skin.(9 t0 21)
Limitation of ionotophoretic systems
' the regulatory limits on the amount of electric current that can be applied on humans (currently set at 0.5 mA cm-2) .
' the irreversible damage of particular area, where current is applied could be a barrier for the skin.
' it has failed to facilitate the transdermal delivery of macromolecules of >7000 Da significantly.
Electroporation is a method create temporary pores across biological barrier for diffusion enhancement. It involves the application of electrical pulse with high voltages('100 V) and short the duration (milliseconds) of treatment frequently employed. Different electrical parameters that may affect delivery, which contain properties of pulse like waveform, rate and number. The generation of transient pores during electroporation which leads to increase in skin permeability. The use of technology has been successful to improve permeability the skin for molecules with differing lipophilicity and size (i.e. proteins, small molecules, oligonucleotides and peptides) also involve biopharmaceuticals with a higher molecular weight more than 7kDA, the current limit for iontophoresis. A prototype electroporation transdermal device have been develop developed by Genetronics Inc (San Diego, California), testing has been done with various components to attain gene delivery, aiding the application of cosmetics and improving drug delivery . Various apparatus have been proposed by different groups based on electroporation through transdermal drug delivery system. To access the commercial prospects in future, like efficacy and safety of the technique more clinical information is needed. For reserved electrical field with the stratum cornea, the electric pulses is given by nearest electrode for painless and safe administration. (23 to 28)
Microneedle technique is recently used in the transdermal drug delivery system to facilitate the skin permeability of drug molecules. It is a hybrid form of transdermal patch and hypodermic needle. Nerve fibers are situated in deep region, then it create pores in upper layer of skin without pain sensation(29,30,31). With the use of this device micron dimensional needles are inserted into the skin
Microneedles are robbed and minute instrument, which are manufactured by micro-mechanical system manufacturing (MEMS) technique and the silicon etching technology. Various drug delivery approaches have been carried out with the use of the microneedles for TDDS. These consists
Biodegradable microneedles- Encapsulated drug in the biodegradable and polymeric microneedles, then inserted into the skin area.
Coat and poke approach- Medicament release through device by dissolution, when drug coated needle inserted into the skin.
Hollow microneedles- The drug through a hollow bore needle injected into the body surface.
Poke with patch approach- penetration into the skin after application of the drug substance at the specific site.
It is a technique through the skin exposure to ultrasound wave frequency facilitate the transport of drugs across the skin is known as term sonophoresis or phonophoresis . The ultrasound waves ranges from 20 kHz to 10 MHz with intensity up to 3W cm-2 are applied to alleviate barrier property of the stratum corneum. This is the combination therapy of topical drug and ultrasound at particular area of skin for therapeutic effects. Furthermore, drug combine with coupling agent transfer ultrasonic wave across skin. Moreover, different topically applied dosages like as ointment, gel or cream are used to transfer the ultrasound through this technique, which disturb the lipid layer of the outermost layer of skin that facilitate permeation of drug content