INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
Review Article Technologies in Transdermal Drug Delivery System: A Review Dharmaraj Dnyneshwar Biradar* and Nikita Sanghavi MET’S Institute of Pharmacy, Bandra (west), Mumbai-400 050, India.
ABSTRACT Transdermal drug delivery system is the system in which the delivery of the drug occurs through skin. It offers a convenient way to deliver drugs without the drawbacks as in case of standard hypodermic injections relating to issues such as patient acceptability and injection safety. The success of transdermal drug delivery has been severely limited due to the inability of most of the drugs to enter the skin at therapeutically useful rates. The stratum corneum acts as a barrier that limits the penetration of substances through the skin. In recent years various passive and active strategies have emerged to optimise delivery. However passive approach do not significantly improve the permeation of drugs with molecular weight > 500 Da. In contrast active methods, normally involving physical or mechanical methods of enhancing delivery has been shown to be generally superior. The delivery of drugs of differing lipophilicity and molecular weight including proteins, peptides and oligonucletides has been showed to be improved by active methods. This review covers the recent findings in various advanced techniques of enhancement of drug delivery which includes jet injectors, iontophoresis, ultrasound, thermal ablation, biodegradable microneedles.
Keywords: Transdermal drug delivery system, iontophoresis, microneedles.
INTRODUCTION Transdermal drug delivery systems (TDDS) To increase skin permeability, a number of are defined as self-contained discrete different approaches has been studied, dosage forms which, when applied to intact ranging from chemical/ lipid enhancers to skin, deliver the drug(s), through the skin, electric fields employing iontophoresis and at a controlled rate to systemic circulation. electroporation to pressure waves The main advantage of this approach is generated by ultrasound or photoacoustic that the drug is entered into the body effects. Although the mechanisms are all undistorted without being passed through different, these methods share a common the body’s various defense systems. In goal to disrupt stratum corneum structure contrast to oral administration the most in order to create “Holes” big enough for convenient way of drug administration, the molecules to pass through. The size of transdermal route does not suffer from disruptions generated by each of these drug degradation in the gastrointestinal methods is believed to be of nanometer tract and reduced potency through first- dimensions, which is large enough to pass metabolism ( i.e. in the liver ). In permit transport of small drugs and, in addition, oral-specific side effects like liver some cases, macromolecules, but probably damages are avoided. Transdermal patches small enough to prevent causing damage were introduced in the late 1970’s, starting of clinical significance. An alternative with a 3 day patch to treat motion approach involves creating larger transport sickness. Since then, the market for drug pathways of micron dimensions using array administration through patches has been of microscopic needles. These pathways steadily increasing. However transdermal are orders of magnitude bigger than delivery is severely limited by the inability molecular dimensions and, therefore, should of the majority of drugs to cross skin at readily permit transport of macromolecules therapeutic rates due to the barrier as well as possibly supramolecular imposed by the skin’s outer stratum complexes and microparticles. Despite their corneum layer. very large size relative to drug dimensions,
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 528 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
on a clinical length scale they remain corneum, a 10-20μm thick layer of 15-30 small. 6, 15 stacked, dead cornified cells. The dermis represents the bulk of the skin and the Advantages of transdermal drug delivery predominant components are collagen systems fibers and a smaller amount of elastin. 1. Easy elimination of drug delivery This fibrous network gives tensile strength during toxicity. and elasticity to the skin and also provides 2. Avoidance of first pass metabolism support for nerve and vascular networks. of drugs In the upper, papillary, region of the 3. Reductions of fluctuations in plasma dermis the collagen fibers are small and levels of drugs, Utilization of drug loosely distributed. The deep reticular candidates region contains densely packed, bundled with short half-life and low collagen fibers mainly running parallel to therapeutic index the skin surface and along certain 4. Reduction of dosing frequency directions, called Langer’s lines. The hence increased patient compliance. dermis rests on the hypodermis which is 5. Self administration is possible with composed of loose fatty connective tissue. these systems. Its thickness varies considerably over the 6. Simplified medication regimen leads surface of the body as well as between to increased patient compliance. individuals.9, 14 7. Avoidance of gastrointestinal incompatibility. Drug delivery routes across human skin 8. When oral route is unsuitable as Drug molecules in contact with the skin with vomiting and diarrhoea then surface can penetrate by three potential transdermal route is an alternative pathways : through the sweat ducts, via to deliver the drug candidate. the hair follicles and sebaceous glands ( collectively called the shunt or appendageal Limitations of transdermal drug delivery route ), or directly across the stratum systems corneum ( fig 2 ). The relative importance of 1. Only potent drugs are suitable shunt or appendageal route versus candidates for transdermal delivery. transport across the stratum corneum has 2. This system is uneconomical. been debated by scientists over the years 3. Skin irritation may occur in some and is further complicated by the lack of patients at the site of application. suitable experimental model to permit 4. The system is not suitable for separation of the three pathways. drugs that require high blood Scheuplein and colleagues19, proposed that levels. a follicular shunt route was responsible for 5. The barrier function of the skin the pre-steady permeation of polar changes from site to site in the molecules and flux of large polar same person, person to person and molecules or ions that have difficulty also with age. diffusing across the intact stratum corneum. However it is generally accepted that as Anatomy of skin the appendages comprise a fractional area The skin is the largest organ of the for permeation of approximately 0.1 % their human body and has several functions. It contribution to steady state flux of most is a physical barrier towards the drugs is minimal. This assumption has environment, it regulates body temperature resulted in the majority of skin penetration and fluid loss, it conveys sensory enhancement techniques being focused on information to the nervous system, and it increasing transport across the stratum processes immunologic information to the corneum rather than via the appendages. immune system. The skin has a surface Exceptions are iontophoretic drug delivery area of about 1.5 to 2 m2 in adults and it which uses an electric charge to drive contains glands, hair and nails. molecules into the skin primarily via the The skin can be divided into three layers : shunt routes as they provide less electrical the superficial epidermis, dermis and charge, and vesicular delivery.5, 9 hypodermis (fig 1). The epidermis is approximately 50-150 μm thick and consists 1. Transappendageal route of constantly renewing, outward moving This is also called as the shunt pathway. cells called keratinocytes. The outermost In this route the drug molecule may layer of the epidermis is the stratum transverse through the hair follicles, the
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 529 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
sebaceous pathway of the pilosebaceous phospholipid bilayer of the cell one more apparatus or the aqueous pathway of the time. This series of steps is repeated salty sweat glands. The transappendageal numerous times to traverse the full pathway is considered to be of minor thickness of the stratum corneum. importance because of its relative smaller area ( less than 0.1 % of total surface ). Intercellular penetration Non polar substances follow the route of 2. Transcorneal penetration intercellular penetration. These molecules Intracellular penetration dissolve in and diffuse through the non- Drug molecule passes through the cells of aqueous lipid matrix imbibed between the the stratum corneum. It is generally seen protein filaments. Although the thickness of in case of hydrophilic drugs. Although this the stratum corneum is about 20μm, the is the path of shortest distance, the drugs actual diffusional path of most molecules encounter significance resistance to crossing the skin is on the order of permeation. This is because the drugs 400μm. The 20-fold increase in the actual must cross the lipophilic membrane of path of permeating molecules greatly each cell, then the hydrophilic cellular reduces the rate of drug penetration. contents containing keratin, and then the
Table 1: Regional variations in water permeability of stratum corneum 2 Diffusivity S.No. Skin region Thickness (μm) Permeation rate (mg/cm /hr) (cm2/sec*1010) 1 Abdomen 15.0 0.34 6.0 2 Volar forearm 16.0 0.31 5.9 3 Back 10.5 0.29 3.5 4 Forehead 13.0 0.85 12.9 5 Scrotum 5.0 1.70 7.4 6 Back of hand 49.0 0.56 32.3 7 Palm 400.0 1.14 535.0 8 Plantar 600.0 3.90 930.0
Factors influencing transdermal drug site to site. These factors significantly affect delivery permeation. The effective transdermal drug delivery can be formulated by considering three factors 5. Skin metabolism as drug, skin and the vehicles. So the Skin metabolises steroids, hormones, factors affecting can be divided into chemical carcinogens and some drugs. So classes as biological and physicochemical skin metabolism determines the efficacy of factors.1, 7 drug permeated through the skin.
A. Biological factors 6. Species differences 1. Skin condition The skin thickness, density of appendages Acids and alkalis, many organic solvents and keratinisation of skin vary from species damage the skin cells and promote skin to species so affects permeation. penetration. Diseased state of patient alters the skin conditions. B. Physicochemical factors 1. Skin hydration 2. Skin age The permeability of the skin increases The young skin is more permeable than significantly when in contact with water. older. The permeability of the skin Hydration is the most important factor decreases as the age of the person increasing the permeation of skin therefore increases. the use of humectants is done in transdermal drug delivery. 3. Blood supply Changes in peripheral circulation can affect 2. Temperature and pH transdermal absorption. The permeation of drug increase ten folds with temperature variation. The diffusion 4. Regional skin site coefficients decrease as the temperature Thickness of skin, nature of stratum falls. Weak acids and weak bases corneum, and density of appendages vary dissociate depending on the pH and pKa
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 530 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
or pKb values. The proportion of unionized since a possible rupture of the membrane drug determines the drug concentration in could result in a sudden release of the skin. Thus temperature and pH are drug. 10, 14 important factors affecting drug penetration. Drug selection criteria for patch 3. Diffusion coefficient The following are the properties required Penetration of drug depends upon diffusion by the drug to be selected for delivery by coefficient of drug. At a constant transdermal route. It includes physico- temperature the diffusion coefficient of drug chemical and biological properties of the depends on its properties, diffusion medium drug. Also, the pharmacokinetic and and interaction between them. pharmacodynamic parameters of the drug must be considered.1, 8, 9 4. Drug concentration The flux is proportional to the Physico-chemical properties concentration gradient across the barrier 1. The drug should have affinity for and concentration gradient will be higher if both lipophilic and hydrophilic the concentration of drug will be more phases. across the barrier. 2. The drug should have a low melting point. 5. Partition coefficient 3. The drug should have a molecular The optimal K, partition coefficient is weight less than 1000 Daltons. required for good action. Drugs with high 4. Since the skin has a pH of 4.2 to K are not ready to leave the lipid portion 5.6, solutions which have this pH of skin. Also drugs with low K will not be range are used to avoid damage to permeated. the skin. However for a number of drugs, there may also be a 6. Molecular size and shape significant transdermal absorption at Drug absorption is inversely related to pH values at which the unionized molecular weight; small molecules penetrate form is predominant. faster than large ones. Because of partition coefficient domination effect of molecular Biological properties size is not known. 1. The drug should be non-irritating and non-allergic to the site of Transdermal patches application. Transdermal patches were introduced in 2. The drug should have a short life. the late 1970’s, starting with a three day 3. Drug should be potent with a daily patch to treat motion sickness. Since then dose of the order of a few mg/day. the market for drug administration through 4. Drugs which degrade in the patches has been steadily increasing. gastrointestinal tract or inactivated Transdermal patches are divided into two by hepatic first pass effect are categories based on their physical structure suitable candidates for transdermal :Reservoir-based and Matrix-based. delivery. Reservoir-based patches hold the drug in a solution ( usually a liquid or a gel ) in a General clinical considerations in the separate compartment. The drug is use of transdermal patches released through a rate- controlling The Patient should be advised regarding permeable membrane placed as an the proper and safe usage of transdermal interface between the reservoir and the patches. The patient must be made aware skin ( fig 3 ). Matrix-based patches have a of the importance of using the more simple design in which the drug is recommended site and rotating locations. incorporated with the adhesive layer. There Rotating location is important to allow the is no membrane that controls the release skin to regain its normal permeability and rate of the drug. Instead, the permeability to prevent skin irritation. 11 The following of the skin governs the rate control. guidelines must be considered while Matrix-based patches are easier to applying a patch fabricate and thus the production cost is 1. A patch must be applied to a lower than for reservoir-based patches ( fig clean, dry skin free of hair and 4 ). On the other hand, reservoir-based oily, inflamed, irritated or broken. patches offer better control of the drug Wet skin can accelerate the drug release but may raise safety concerns permeation rate. Oily skin can
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 531 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
impair the adhesion of patch. If replacement with a fresh hair is present at the application transdermal patch. site then it should be carefully cut 6. The patient or the person applying and not wet shaven nor should a the patch should clean the hands depilatory agent be used, since before and after applying the patch. later can remove the stratum They should not rub eye or touch corneum layer and affect the the mouth during handling of the permeation rate and extent of the patch. drug. 7. If the patient exhibits sensitivity or 2. Use of skin lotion must be avoided intolerance to the transdermal at the site of application since it system or if undue skin irritation affects the hydration of skin and results, the patient should seek alter the partition coefficient of revaluation or consult a physician. drug. 8. Upon removal of the transdermal 3. Patient should take care that the patch, it should be folded in its patch is not being physically half with the adhesive layer altered, since it can destroy the together. The used patch must be integrity of the system. discarded in a manner safe to 4. The patch should be placed at a childrens and pets. site that will not subject it to being 9. It is important to use a different rubbed-off by clothing or movement. application site everytime the patch While bathing or showering the is changed to avoid skin irritation. transdermal patch should be left Suggested rotation is : on. Day 1 : Upper right arm 5. The product’s usage instructions Day 2 : Upper right chest must be carefully read and Day 3 : Upper left chest followed for the period to be worn Day 4 : Upper left arm, as well as its removal and Then repeat from Day 1.
Table 2: List of transdermal drugs approved by the US FDA Approval year Drug Indication Product name Marketing company 1979 Scopolamine Motion sickness Transderm-scop® Novartis consumer health 1981 Nitroglycerin Angina pectoris Transderm-nitro® Novartis 1984 clonidine Hypertension Catapress TTS® Boehringer Ingelheim Menopausal ® 1986 Estradiol Estraderm Novartis symptoms 1990 Fentanyl Chronic pain Duragesic® Janssen pharmaceutica Nicoderm®, GSK, 1991 Nicotine Smoking cessation Habitrol®, Novartis, proStep® Elan Testosterone ® 1993 Testosterone Testoderm Alza deficiency Lidocaine/ epinephrine Local dermal ® 1995 Iontocaine Iomed (iontophoresis) analgesic Menopausal 1998 Estradiol / norethidrone Combipatch® Novartis symptoms Post-herpetic neuralgia ® 1999 Lidocaine Lidoderm Endo pain 2001 Estradiol / norelgestromin Contraception Ortho Evra® Ortho-McNeil 2003 Estradiol / levonorgestrol Menopausal symptoms Climara Pro® Bayer healthcare 2003 Oxybutynin Overactive bladder Oxytrol® Watson pharma Lidocaine Local dermal ® 2004 SonoPrep Echo therapeutics ( ultrasound ) anesthesia Local dermal ® 2005 Lidocaine / tetracaine Synera Endo pharmaceuticals analgesia Attention deficit ® 2006 Methylphenidate Daytrana Shire hyperactivity disorder Major depressive 2006 Selegiline Emsam® Bristol-myers squibb disorder 2007 Rotigotine Parkinson’s disease Neupro® Schwarz pharma 2007 Rivastigmine Dementia Exelon® Novartis 2013 sumatriptan migraine Zecuity® NuPathe Inc.
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 532 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
Recent advanced techniques for Electroporation enhancing drug delivery via transdermal Electroporation involves the use of high route voltages (≥ 100 ) and short treatment In the past few years numerous methods durations ( milliseconds ). It reversibly and techniques have been developed to disrupts the cell membranes. Although the overcome the skin barrier. These methods electric field applied for milliseconds during can be broadly categorised into passive electroporation provides an electrophoretic methods and active methods of drug driving force, diffusion through long-lived delivery via transdermal delivery. electropores can persist for up to hours, such that transdermal transport can be Passive methods for enhancing increased by orders of magnitude for small transdermal drug delivery model drugs, peptides, vaccines and DNA. Passive approach involves the optimization Since the stratum corneum electrical of formulation or drug carrying vehicle to resistance is orders of magnitude greater increase the skin permeability. The than deeper tissues, the electric field conventional means of applying drug to applied during electroporation is initially skin include the use of vehicles such as concentrated in the stratum corneum. ointments, gels, creams and “passive” However during electroporation of stratum patch technology. In recent years, corneum lipid bilayers, stratum corneum approaches such as the use of penetration resistance rapidly and dramatically drops, enhancers, supersaturated systems, and the electric field correspondingly prodrugs, liposomes and other vesicles has distributes to a greater extent into the been developed. However, the amount of deeper tissues, which contain sensory and drug that can be delivered through these motor neurons. The associated pain and methods is still limited since the barrier muscle stimulation can be avoided by properties of the skin are not using closely spaced microelectrodes that fundamentally changed. constrain the electric field within the stratum corneum. Active methods for enhancing Genotronics Inc. have developed a transdermal drug delivery prototype electroporation transdermal Active approach involves the use of device, which has been tested with various external energy to act as a driving force compounds in order to achieve gene and/ or act to reduce the barrier nature of delivery, improving drug delivery and aiding the stratum corneum in order to enhance the application of cosmetics. Transdermal the permeation of drug molecules across device based on electroporation has been the skin. Recent progress in these proposed by various groups however, more technologies has occurred as a result of clinical information on the safety and advances in precision engineering ( efficacy of the technique is required to bioengineering ), computing, chemical assess the future commercial aspects.6, 14 engineering and material sciences which all have contributed to the creation of Iontophoresis miniature, powerful devices that can Iontophoresis refers to the delivery of generate the required clinical response. drugs across the skin by means of an The use of active enhancement methods electric field. By having two electrodes has gained importance due to the advent placed on the skin, drugs at the electrodes of biotechnology in the latter half of 20th will start to migrate through the skin once century, which has led to the generation of a voltage is supplied to the electrodes. therapeutically-active, large molecular weight Once in the skin, the drug will be ( > 500 Da ) polar and hydrophilic absorbed by the capillaries and molecules, mostly peptides and proteins. systemically distributed. The current density However gastrointestinal enzymes often is usually below 0.5 mA / cm2 in order not cause degradation of such molecules and to cause patient any discomfort. Three hence there is a need to demonstrate main physical mechanisms are involved in efficient delivery of these molecules by iontophoresis : charged species are driven alternate route of administration. Passive from the electrodes as a result of the methods of delivery are incapable of electric field, ( electrophoresis), the flow of enhancing permeation of such large current increases the permeability of the solutes, which has led to studies involving skin; and, the established potential the use of alternative active strategies. difference between the electrodes give rise to an electro-osmotic flow. Since electro-
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 533 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
osmosis occurs, uncharged species can be Cavitational ultrasound delivered as well. In addition to heating, ultrasound is also Parameters that affect design of an known to generate cavitation, which is the iontophoretic skin delivery system include; formation, oscillation and, in some cases, electrode type, current intensity, pH of the collapse of bubbles in an ultrasonic system and competitive ion effect. The pressure field. Cavitation is only generated strongest asset of iontophoresis is that the under specific conditions ( e.g. low frequency rate of delivery scales with the electrical ultrasound ) that differ from those of current, which can be readily controlled by ultrasonic heating or imaging devices. The a microprocessor or, in some cases, the opportunity for transdermal drug delivery is patient. In this way, drug delivery can be that cavitation bubbles concentrate the turned on and off and even modulated energy of ultrasound and thereby enable over time to enable complex delivery targeted effects at the site of bubble profiles. However, the maximum current activity. Since bubbles are more difficult to and the maximum delivery rate is limited grow and oscillate within densely packed by skin irritation and pain caused by the tissue, cavitation preferentially occurs within general inability of iontophoresis to localize the coupling medium ( e.g. a hydrogel ) its effect to the stratum corneum. Due to between the ultrasound transducer and these strengths and weaknesses, current skin. The expected mechanism of applications emphasize the ability of cavitational ultrasound is that bubbles iontophoresis to provide control over drug oscillate and collapse at the skin surface, dosing, because it scales with the amount which generate localized shock waves and of charge delivered to the skin. liquid microjets directed at the stratum In January 2013, FDA announced the corneum. This disrupts stratum corneum approval of Zecuity™ by Nu Pathe Inc. lipid structure and thereby increases skin Which is a sumatriptan iontophoretic permeability for upto many hours without transdermal system indicated for the damaging deeper tissues. treatment of migraine with or without aura. In the year 2004, FDA approved the first FDA also approved the Ionsys™ sonophoretic transdermal system manufactured by ALZA corporation which is SonoPrep® by Sontra medical corp. Aimed a fentanyl iontophoretic transdermal system for lidocaine administration ( pain relief ) and indicated for the management of acute consists of a portable base unit connected post-operative pain in adult patients to an ultrasonic horn that is pressed onto requiring opioid analgesia during the area of the skin to be treated. hospitalization.6, 10 Cavitational ultrasound has been studied extensively in animals for delivery of Ultrasound (sonophoresis and insulin, heparin, tetanus toxoid vaccine and phonophoresis ) other compounds. Ultrasound can be Ultrasound involves the use of ultrasonic applied using hand held devices, as well energy to enhance the transdermal delivery as low-profile, cymbal transducers that of solutes either simultaneously or via pre- could be integrated into a patch.13, 14 treatment and is frequently referred to as sonophoresis or phonophoresis. Laser radiation and photomechanical waves Non-cavitational ultrasound Lasers have been used in the clinical Ultrasound is an oscillating pressure wave therapies for decades, therefore their at a frequency too high for humans to effects on the biological membranes are hear. Although some have hypothesized well established and documented. Lasers that pressure gradients and oscillation are frequently used for the treatment of associated with ultrasound act as a driving dermatological conditions such as acne and force to move drugs into the skin, it to confer “facial rejuvenation” where the appears that the dominant effect is to laser radiation destroys the target cells disrupt stratum corneum lipid structure and over a short frame of time ( ̴300 ns ). Such thereby increase permeability. The effects direct and controlled exposure of the skin of non-cavitational ultrasound on skin to laser radiation results in ablation of the permeability have generally been limited to stratum corneum without significant damage enhancing small, lipophilic compounds. to the underlying epidermis. Removal of the stratum corneum via this method has been shown to enhance the delivery of lipophilic as well as hydrophilic drugs. The
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 534 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
extent of barrier disruption is known to be Experiments in rats have shown the device controlled by the parameters such as to enhance the delivery of granisetron wavelength, pulse length, pulse energy, HCL, with blood plasma levels recorded pulse number and pulse repetition rate. after 12 h rising to 30 times higher levels A hand-held portable laser device has than that recorded for untreated skin after been developed by the Norwood Abbey 24 h. A similar enhancement in diclofenac Ltd. In a study involving human volunteers, skin permeation was also observed in the the device was found to reduce the onset same study. The device is reported not to of action of lidocaine to 3-5 mins., whilst cause any damage to the skin with the 60 mins. was required to attain a similar radio-frequency induced microchannels effect in control group. The Norwood remaining open for less than 24 h. The Abbey system has been approved by the skin delivery of drugs such as testosterone US and Australian regulatory bodies for the and human growth hormone by this device administration of a topically applied is also currently in progress. 6, 13 anaesthetic. Photomechanical waves are the pressure Magnetophoresis pulses produced by ablation of a material This method involves the application of a target such as polystyrene by Q-switched magnetic field which acts as an external or mode-locked lasers. Photomechanical driving force to enhance the diffusion of a waves are able to render the stratum diamagnetic solute across the skin. Skin corneum more permeable to exposure to a magnetic field might also macromolecules via a possible transient induce structural alterations that could permeabilisation effect due to the formation contribute to an increase in permeability. In of transient channels. The largest molecule vitro studies by Murthy showed a that has been reported to be delivered magnetically induced enhancement in through the rat skin to date has a benzoic acid flux, which was observed to molecular weight of 40,000 Da. Suggestions increase with the strength of the applied have been made that many clinically magnetic field. Other In vitro studies using important proteins such as insulin ( 6000 Da a magnet attached to transdermal patches ) and hematoprotein ( 48,000 Da ) are within containing terbutaline sulphate, or close to the delivery capability range of demonstrated an enhancement in permeant photomechanical waves. However this new flux which was comparable to that attained technique does not yet seem to have when 4 % isopropyl myristate was used as produced any human clinical data.12 a chemical enhancer. In the same paper, the effect of magnetophoresis on the Radio-frequency permeation of terbutaline sulphate was Radio-frequency involves the exposure of investigated In vivo using guinea pigs. The skin to high frequency alternating current (̴ preconvulsive time of guinea pigs for those 100 KHz ) resulting in the formation of subjected to magnetophoretic treatment was heat-induced microchannels in the found to last for 36 h which was similar to membrane similar to when laser radiation that observed after application of a patch is employed. The rate of drug delivery is containing 4 % isopropyl muristate. This controlled by the number and depth of the was in contrast to the response elicited by microchannels formed by the device, which the control ( patch without enhancer ), when is dependant on the properties of the the increase in preconvulsive time was microelectrodes used in the device. The observed for only 12 h. In human subjects, viaderm device ( Transpharma Ltd ) is a the levels of terbutaline sulphate in the hand held electronic device consisting of a blood was higher but not significantly microprojection array ( 100 microelectrodes/ different to that observed with the patch cm2 ) and a drug patch. The microneedle containing 4 % isopropyl myristate. array is attached to electronic device and The fact that this technique can only be placed in contact with the skin to facilitate used with diamagnetic materials will serve the formation of the microchannels. as a limiting factor in its applicability and Treatment duration takes less than a hence result in lack of interest.13 second, with a feedback mechanism incorporated within the electronic control Thermophoresis providing a signal when the microchannels The temperature of the skin surface is have been created, so as to ensure 32°C in the humans which is regulated by reproducibility of action. The drug patch is homeostatic controls. Previous studies have then placed on the treated area. demonstrated the 2-3 fold increase in the
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 535 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
flux for every 7-8°C rise in the method. The device ( fig 5 ) as described in temperature of skin surface. This has led the patent consists of a drug reservoir and to the interest of various development a number of projections extending from the scientists and researchers in using reservoir. These microneedles of length 50- thermoregulation as a means of improving 110 μm will penetrate the stratum corneum the delivery profile of topical medicaments. and epidermis to deliver the drug from the The increased permeation following heat reservoir. As a result of the current treatment has been attributed to an advancement in microfabrication technology increase in drug diffusivity in the vehicle in the past years, cost effective methods and an increase in drug diffusivity in the of developing devices in this area are now skin due to increased lipid fluidity. becoming increasingly common. Vasodilation of the subcutaneous blood Microneedles are promising microfabricated vessels as a homeostatic response to a devices for minimally invasive drug delivery rise in skin temperature also plays an applications. Drug delivery with important role in enhancing the transdermal microneedles aims to deliver a drug delivery of topically applied compounds. through the skin rather than biological The In vivo delivery of nitroglycerin, circulatory systems such as blood vessels testosterone, lidocaine, tetracaine and or lymphatic vessels. Accordingly, the fentanyl from transdermal patches with microneedles should not cause pain when attached heating devices was shown to they penetrate the skin, and should have increase as a result of the elevated sufficient length such that they can deliver temperature at the site of delivery. drugs to the target site. In addition, the The controlled heat-aided drug delivery microneedles should have excellent patch ( CHADD ) by Zars Inc., consists of a physical hardness such that they can patch containing a series of holes at the penetrate the stratum corneum having a top surface which regulate the flow of thickness of 10-20 μm. oxygen in to the patch. Heat is generated Microneedles are classified on the basis of chemically in a powder filled pouch by an fabrication process as : In-plane and Out-of- oxidative process regulated by the rate of plane microneedles. In-plane microneedles flow of oxygen through the holes in the are fabricated with the shaft being parallel patch. The CHADD technology was used to substrate surface. The advantage of this in the delivery of a local anesthetic system arrangement is that the length of the ( lidocaine and tetracaine ) from a patch ( needle can be accurately controlled. A S-Caine® ) and found to enhance the disadvantage is that it is difficult to depth and duration of the anesthetic action fabricate two-dimensional arrays. Out-of- in human volunteers when the results plane microneedles protrude from the obtained in active and placebo groups substrate and are easy to fabricate in were compared. Zars Inc. Together with arrays. Instead the length and high aspect- Johnson and Johnson, recently submitted ratios become significant challenges in the an investigational new drug ( IND ) fabrication of these kind of needles. application to the FDA for Titragesia™ ( a Another way of distinction is whether the combination of CHADD disks and needles are solid or hollow. Hollow Duragesic® patches, the latter contains needles with a needle bore or lumen allow fentanyl for treatment of acute pain ). The an active liquid transport through the studies described above employed an microneedle. upper limit skin surface temperature of 40- Various possible strategies can be 42°C, which can be tolerated for a long employed to deliver drugs across skin via period ( > 1 h ) microneedles. The simplest way is to In heat patch systems where patient perforate the skin with microneedles and exposure to heat is ≤ 24 h, such an upper then apply the drug onto the skin for limit may be necessary for regulatory subsequent diffusive spread into the body. compliance. In addition, the issue of drug The drug can be applied to the skin stability may also need to be addressed surface as a gel or through a medicated when elevated temperatures are used. 3, 6, patch to achieve prolonged release. 14. Another way is to precoat the microneedles with the drug before they are Microneedles inserted into the skin. A third option is to One of the first patents ever filed for a fabricate the microneedles in a drug delivery device for the percutaneous biodegradable material that incorporates the administration of drugs was based on this drug. When the needles are inserted into
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 536 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
the skin, the needles dissolve and the and cuts as a result of a defined drug is subsequently released. If the movement when in contact with the skin. microneedles are hollow, the drug can be Godshall and Anderson, described a actively injected into the tissue. Hollow method and apparatus for disruption of needles can also be used with passive, epidermis in a reproducible manner. The diffusion-driven, delivery. To maximize the apparatus consists of a plurality of delivery rate, a rational strategy is to microprotrusions of a length insufficient for distribute the delivery over several penetration beyond epidermis. The microneedles. That is, by using an array of microprotrusions cut into the outer layers microneedles over a larger skin surface of the skin by movement of the device in area, it exposes a larger area of the drug a direction parallel to the skin surface. which promotes further diffusion to the After disruption of the skin, passive ( capillaries. solution, patch, gel, ointment ) or active ( Theraject Inc. Has developed two patches iontophoresis, electroporation ) delivery with microneedles, Drugmat® and Vaxmat®, methods can then be utilised. 6, 13 intended for topical, transdermal delivery. The company manufactures the Needleless injection microneedles from a sugar polysaccharide, Needleless injection is reported to involve combining it with drug and molding these a pain free method to administer drugs components into sharp needles. The across skin. This method therefore avoids resulting product is inert and safe, and the the issues of safety, pain and fear needles dissolve with use, thereby avoiding associated with the use of hypodermic issues of disposal and contamination.10, 15, needles. Transdermal delivery is achieved 16. by firing the liquid or solid particles at supersonic speeds through the outer layers Solid microneedle arrays of the skin using a suitable energy source. Solid microneedles can be used to create Over the years there have been a micronscale holes in the skin through numerous examples of both liquid ( Ped-O- which molecules can more easily transport. Jet®, Iject®, Biojector 2000®, Medi-jector®, The first microneedle arrays reported in the Intraject® ) and powder ( PMED™ device literature were etched into the silicon wafer formerly known as Powderject® injector ) and developed for intracellular delivery in systems. The latter device has been vitro by Hashmi et al. These needles were reported to successfully deliver inserted into cells and nematodes to testosterone, lidocaine hydrochloride, and increase molecular uptake and gene macromolecules such as calcitonin and transfection. Shortly after this work was insulin.1, 4, 12 published, microneedles were developed for The problems facing needleless injection transdermal delivery applications, which systems include the high developmental have been shown to insert into skin and cost of both the device and the dosage thereby deliver a variety of different form and the inability to control drug compounds in vitro and in vivo. delivery to compensate for inter-subject differences in skin permeability. Hollow microneedle arrays In contrast to solid microneedles discussed Suction ablation above, microneedles containing hollow bore It involves the application of a vacuum or offer the possibility of transporting drugs negative pressure to remove the epidermis, through the interior of well-defined needles whilst leaving the basal membrane intact. by diffusion or, for more rapid rates of The Cellpatch® (Epiport pain relief, Sweden) delivery, by pressure driven flow. A variety is a commercially available product based of hollow microneedles have been on this mechanism. It comprises of a fabricated, but only limited work has been suction pump, epidermatome (to form a published on their possible use to deliver blister) and device (which contains compounds into skin. morphine solution) to be attached to the skin. Skin puncture and perforation The disadvantages associated with this These devices are similar to microneedle method include the prolonged length of devices produced by microfabrication time required to achieve a blister ( 2.5 h ), technology. They include the use of although this can be reduced to 15-70 min needle-like structures or blades, which by warming the skin to 38° C.13 disrupt the skin barrier by creating holes
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 537 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
Application of pressure development scientists. Rising interest of The application of modest pressures ( upto the researchers to improve vaccine 25 kPa ) has been shown to provide a administration via this route since vaccine potentially non-invasive and simple method delivery via the skin targets the potential of enhancing skin permeability of molecules epidermal langerhans and dermal dendritic such as caffeine. These workers attributed cells generate a strong immune response the increase in transcutaneous flux to at much lower doses than deeper injection. either an improved transappendageal route Elimination of the need for hypodermic or an increased partition of the compound needles further motivates transdermal into the stratum corneum when pressure vaccine development. was applied.13, 6 In the future, It is likely that transdermal patches will continue to be used for Skin stretching delivery of small molecule drugs. The These devices hold the skin under tension techniques such as iontophoresis, in either a unidirectional or multidirectional ultrasound, microneedles that enable manner. The authors claim that a tension targeted disruption of stratum corneum of about 0.01 to 10 mP results in the while protecting deeper tissues have reversible formation of micropathways. The brought the field to a new level of efficiency of the stretching process was capabilities that position transdermal drug demonstrated by the monitoring the delivery for increasingly widespread impact delivery of a decapeptide ( 1 kDa ) across on medicine. the skin of hairless guinea pigs using a microprotusion array. The results of the CONCLUSION study showed that bidirectional stretch The transdermal drug delivery is a allowed the skin to remain open and painless, convenient, and potentially facilitate drug permeation to a greater effective way to deliver regular doses of extent ( 27.9 ± 3.3 μg/ cm2 h ) than in the many medications. The use of transdermal control group ( 9.8 ± 0.8 μg/ cm2 h ), where drug delivery has experienced a the skin was not placed under tension remarkable increase in recent years due to after microneedle treatment.6 the advancements in techniques for transdermal drug delivery system. With the Skin abrasion rising interest of the researchers more This technique involves the direct removal number of drugs are becoming available or disruption of the upper layers of skin to for delivery via this route. The properties enhance the permeability of the topically of the drug, the characteristics of the skin applied compounds. The delivery potential and the status of patient’s skin are all of the skin abrasion techniques are not important factors for safe and effective restricted by the physic-chemical properties delivery of the drug. of the drug and previous work has illustrated that such methods enhance and ACKNOWLEDGEMENT control the delivery of a hydrophilic The corresponding author would like to permeant, vitamin C, vaccines and thank The Principal, MET Institute of biopharmaceuticals.13 Pharmacy, and Mrs. Nikita Sanghavi for their valuable support and guidance. The Future outlook author would also like to thank MET’S Transdermal delivery offers compelling Institute of Pharmacy, for providing opportunities to the researchers and necessary facilities to search the literature.
Fig. 1: Structure of skin
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 538 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
Fig. 2 : Routes of drug delivery across skin : 1,3- transappendageal route, 2- transcorneal route
Fig. 3: Reservoir-based transdermal patch
Fig. 4: Matrix-based transdermal patch
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 539 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
Fig. 5: Microneedle-based transdermal system
REFERENCES system. Intl Res J Pharm. 1. Deshwal S and Verma N. 2012;3(8):39-44. Optimization techniques in 9. Gaikwad AK. Transdermal drug transdermal drug delivery systems. delivery system : formulation Int J Pharm Sci Res. 2012;(8) : aspects and evaluation. 2362-2370. Comprehensive J Pharm Sci. 2. Heather AE and Benson. Current 2013;1(1): 1-10. drug delivery, Edition 2, Bentham 10. Roxhed N. A fully integrated science publishers ltd, 2005;23-33. microneedle-based transdermal 3. Wilson JE. Three generations : drug delivery system; KTH- Royal The past, present, and future of ins. Tech. Sweden. 2007;1-82. transdermal drug delivery 11. Nikhil Sharma, Geeta Agarwal, systems., Pharmacon Inc. 2001;1- Rana AC, Zulfiqar Ali Bhat and 22. Dinesh Kumar. A Review : 4. Sharma N, Parashar B, Sharma S Transdermal drug delivery system : and Mahajan U. Blooming pharma A tool for novel drug delivery industry with transdermal drug system. Int J Drug Dev and Res. delivery system, Indo global 2011;3(3):70-84. Journal of pharmaceutical 12. Jatav VS, Saggu JS, Jat RK, sciences. 2012;2 (3): 262-278. Sharma AK and Singh RP. Recent 5. Patel H, Patel U, Bhimani B, advances in development of Daslaniya D and Patel G. transdermal patches; Transdermal drug delivery system Pharmacophore. 2011;2(6):287-297. as prominent dosage forms for 13. Patil PM, Chaudhari PD, Jalpa K, the highly lipophilic drugs; Int J Patel KA, Kedar and Katolkar PP. Pharm Res and Bio-science. Recent trends in challenges and 2012;1(3):42-65 opportunities of transdermal drug 6. Marc B Brown, Matthew JT, Gary delivery system. Int J Drug Dev PM and Franklin KA Transdermal and Res. 2012;4(1): 39-50. drug delivery systems. skin 14. Prausnitz MR and Langer R. perturbation devices. Transdermal drug delivery; NIH 7. Prabhakar V, Agarwal S, Sharma Public Access, Nat. Biotechnol. R and Sharma S. Transdermal 2008;26(11):1261-1268. drug delivery system. Review Int 15. Prausnitz MR. Microneedles for Res J Pharm. 2012;3(5):50-53. transdermal drug delivery; Adv. 8. Vishwakarma SK, Niranjan SK, Drug Delivery Reviews. Irchhaiya R, Kumar N and Ali A. 2004;56:581-587. A Novel Transdermal drug delivery 16. Tabassum N, Sofi A and Khuroo T. Microneedle technology : A new
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 540 INTERNATIONAL JOURNAL OF PHARMACEUTICAL AND CHEMICAL SCIENCES ISSN: 22775005
drug delivery system. Intl J Res Publishers and Distributors, Pharm and Biomedical Sci. 2002;411-447. 2011;2(1):59-62. 19. Scheuplein RJ, Blank IH, Brauner 17. Jain NK. Controlled and novel GJ and MacFarlane DJJ. Invest drug delivery, CBS Publishers and Dermatol. 1969;52: 63-70. Distributors. 2002. 20. Scheuplein RJ and Blank IH. 18. Vyas S.P and Khar RK. Targetted Physiol Rev. 1971;51:702-747. and controlled drug delivery novel 21. Higuchi WI. Journal of carrier system, 1st edition, CBS Pharmaceutical Sciences. 1962;51:802-804.
Vol. 3 (2) Apr-Jun 2014 www.ijpcsonline.com 541