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Pooja Mathur * et al. /International Journal Of Pharmacy&Technology
IJPT | June-2011 | Vol. 3 | Issue No.2 | 2373-2401 Page 2373
ISSN: 0975-766X Available Online through Research Article
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VARIOUS PENETRATION ENHANCEMENTS TECHNIQUES IN TRANSDERMAL DRUG DELIVERY
Vinay Valecha1, Pooja Mathur*2, Navneet Syan2, Surender verma3
1B.S.Anangpuria College of Pharmacy, Faridabad-121001, Haryana, India. 2Ganpati Institute of Pharmacy, Bilaspur, Yamunanagar-135102, Haryana, India.
3Institute of pharmaceutical sciences, kurukshetra uiversity, kurukshetra. Email: [email protected]
Received on 06-04-2011 Accepted on 19-04-2011
Abstract
Transdermal drug delivery (TDD) via skin to the systemic circulation provides a convenient route of
administration for a variety of clinical situations. The skin layer stratum corneum is the main barrier for
permeation of drug into the skin. So to pass the stratum corneum and to increase the flux through skin membrane,
different approaches of penetration enhancement are to be used. Transdermal drug technology specialists are
continuing to search for new methods that can effectively and painlessly deliver the larger molecules into the skin.
Several new active rate controlled transdermal drug delivery system (TDDS) technologies (chemical based,
physical based, electrically-based, structure-based, velocity-based, etc.) have been found, developed and
commercialized for the TDD. This review article covers most of the new active transport enhancement
technologies involved in enhancing the transdermal permeation into an effective drug delivery system. An attempt
has been done in depth to cover the penetration enhancement techniques (chemical, physical and various important
approaches) which are useful for a optimized and successful TDD.
Key words: Stratum Corneum, Transdermal Drug Delivery (TDD), Transdermal Drug Delivery System (TDDS)
Introduction
The main focus on specialty pharmaceuticals that add value and patient protection in major pharmaceutical
markets by providing better delivery (e.g. oral controlled-release, inhalation, implant and transdermal
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delivery systems) is further pushing the boundaries of the practical applications of basic pharmaceutical research.
Transdermal drug delivery (TDD) is now considered to be a well established technology [1]. Transdermal delivery
of drugs across the skin to the systemic circulation provides a convenient route of administration for a variety of
drugs [2]. Transdermal drug delivery system is capable of delivering those drugs having poor oral bioavailability,
side effects associated with high peaks or poor patient compliance because of high frequent dosing. However, skin
irritation, high manufacturing costs and less than ideal cosmetic appearance is the major draw back of TDD. The
main focus of recent advances with traditional passive TDD systems is on reducing skin irritation and making
products more aesthetically acceptable for patients. Other alternative systems are also in developing stage for
example physical enhancement; they are more focused on the delivery of the larger molecules such as peptides and
nucleotides. For the successful delivery of drugs, the transdermal route gaining the main focus for research in drug
delivery, around 40% of the drug candidate under clinical evaluation are related to transdermal system. The first
transdermal patch was approved in 1981 by FDA. The demand for transdermal products has been rising day by
day and this is likely to continue for the coming future. The number of new TDD products is now increasing very
fast to deliver real therapeutic benefit to patients around the world. More than 35 TDD products have now been
approved for sale in the US, and approximately 16 active ingredients have been approved now for use globally [3].
Some of Currently available marketed preparations of TDDS containing scopolamine (hyoscine) for the treatment
of motion sickness, clonidine and nitroglycerin for cardiovascular disease, fentanyl for chronic pain, nicotine to aid
smoking cessation, oestradiol (alone or in combination with levonorgestrel or norethisterone) for hormone
replacement and testosterone for hypogonadism [2]. A list of marketed preparations is mentioned in table no. 1 [3].
The worldwide transdermal patch market basically focused on the following drugs as- scopolamine (hyoscine),
nitroglycerine, tulobuterol, clonidine, estradiol (with and without norethisterone or levonorgestrel), testosterone,
fentanyl and nicotine [4]. Some of the marketed products of modified TDD technologies have been summarized in
table no. 2.
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Table-1: Marketed preparations [3].
Brand Name Company Name Drug product
Climara 3M Pharmaceuticals/Berlex Labs Estradiol
Androderm TheraTech/GlaxoSmithKline Testosterone
Alora TheraTech/Proctol and Gamble Estradiol
Deponit Schwarz-Pharma Nitroglycerin
Duragesic® Alza/Janssen Pharmaceutica Fentanyl
Estraderm Alza/Norvatis Estradiol
Fematrix Ethical Holdings/Solvay Healthcare Ltd. Estrogen
FemPatch Parke-Davis Estradiol
Habitraol Novartis Nicotine
Minitran 3M Pharmaceuticals Nitroglycerin
Nicoderm® Alza/GlaxoSmithKline Nicotine
Nitrodisc Roberts Pharmaceuticals Nitroglycerin
Nitro-dur Key Pharmaceuticals Nitroglycerin
Nuvelle TS Ethical Holdings/Schering Estrogen/Progesterone
Prostep Elan Corp./Lederle Labs Nicotine
Testoderm TTS® Alza Testosterone
Transderm- Scop® Alza/Norvatis Scopolamine
Transderm- Nitro® Alza/Norvatis Nitroglycerin
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Table-2: Marketed products of modified TDD technologies [3].
Enhancement
Method
Brand Name Company Name Drug product available/under
consideration
Microprojection,
M acroflux Alza Corporation
Vaccines
Therapeutic
proteins
Iontophoresis E-Trans Alza Corporation Fentanyl
Ultrasound
SonoPrep® Sontra Medical
Corporation
Peptides, Other large
molecules
Ultrasound SonoDermTM Imarx Large molecules (Insulin)
Needleless
injectors
Intraject Weston Medical Vaccines
Needleless
injectors
Powder Ject PowderJect
Pharmaceuticals
Insulin
Medicated
Tattoos
Med-Tat Lipper-Man Ltd. Acetaminophen, Vitamin C
Heat
CHADD Zars, Inc S-Caine (lidocaine and tetracaine)
Laser Radiation Transdermal
laser assisted
delivery
Norwood Abbey Wide range of drugs
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ADVANTAGES OF TDDS [5-7]
1. TDDS utilizes the drug candidates having short half-life and low therapeutic index.
2. It reduces the dosing frequency and enhances the patient compliance.
3. Sustained delivery of drugs can be achieved which provides a steady plasma profile and hence reduces
systemic side effects.
4. Reduces the typical dosing schedule to once daily or even once weekly, so improves the patient compliance
5. Avoidance of the first-pass metabolism effect for drugs with poor oral bioavailability.
6. TDD represents a convenient, patient-friendly route for drug delivery with flexibility, allows easily dose
changes according to patient needs and also allows self-regulation of dosing by the patient.
7. TDD requires almost minimal patient cooperation.
8. TDD is accessible to a wide range of patient populations and a highly acceptable option for drug dosing
because of its non-invasive character.
Potential limitations of TDDS
• Pharmacokinetic Issues
The skin has low intrinsic permeability for many high molecular weight, hydrophilic, and/or ionized drugs, which
permeate very slowly to achieve therapeutic drug plasma levels. For maintaining the constant delivery rate, most
of the patches contain 20 times the drug quantity to be absorbed while worn to produce a stable concentration
gradient. However due to such a design which does not allow for pulsatile delivery, the large amounts of drug in
the transdermal devices cannot achieve high drug serum levels [8].
• Safety issues
The used patches must be discarded properly as they still contain drug after removal. The damage to patches via
worn or by exposure to excessive heat (sunlight, electric blankets, hot tubs etc.) affects the drug delivery. It
increases the skin permeability and blood flow, which may leads to toxicity because of increased drug absorption
[9]. Some of the patches (nicotine transderm, nicotine CQ, nicotrol, deponit, androderm) contain traces of
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metal, when the patients wearing them undergo magnetic resonance imaging; they have the chances for burns [10].
For transdermal gels and creams transference is a potential issue. Virilization in female sex partners has been
reported with men treated with topical testosterone and in a 2 years old boy a precocious sexual development has
been occurred when exposed to testosterone cream on his father’s arms and back [11]. Application sites most of
the time required to be washed thoroughly with soap and water. With some of the topical preparations, patients
should have to wait for at least two hours for optimal absorption.
• Cutaneous reactions
The skin reactions on application site can result from exposure to the drug, adhesive, or excipients of transdermal
systems for example in the patients treated with testosterone containing patches [12-14]. Contact dermatitis after
the use of a transdermal system may be treated by cleaning the area with bland soap and cool water or topical
corticosteroid or antihistamine can also be used. The irritation associated with repeated patch applications can be
overcome by site rotation, if the reaction is extensive or systemic the use should be discontinued. Transdermal
estrogen patches may be applied to the abdomen, buttock, thigh, or upper arm. No change has been found during
movement from one site to another in serum hormone concentrations [12, 15]. The discontinuation of therapy is
usually found less than 10% in case of intolerable or unmanageable application site reactions with many
transdermal preparations [14-17].
• Patient related issues
The safety issues reported by the Food and Drug Administration related to the use of transdermal systems includes
partial removal of the backing of the patch before application, resulting in under dosing and patients
misunderstanding of the instructions [18]. So the patients should receive clear, concise instructions on skin
preparations, potential application sites, the number of patches to apply at one time and application site rotation if
any. Transdermal delivery systems should be applied with uniform pressure on clean, dry, hairless skin and not to
an oily, inflamed or broken skin. Hair removal with a depilatory agent just before application of a patch can
damage the stratum corneum and alter the drug permeation. Topical products should never be applied
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over open wounds or broken skin [19]. Showering, bathing, or excess sweating rarely results in loss of adhesion
and the detachment of transdermal systems. A detachment of estrogen patches occurs during showering or bathing
in 1% to 3% of applications and loss of adhesion with excessive sweating occurs in less than 1% [20].
• Design related issues
Clear patches are popular because they cannot be detected easily on exposed skin. However the lack of visibility
also difficult to locate them when it is time for their removal in addition, differences in units of measure (e.g.
milligrams per hour, milligrams per day, milligrams, micrograms per hour, and milligrams per day per week) also
create confusion for healthcare professionals and patients. Some patches may be cut to adjust the dosage or to
optimize the dosing. Cutting oxybutynin-TDS matrix patches shows no significant effect on the drug
concentration/cm2, drug release, or adhesion, even after storing the patch for up to 7 days [10, 20].
Drug delivery across human skin
It is well documented fact that the skin is the largest and most easily accessible organ of the body for topical and
systemic delivery of drugs [21, 22]. The human skin thickness is approximately 2.97 mm, covers a surface area of
approximately two square meters of our body, having hair follicles about 10-70 on every square centimeter and
sweat glands 200-250 on every square centimeter. Skin is multilayered tissue consisting of epidermis, dermis and
hypodermis. Stratum corneum has compacted, flattened, dehydrated and keratinized cells. They have the water
content of only 20% as compared to other organs having up to 70%. Ointments, gels, creams and medicinal
plasters containing natural herbs are traditional TD preparations. There are currently more than 35 TDD products
approved in the USA for the treatment of various conditions including hypertension, angina, motion sickness,
female menopause, male hypogonadism, severe pain, local pain, nicotine dependence, contraception and urinary
incontinence. There are also several products in late-stage development in new therapeutic areas including,
parkinson’s disease, attention deficit, hyperactivity disorder and female sexual dysfunction [1].
Limitations of skin as a delivery method
• The barrier
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The intercellular pathway is widely accepted main route of permeation through the skin for small molecules. For
some compounds the intracellular domain is also important parameter and often several mechanisms might be
working in parallel. It is thought that the organization of lipids in skin layers dictate the required physicochemical
properties of a molecule to ensure its rapid diffusion through the skin. The small molecules with good water and
lipid solubility are generally accepted as suitable candidates for TDDS. These solubility characteristics are often
also indicated by the possession of a low melting point, typically < 200 °C [22-26].
Drug Related Factors
• Partitioning
According to the Fick’s Law, drug related properties that influence flux across the skin are the concentration
gradient of drug within the skin and the diffusivity. The ability of the drug to partition into the skin influenced the
concentration gradient. The octanol-water partition coefficient can be used as reference to predict this partitioning
behavior within the skin. The generally accepted range of logP for maximum permeation is found to be 1-3. The
partitioning of the drug can be improved by increasing the concentration of drug in the applied vehicle or by
manipulating the vehicle to reduce drug solubility. Permeation enhancers can also increase diffusivity of drug [27-
32].
• Diffusivity
The chemical structure of the drug also influences the diffusivity, it occurs basically due to interactions between
the polar head groups of the intercellular lipids and H-bond forming functional groups present in the drug
structure. The number of H-bonding groups in the permeant should not exceed two. The functional properties of
skin also limit the access of drugs into and across the epidermis. The outer layer, stratum corneum, is a main
contributor to the skin’s impermeability. A lot of efforts have to be done in the respective field, for developing
more efficient TDD products [33-35].
Occlusion
To improve the efficiency of TDD systems, traditional TDD products depend mainly on their occlusive nature.
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Although the mechanism by which occlusion increases the diffusivity of many drugs is not known, some of the
important effects of occlusion include: water accumulation within the skin, thereby swelling of the corneocytes
and increased water content of the intercellular matrix [36]; increase in skin temperature and decreased evaporative
loss of co- solvents [37]. Occlusion often causes an increased propensity for skin irritation at the application site
might be due to the affects of the accumulated water or to trap sweat [36-38]. Now day’s efforts have been focused
on the development of newer generation products with less potential for this reaction. Occlusive systems also
provide an environment for microbial proliferation. Skin offers the advantages of easy access and large surface
area. However, it also behaves like an effective barrier that limits penetration of large, hydrophilic polypeptides
(Insulin). Stratum corneum is responsible for this impermeability via its lipid rich matrix [39, 40]. Various
methods have been tested to overcome the skin barrier. They can be separated mainly into chemical enhancers and
physical methods (mainly iontophoresis and sonophoresis along with some other useful techniques.
VARIOUS APPROACHES FOR PENETRATION ENHANCEMENTS [2]
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PHYSICAL APPROACHES TO OVERCOMING THE BARRIER
The various classes of active systems under development are available as penetration enhancers, which include
iontophoresis, electroporation, microneedles, abrasion, needleless injection, suction, stretching, ultrasound,
magnetophoresis, radio frequency, lasers, photomechanical waves, and temperature manipulation. Some most
commonly employed techniques are as following:
• Iontophoresis
• This technology enhances the drug transport across the skin barrier with the assistance of an electric field.
The mechanisms involve in transdermal iontophoresis include electrophoresis, electroosmosis and electroporation.
Direct current (DC) iontophoresis with a constant current is the most common form of transdermal iontophoretic
drug delivery. It has been suggested that AC can eliminate potential electrochemical burns and also reduce skin
irritation and sensation, which can occur during long iontophoresis application or when an inappropriate electrode
design is used [41-49].
A number of published studies for macromolecules and protein and peptide structures are listed below which
includes: calcitonin, corticotrophin-releasing hormone, delta sleep-inducing peptide, dextran sulphate, inulin,
insulin, vasopressin, gonadotropin releasing hormone, growth hormone-releasing factor, leuprolide acetate,
leutenising hormone releasing hormone, neutral thyrotrophin-releasing hormone, oligonucleotides, parathyroid
hormone. To date, however, clinical studies have been limited only to smaller molecules such as lidocaine,
dexamethasone etofenamate, naproxen, metoclopramide with hydrocortisone, cortisone, vincristine and fentanyl
[46,50-78].
• Electroporation
This method involves the high voltage pulses (10µs–100ms) to the skin that has been suggested to induce transient
pores. High voltages (•100 V) and short time durations (milliseconds) are mostly used. By using this technology
the enhancement in the skin permeability has been successfully used for the molecules with different lipophilicity
and size (i.e. small molecules, proteins, peptides and oligonucleotides) with molecular weights greater that
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7kDA. The theory behind the application of electroporation to skin is that the intercellular lipid bilayers of the skin
should behave in the same way as those of cell membranes and be susceptible to pore formation by high voltage
electrical pulsing. Increase in transdermal penetration has been reported in-vitro for various sizes of molecules, for
e.g. Drug molecules as, tetracaine, timolol and fentanyl, cyclosporin A, insulin,dextrans and microspheres [79-
87].
• Ultrasound (sonophoresis and phonophoresis)
The ultrasonic energy has been used to enhance the transdermal delivery of solutes either simultaneously or via
pretreatment. It uses low frequency ultrasound (55 kHz) for an average duration of 15 seconds to enhance the skin
permeability [88]. S. Mitragotri et al., reported in-vitro permeation enhancement of several low molecular weight
drugs under the same ultrasound conditions [89]. D Bommannan and co workers [90,91] found that a 20 min
application of ultrasound (0.2 W/cm2) at a frequency of 2 MHz is not sufficient for enhancing salicylic acid
penetration into the skin. However, 10 MHz ultrasound under the same conditions resulted in a 4-fold increase and
16 MHz ultrasound resulted in about a 2.5 fold increase in transdermal salicylic acid transport.
• Micro needle based devices
The first micro needle system was described in 1976, consisted of a drug reservoir and a plurality of projections
(micro needles 50 to 100 mm long) [92]. Micro needles are tiny micron-sized structures which penetrate to the
upper dermal layers. This delivery method has the advantages like minimally invasive, pain free and lot of
potential for drug delivery across skin. Recently, Kolli and Banga, et al., describes use of soluble maltose micro
needles which dissolve [93].
• Needle-less Injection
These are the devices in which transdermal delivery is achieved by injecting the liquid or solid particles at
supersonic speeds by using a suitable energy source. The mechanism involves forcing of compressed gas (helium)
along with the drug particles through the nozzle, within the jet flow at sufficient velocity for skin penetration [92,
93].
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• Controlled heat aided drug delivery system (CHADD)
Skin temperature increases due to heat that leads to increase in microcirculation and blood vessel permeability,
thus facilitating drug transfer to the systemic circulation. Zars, lnc [Salt Lake City, UT, USA] has developed a
technology that takes advantage of heat’s ability to increase transdermal permeation. CHADD is a very small
heating unit that can be placed on top of a traditional transdermal patch. An oxidation reaction in the transdermal
patch provides heat at a limited intensity and duration. The drawbacks of this technology are that heat can slightly
compromise the barrier function of the skin [94].
• Laser radiation
For enhancing topical delivery of drugs lasers are used to remove the stratum corneum barrier by controlled
ablation. This method involves ablation of the stratum corneum with direct and controlled exposure of a laser to
the skin without damaging the epidermis. This method has been successfully used to enhance the delivery of
lipophillic and hydrophilic drugs [95]. However, the structural changes in the skin layers caused by this technique
still need to be studied for safety and reversibility [96, 97].
• Magnetophoresis
To enhance the drug delivery across biological barriers a novel approach magnetophoresis can be used, e.g.
benzoic acid was selected as a drug candidate along with diamagnetic substance and influence of magnetic field
strength on diffusion flux was studied and was found to increase with increasing applied strength [98].
• Combination of electrically based physical enhancement techniques
A number of studies have been investigated for the achievement of a synergistic enhancement effect with a
combination of two techniques in topical delivery. For example, the combination of skin electroporation followed
by iontophoresis has been shown a five times more release of luteinizing hormone over that of iontophoresis alone
[99,100]. An increases flux of salmon calcitonin has been reported by electroporation combined with iontophoresis
through human epidermis compared to each technique used alone [101]. Kost et al., also observed that the
combination of electroporation with ultrasound produces a synergistic interaction, which may be caused by
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ultrasound disorganizing stratum corneum lipids to an extent where they were more susceptible to the
electroporation [102]. The heparin flux also increases with combination of low-frequency ultrasound and
iontophoresis across pig skin above that observed for each of the techniques alone [103].
Chemical methods for permeation enhancement
The perfect chemical enhancer in the TDDS is, as reviewed by Barry et al., and Sinha et al., [104, 105].
Considerable efforts have been made on chemicals or combinations of chemicals as penetration enhancers
[106,107]. Chemicals generally interfere with the highly ordered lipid bilayer structure which is a primary barrier
to diffusion of drug. Chemical permeation enhancers are relatively economic, simple in application, easy to
prepare, offer flexibility in their design and allow the freedom of self administration to the patient. The chemical
enhancers can be formulated with the active therapeutic agent as a topical cream or gel, or an adhesive skin patch.
Mechanism of action of chemical permeation enhancers
A variety of complex mechanisms are involved to enhance the permeation across the skin. Chemical enhancers
either extract lipids from the skin, hence creating diffusion pathways for the drug to permeate or they can partition
themselves into the lipid bi-layers thereby disrupting the highly ordered lipid lamellae which results fluidization
[108-110]. Alternately, chemical enhancers can also act by enhancing thermodynamic activity of drug in the
formulation, for e.g., by super saturating the drug in the formulation. Such a classification is purely out of practical
benefits because permeation enhancers can act on skin by a variety of different mechanisms. Depending on their
individual physico chemical properties, chemicals belonging to the same group can act on skin by different
mechanisms. We briefly discuss the most widely accepted permeation enhancers based on their chemical
structures.
• Water
Water is a natural penetration enhancer. Usually, the increased hydration of the stratum corneum increases
transdermal flux of a variety of drugs [111].
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• Hydrocarbons
Buyuktimkin et al., reviewed several other hydrocarbons and their effect on skin permeation of a variety of drugs
in their study [110]. Hydrocarbons including alkanes, alkenes, halogenated alkanes, squalane, squalene and
mineral oil have been used as penetration enhancers to increase permeation of a variety of drugs across the skin.
They work by partitioning into the stratum corneum and disrupting the ordered lipid bilayer structure. Alkanes
with 9-10 carbon atoms showed highest skin permeation enhancement of propranolol and diazepam while shorter
alkanes (5-6 carbon atoms) showed highest permeation enhancement of caffeine [112]. In the study squalane and
squalene improved permeation of diclofenac, mineral oil was effective for methyl nicotinate and chloro dodecane
enhances the permeation of timolol maleate [113].
• Alcohols
Alcohols including alkanols, alkenols, glycols, polyglycols and glycerols generally used as vehicles, solvents or
penetration enhancers in TDDS. They enhances skin permeation by a variety of mechanisms such as extraction of
lipids and proteins, swelling of the stratum corneum or improving drug partitioning or solubility of drug [110].
• Acids
Fatty acids are commonly studied in this category. These chemicals enhance transport of drug by partitioning into
the lipid bilayers and disrupting their order, by improving drug partitioning into the stratum corneum and by
forming lipophillic complexes with drugs [114]. Oleic acid is an example in this category that is extensively
studied as a permeation enhancer [115-116].
• Amines and amides
Primary, secondary and tertiary amines and cyclic and acyclic amines or amides have been used successfully in
enhancing skin permeation. They enhance the skin permeation by improving drug partitioning into the skin [114,
1118]. Azone and pyrrolidones are the most extensively studied amides [114].
• Esters
Esters of fatty acids show skin permeation enhancement of a wide variety of drugs in various studies [118-119].
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The most widely studied ester is Isopropyl myristate. These chemicals work by partitioning themselves in the
ordered lipid layers of the stratum corneum [118].
• Surfactants
A wide variety of surfactants include anionic, cationic, zwitter ionic and non ionic surfactants are usually used
with a vehicle or solvent system as skin permeation enhancers [118-120]. Their activity depends upon the
hydrophilic to lipophillic balance, charge and lipid tail length [117]. Anionic and non-ionic surfactants are more
widely studied as compare to others surfactants [114].
• Terpenes, terpenoids and essential oils
Terpenes are a popular choice for permeation enhancers in transdermal drug delivery [121-123]. The effect of a
specific terpene on skin depends upon its exact physicochemical properties, particularly its lipophilicity. In general
smaller terpenes with hydrophobic groups are better skin permeation enhancers [118].
• Sulfoxides
Di methyl sulfoxide was the first chemical which was originally used as a solvent to improve drug partitioning into
the skin; however several studies have reported the use of dimethyl sulfoxide as enhancers in other solvent systems
[118].
• Lipids
Phospholipids have been successfully used as permeation enhancers in the form of vesicles, micro emulsions and
micellar systems [124-125]. They can fuse with the lipid bilayers of the stratum corneum in the form of self-
assembled structures such as vesicles or micelles, thereby enhancing partitioning of encapsulated drug as well as
disruption of the ordered bilayer structure [114].
• Miscellaneous
In addition to the above mentioned groups, several other chemical groups have been studied for their ability to
enhance drug transport across the skin as beta cyclodextrins, amino acids and thioacyl derivatives of amino acids,
alkyl amino esters, ketones and oxazolidinones. Enzymes as papain are a relatively new class of
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chemicals studied as permeation enhancers [110, 126-130].
• Synergistic mixtures of chemical permeation enhancers
Many classical permeation enhancers include solvents such as water, fatty acids, alcohols, glycols and fatty esters
used in their pure state as permeation enhancers. A number of studies concluded that certain chemicals in a
mixture interact synergistically and induce skin permeation enhancements higher than that by the individual
components [120]. A mixture of two or more solvents is one of the most widely studied formulation design to
facilitate drug transport across the skin layers. The mechanisms behind it may be
(a) change in the thermodynamic activity (e.g., by increasing the degree of saturation in the solvent and, hence,
increasing the escaping tendency) or (b) specific interaction with the stratum corneum, either by increasing the
drug solubility in the stratum corneum or by altering the various transport pathways (i.e., the polar and non polar
pathways) in the stratum corneum [131]. Table no. 3 lists a few mixtures of chemical enhancers.
Table 3: List of various combination solvent mixtures for permeation enhancement
Solvent mixture Active molecule Ref no.
diethylene glycol
monoethyl ether:isopropyl myristate(40:60)
Clebopride 132
ethanol:water(60:40) Ondansetron hydrochloride 117
propylene glycol:ethanol(33:67) Naloxone 133
isopropyl myristate:glyceryl
monocaprylate(90:10)
Pentazocine 118
propylene glycol:lauric acid(90:10) Lipophillic antiestrogens 134
ethanol:tricaprylin(40:60) Tegafur 135
Isopropyl
myristate:n-methyl pyrrolidone(25:75)
Lidocaine 136
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menthol:n-methyl pyrrolidone Formoterol fumarate 137
isopropyl myristate:n-methyl pyrrolidone Formoterol fumarate 137
triethylene glycol monomethyl
ether:isopropyl palmitate
Estradiol 138
cineole and oleic acid Zidovudine 139
aqueous solutions of n-lauroyl sarcosine and
ethanol
Fluorescein 110
linoleic, linolenic and arachidonic acid Dapiprazole base (DAP-B) 140
oleyl alcohol and azone Furosemide 141
azone and propylene glycol Clonazepam and lorazepam 142
Miscellaneous techniques
• Prodrugs and ion pairs
The prodrug approach was investigated for the drugs having unfavorable partition coefficients to enhance their
dermal and transdermal delivery. A promoiety was added into the design to increase partition coefficient and hence
solubility and transport of the parent drug in the stratum corneum. Upon reaching the viable epidermis, esterase
releases the parent drug by hydrolysis. The study concluded that the permeability of the very polar 6-mercapto
purine was increased up to 240 times using S-6- acyloxy methyl and 9- dialkyl amino methyl promoieties74.
Permeability of 5-fluorouracil, a polar drug was increased up to 25 times by forming N acyl derivatives. The
prodrug approach has also been investigated for increasing skin permeability of non steroidal anti-inflammatory
drugs, nalbuphine. Formation of lipophillic ion pairs has been investigated to increase stratum corneum penetration
of charged species. This strategy involves adding an oppositely charged species to the charged drug, forming an
ion-pair in which the charges are neutralized so that the complex can partition into and permeate through the
stratum corneum. The ion-pair then dissociates in the aqueous viable epidermis releasing the parent charged drug,
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which can diffuse within the epidermal and dermal tissues [143].
• Eutectic systems
The melting point of a drug affect solubility and hence skin penetration. According to solution theory, lower the
melting point, greater the solubility of a material in a given solvent, including skin lipids layers. The 1:1 eutectic
mixture (melting point 18°C) is oil, which is formulated as an oil-in-water emulsion it maximizes the
thermodynamic activity of the local anesthetics. A list of eutectic systems with a penetration enhancer as the
second components has been documented here, for example: Ibuprofen with terpenes, and methyl nicotinate,
propranolol with fatty acids, and lignocaine with menthol. In all cases, the melting point of the drug was depressed
to around or below skin temperature thereby enhancing drug solubility [143].
• Complexes
To enhance aqueous solubility and drug stability complexation of drugs with cyclodextrins has been used mostly.
Cyclodextrins are large molecules, with high molecular weights greater than 1000 Da, therefore would not readily
permeate the skin. Complexation with cyclodextrins has been variously reported to both increase and decrease skin
penetration [143]. Cyclodextrin complexes have been shown to increase the stability, wettability and dissolution of
the lipophillic insect repellent N, N-di methyl- toluamide and the stability and photo stability of sunscreens. It has
been reported that complexation with cyclodextrins can both increase and decrease skin penetration. Loftsson and
Masson et al. concluded that the effect on skin penetration may be related to cyclodextrin concentration, a reduced
flux generally observed at relatively high cyclodextrin concentrations. At higher cyclodextrin concentrations, the
excess cyclodextrin would be expected to complex free drug and hence reduce flux. Shaker et al. recently
concluded that complexation with HP-beta-cyclodextrin had no effect on the flux of cortisone through hairless
mouse skin by either of the proposed mechanisms [144-148].
• Vehicles
To date, the most promising transdermal drug carrier is the recently developed and patented Transfersome® which
penetrates the skin barrier along the transcutaneous moisture gradient. Transfersome carriers can create a
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highly concentrated drug depot in the systemic circulation [149]. Liposomes are microscopic bilayer vesicles,
which are usually made of phospholipids (mainly phosphatidyl choline) and cholesterol, contain both hydrophilic
and lipophillic portions and can serve as carriers for polar and non polar drugs. Niosomes have a similar
morphology, but are made of nonionic surfactants, mixed with cholesterol [150]. Transfersomes contain at least
one component to destabilize the lipid bilayers, e.g. Bile salts, poly sorbates, glycolipids, alkyl or acyl poly
ethoxylenes etc. Polypeptides such as calcitonin, insulin, α- and γ- interferon, and, Cu-Zn super oxide dismutase,
serum albumin, and dextrose have been successfully delivered across the skin with transfersome carriers [151].
• Medicated tattoos
Medicated Tattoo (Med-Tat) is a modification of temporary tattoo which contains an active drug substance useful
for transdermal delivery. Med-Tats are a novel means of delivering compounds transdermally and are produced by
Lipper–Man Ltd [Morristown, N.J.]. They are applied to clean, dry skin like temporary tattoos. There is no
predetermined duration of therapy for Med–Tats; instead, a color chart is provided by the manufacturer that can be
compared to the color of the patient’s tattoo to determine when the tattoo should be removed. Drugs and other
compounds used in Med-Tats prototypes are acetaminophen and Vitamin C [3].
• Skin abrasion
The abrasion technique involves the direct removal or disruption of the upper layers of the skin to facilitate the
permeation of topically applied drugs. These devices are based on techniques employed by dermatologists for
superficial skin resurfacing (e.g. micro derma abrasion) which are used in the treatment of acne, scars, hyper
pigmentation and other skin blemishes. Micro scissuining is a process which creates micro channels in the skin by
eroding the impermeable outer layers with sharp microscopic metal granules. Med. Pharm. Ltd. [Charlbury, U.K.]
had developed a novel dermal abrasion device (D3S) for the delivery of difficult to formulate therapeutics ranging
from hydrophilic low molecular weight compounds to biopharmaceuticals. In vitro data have shown that the
application of the device can increase the penetration of angiotensin into the skin compared to untreated human
skin [3,152].
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IJPT | June-2011 | Vol. 3 | Issue No.2 | 2373-2401 Page 2392
REGULATORY STRATEGY FOR NEW DRUG APPLICATION SUBMISSIONS FOR TDDS [143]
1. A standard irritation and sensitization studies should be performed with the patch itself in animals or humans.
2. Negotiation in the timing and implementation of the toxicology requirements has to be done.
3. FDA should review dermal aspects of the IND and New drug Application (NDA).
4. Primary review should occur at the division that handles the indication under study.
5. Dose ranging studies should be there in Phase II.
6. Single Phase III study could be negotiated.
Conclusion
Transdermal drug delivery is an old technology, due to recent advances in technology and the ability to apply the
drug to the site of action without rupturing the skin membrane, transdermal route is becoming a widely accepted
route of drug administration. Successful transdermal drug delivery requires numerous considerations related to the
nature and function of the site of application in skin. The newer developed API’s are far more active and hence
they need to be delivered in a controlled manner. Modification of transdermal drug delivery systems can enhance
the bioavailability of poorly absorbed drugs. Transdermal drug delivery technologies are becoming one of the
fastest growing sectors in the pharmaceutical industry. The future of transdermal rate controlled drug delivery is
expected to grow day by day, and biomedical application of TDDS is expected to increase along with the
successful development of new approaches. Synergistic systems such as chemical mixtures, physical measures,
combinations of chemicals and various other permeation enhancing systems can be used not only to improve the
potency of permeation enhancers but also their safety factor. Application of developments in nanotechnology
could lead to systems where a single device could monitor drug levels by sampling through the skin and thus
provide controlled delivery of the drug. The safe and effective drug delivery is the aim for each and every new
technology ever explored.
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Corresponding Author:
Pooja Mathur*,
Assistant Professor,
Dept. of Pharmaceutics,
Ganpati Institute of Pharmacy, Bilaspur,
Yamunanagar-135102, Haryana, India.
Email: [email protected]