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International Journal of Pharmaceutical Sciences

INT.J.PH.SCI.,SEP-DEC, 2010;2(3):708-716
ISSN 0975-4725
www.ijps.info

Original Research Manuscript


Date of Submission: 20-07-2010
Date of Acceptance: 13-10-2010

APPROACHES USED FOR PENETRATION ENHANCEMENT IN


TRANSDERMAL DRUG DELIVERY SYSTEM

SINGH ANISHA*, SHARMA PRAMOD KUMAR, GARG VIPIN KUMAR, GARG GARIMA

Department of Pharmaceutical Technology, Meerut Institute of Engineering & Technology, NH-58, Baghpat
Bypass Crossing, Delhi- Haridwar Highway, Meerut – 250005, U.P., India
*Corresponding author email id: anishapharma24@gmail.com, Mob. no: 09557501533

ABSTRACT
Transdermal route of drug delivery is preferred over the other routes for administration of drugs as it has several additional advantages, to
name a few, it is a non-invasive technique requiring less dosing frequency and abolishes the first pass metabolism. However, the drug is
unable to permeate the skin barriers properly, so penetration enhancers are used to overcome this problem. The present review focuses on
transdermal drug delivery system, the role of penetration enhancers and various techniques which are used to increase the penetration of
drug through the skin.
Key Words: Transdermal, Penetration enhancers, Iontophoresis, Lipid Fluidisation

INTRODUCTION the barrier properties of the stratum corneum to enhance


Transdermal therapeutic systems are self contained drug penetration and absorption through skin may be
discrete dosage forms for administering drugs topically classified into the following categories[4]
to healthy intact skin for 1. Chemical enhancement
 localized treatment of tissues underlying the skin or 2. Physical enhancement
for 3. Biochemical enhancement
 systemic therapy 4. Supersaturation enhancement
The goal of transdermal products is to maximize the flux 5. Bioconvertable prodrug
through the skin into the systemic circulation and The system designs for transdermal patches include
simultaneously minimize the retention and first-pass  matrix
[1]
metabolism associated with gastro-intestinal  microreservoir
administration of drugs. The TDDS thus maintain  reservoir
constant drug level in blood. Further it is possible to  adhesive and
enhance the transdermal permeation of drug using  Membrane matrix hybrid[5]
[2]
penetration enhancers . They reversibly reduce the
barrier resistance of the stratum corneum without Need of penetration enhancement
[3]
damaging viable cells Techniques used for modifying

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Penetration enhancement is the most important where Cp-Cr is the difference in permeant concentration
consideration for improving flux. Flux (J) can be defined across the membrane and A is the area of application[7]
as the amount (M) of material flowing through unit area
of cross section (S) of a barrier in unit time (t). Flux can Approaches of penetration enhancement
[6]
be given by : A. Drug vehicle based
J=dM/S.dt 1. Drug selection
Each phase of the membrane can be characterized in 2. Vesicles and particles
terms of diffusional resistance(R), which usually is the 3. Prodrugs and ion pairs
function of thickness (hs) of the phase, the permeant 4. Chemical potential of drug
diffusion coefficient (Ds) within the phase, and the 5. Eutectic systems
partition coefficient (Ks) between the membrane phase 6. Complexes
and external phase.It can be expressed as: B. Physical method
R=hs/Ds.Ks, P=Ds.Ks/hs 1. Iontophoresis
where P is permeability coefficient. The permeability 2. Ultrasound (phonophoresis and sonophoresis)
coefficient is related to membrane flux (J) as given 3. Mechanoporation (Microneedle based devices)
J=APs (Cp-Cr), 4. Electroporation

C. Chemical penetration enhancers

Chemical penetration enhancer Examples


Sulphoxides and similar chemicals Dimethyl sulphoxide(DMSO), DMF
Pyrrolidones N-methyl-2-pyrolidone
Fatty acids Oleic acid, Lauric acid, Myristic acid, Capric acid
Essential oils of eucalyptus, chenopodium and ylang-ylang,
Essential oils, terpenes and terpenoids
sesquiterpene oil, L-menthol
Oxazolidinones 4-decyloxazolidin-2-one
Surface active agents Polyoxyethylene-2-oleylether,polyoxyethylene-2-stearyl ether
Alcohols Diethylene glycol, Tetraethylene glycol
Azone ------

D. Stratum corneum modification 1. Drug vehicle based


1. Hydration a) Drug selection
2. Lipid Fluidisation Drug should be selected in such a way that it fits in the
criteria of transdermal delivery as given in table below

Table 1: Parameters for Drug selection [1,8, 9, 10, 11, 12]


Parameters Ideal limits
Aqueous solubility >1mg/ml
Lipophilicity 10<Ko/w<1000
Molecular weight <500 Daltons
Melting point <200oC
pH of aqueous saturated solution 5-9
Dose deliverable <10mg/day

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b) Vesicles and particles squeeze to penetrate the stratum corneum barrier up to


(1) Liposomes 500nm. Transdermal gradient acts as the driving force
Liposomes are colloidal lipid vesicles formed as for penetration into the skin caused by the difference in
concentric bimolecular layers that are capable of water content between the restively dehydrated skin
encapsulating drugs. They fully enclose an aqueous surface (approximately 20% water) and the aqueous
volume. These lipid molecules are usually phospholipids viable epidermis (close to100%).
[13].
with or without some additives Cholesterol is added
to improve bilayer characteristics; increasing (3) Ethosomes
microviscosity of the bilayer, reducing permeability of These are liposomes with a high alcohol content (up to
the membrane to water soluble molecules, stabilizing the 45%) capable of enhancing penetration to deep tissues
[20-23].
membrane and increasing rigidity of the vesicles. Their and the systemic circulation Her alcohol fluidises
delivery mechanism is associated with accumulation of the ethosomal and stratum corneum bilayer lipids thus
the liposome and associated drug in the strateum allowing the soft, malleable ethosomes to penetrate.
corneum and upper skin layers, with minimum drug Studies have been focused on transdermal ethosomal
penetrating to the deeper and systemic circulation delivery of drugs like minoxidil, testosterone and
tissues. Then, they may act as penetration enhancers, stavudin40, and comparative study had also been done
loosening the lipid structure of the stratum corneum and on ethosomal vs liposomal system of trihexyphenidyl
promoting impaired barrier function of these layers to hydrochloride (THP). THP encapsulated in classical
the drug, with less well-packed intercellular lipid liposomes remained primarily at the surface of the skin,
structure forms, and subsequent increased skin while the ethosomal system was shown to be a highly
[14].
partitioning of the drug Examples of drugs that have efficient carrier for enhanced THP delivery.
been delivered via liposomes are anti-psoriatic agent via
ethanolic liposomes, caffeine for hyperproliferative (4) Niosomes
[15], [16] [17]
diseases catechins enoxacin It also increases Niosomes are vesicles composed of nonionic surfactants
the stability of some drugs like amphotericin B. Lipid that have been evaluated as carriers for a number of drug
compositions of liposomes also affect permeation and cosmetic applications. As compared to conventional
through skin. When Triamcinolone permeation was liposomes (phospholipids) niosomes (non ionic
compared among various lipid compositions, all the surfactant vesicles) offer higher chemical stability, lower
liposomal formulations resulted in significantly higher costs, and great availability of surfactant classes.
flux and permeability oftriamcinolone acetonide than a Niosomes are helpful in the treatment of dermatological
[18].
commercial triamcinolone acetonide ointment Recent disorders. Topically applied niosomes can increase the
studies focus on delivery of macromolecules viz. residence time of drugs in the stratum corneum and
[19],
interferon gene delivery. This system also prevents epidermis, while reducing the systemic absorption of the
the drug from degradation eg. enkephalin. drug.

(2) Transfersomes (5) Solid lipid nanoparticles (SLN)


These are vesicles composed of phospholipids as their Nanoparticles are colloidal drug delivery systems having
main ingredient with 10-25% surfactant and 3-10% a diameter of approximately 200-500nm. They have
ethanol. Liposomes are large enough to pass through been employed as carriers for enhanced skin delivery of
pores of less than 50nm in size while transfersomes can sunscreens, vitamins A and E, triptolide and

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SINGH ANISHA ET AL: APPROACHES USED FOR PENETRATION ENHANCEMENT
[24-28]
glucocorticoids .There are mainly three structures permeability of non-steroidal anti-inflammatory
[39] [40]
viz. homogeneous matrix, drug- enriched shell and drug- drugs , nalbuphine , and steroid esters (e.g.
enriched core. Their enhanced skin penetration is mainly betamethasone-17-valerate).
due to an increase in skin hydration caused by the
occlusive film formed on the skin surface by the SLN. A Formation of lipophilic ionpairs facilitates penetration of
31% increase in skin hydration has been reported charged species into stratum corneum. It involves adding
following four weeks application of SLN-enriched an oppositely charged species to the charged drug,
cream. It can also protect active components against forming an ion-pair in which the charges are neutralised
chemical degradation and modulate compound release. so that the complex can partition into and permeate
Studies have been done on transcutaneous vaccine through the stratum corneum. The ion-pair then
[29] [30]
delivery ,transdermal DNA delivery , minoxidil dissociates in the aqueous viable epidermis releasing the
[31]
with block copolymer nanoparticles etc. parent charged drug, which can diffuse within the
epidermal and dermal tissues [41].
(6) Aspasomes d) Chemical potential of drug
Aspasomes are Ascorbyl palmitate formed vesicles in The maximum skin penetration rate occurs in case of
[42]
presence of cholesterol and charge inducer (dicetyl supersaturated solution The technique involves
phosphate), encapsulating azidothymidine solution. Its increasing the thermodynamic activity and as flux is
antioxidant potency was found to be much better than proportional to thermodynamic activity, an increase in
that of ascorbic acid. Thus, it finds application as drug the latter can lead to an increase in flux. Supersaturated
delivery system in disorders implicated with reactive solutions (i.e. nonequilibrated systems) may arise; either
oxygen species. They enhanced the transdermal by evaporation of solvent from the skin or by mixing of
permeation of azidothymidine. The antioxidant and skin co-solvent evaporating on the skin [43].
permeation enhancing property together facilitate
aspasome as a carrier for transdermal drug delivery e) Eutectic systems
[32].
system The melting points of a drug influences solubility and
hence skin penetration. The melting point of a drug
(7) High velocity particles delivery system can be lowered by formation of a
The powderject system fires solid particles (20–100 mm) eutectic mixture: a mixture of two components which, at
through stratum corneum into lower skin layers, using a a certain ratio, inhibit the crystalline process of each
supersonic shock wave of helium gas. Developmental other, such that the melting point of the two components
products include lignocaine and levobupivacaine for in the mixture is less than that of each component alone.
local anesthesia, proteins (follicle stimulating hormone EMLA cream, a formulation consisting of an eutectic
and interferon) and hepatitis B DNA and other vaccines mixture of lignocaine and prilocaine applied under an
[33-37].
occlusive film, provides effective local anaesthesia for
pain-free venepuncture and other procedures.
c) Prodrugs and ion pairs
[38]
The prodrug concept involves addition of a f) Complexes
promoiety to increase partition coefficient and hence Complexation of drugs with cyclodextrin enhances
[44]
solubility and transport of the parent drug in the stratum aqueous solubility and drug stability . As flux is
corneum. The approach is employed for increasing skin proportional to the free drug concentration, where the

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cyclodextrin concentration is sufficient to complex only region compared to the higher 1MHz energy used in
the drug that is in excess of its solubility, an increase in physiotherapy, across the skin. The ultrasound energy
flux might be expected. However, at higher cyclodextrin pulses have the capability of producing both a physical
concentrations, the excess cyclodextrin would be increase in air pressure above the topical application site
expected to complex free drug and hence reduce and the tissue effects utilised in medical therapy
flux.Complexation with cyclodextrins has been variously applications. However, ultrasound-facilitated
reported to both increase and decrease skin penetration. transdermal delivery has not yet been tried and tested in
Skin penetration enhancement has also been attributed to the clinical field. Therefore, it’s acceptance as a routine
extraction of stratum corneum lipids by cyclodextrins mechanism for topical delivery of macromolecules is
[45].
still hypothetical [46, 47].

2. PHYSICAL METHODS (c) Mechanoporation (microneedle based


(a) Iontophoresis devices)
It involves the application of low level electric current They are needles of micron dimensions, termed
either directly to the skin or indirectly to the skin via the microneedles, used to pierce skin to effectively deliver
dosage form in order to enhance permeation of a drugs, but it does so in a minimally invasive and painless
topically applied therapeutic agent. Increased drug manner that lends itself to self-administration and slow
permeation can be attributed to either one or a delivery over time. Microneedles produce pores
combination of the following mechanisms: proportional to the needle diameter, typically in the
 Electro-repulsion (for charged solutes), N104nm range that increases with the needle length
 Electro-osmosis (for uncharged solutes) and employed. In vivo studies have demonstrated delivery of
 Electro-pertubation (for both charged and oligonucleotides, desmopressin, and human growth
uncharged). hormone, reduction of blood glucose levels from insulin
There have been numerous research applications of delivery, increase of skin transfection with DNA, and
iontophoresis in topical drug delivery for lower elicitation of immune response from delivery of DNA
molecular weight solutes (<500Da). For and protein antigens [48, 49].
macromolecules, protein and peptide structures there
also have been a number of encouraging published (d) Electroporation
studies including: calcitonin (salmon), corticotrophin- This method involves the application of high voltage
releasing hormone, delta sleep-inducing peptide, dextran pulses to the skin that induces the formation of transient
[46].
etc pores. High voltages (•100 V) and short treatment
durations (milliseconds) are most frequently employed.
(b) Ultrasound (Phonophoresis and The technology has been successfully used to enhance
sonsphoresis) the skin permeability of molecules with differing
This technique involves the application of ultrasonic lipophilicity and size (i.e. small molecules, proteins,
energy to enhance the transdermal delivery of solutes peptides and oligonucleotides) including
either simultaneously or via pre-treatment. It uses low biopharmaceuticals with molecular weights greater that
frequency ultrasound (55 kHz) for an average duration 7kDA[46].
of 15 seconds to enhance skin permeability. Ultrasound
devices deliver low frequency energy, in the 20 kHz (3) Chemical penetration enhancers

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(a) Pyrrolidones enhancement mechanism may be a consequence of both


They are used as permeation enhancers for numerous hydrophilic activity and lipid disruption mechanism [50].
hydrophilic (e.g. mannitol and 5-flurouracil) and
lipophilic (progesterone and hydrocortisone) permeants. (d) Azone
N-methyl-2- pyrolidone was employed with limited Azone (1-dodecylazacycloheptan-2-one or laurocapran)
success as a penetration enhancer for captopril when was the first molecule specifically designed as a skin
formulated in a matrix-type transdermal patch. The penetration enhancer. It is a colourless, odourless liquid
pyrrolidones partition well into human stratum corneum with a melting point of -7 ºC and posseses a smooth, oily
within the tissue and they may act by altering the solvent but yet non-greasy feel, is highly lipophilic material with
nature of the membrane. Pyrrolidones have been used to a log p octanol / water of around 6.2 and soluble in and
generate reservoirs within the skin membrane which compatible with most organic solvents. Azone enhances
offers potential for sustained release of a permeant from the skin transport of a wide variety of drugs including
[50]
the stratum corneum steroids, antibiotics and antiviral agents.It is most
effective at low concentrations, being employed
(b) Oxazolidinones typically between 0.1- 5% but more often between 1-
Oxazolidinones are a new class of chemical agents 3%. Azone partitions into a bilayer lipid to disrupt their
which having potential for use in many cosmetic and packing arrangement but integration into the lipid is
personal care product formulations. Its due to their unlikely to be homogeneous. Azone molecules may exist
ability to localize co -administered drug in skin layers, dispersed within the barrier lipoid or separate domains
resulting in low systemic permeation. Their structural within the bilayer .[50]
features are closely related to sphingosine and ceramide
lipids which are naturally found in the upper skin layers. Mechanism of chemical penetration enhancement
Oxazolidinones viz. 4-decyloxazolidin-2-one has been Penetration enhancers may act by one or more of three
reported to localize the delivery of active ingredients main mechanisms
such as retinoic acid and diclofenac sodium in skin 1. Disruption of the highly ordered structure of stratum
layers. They have higher molecular weight and corneum lipid.
lipophilicity (than other solvent-type enhancers) and 2. Interaction with intercellular protein.
physical characteristics that may be beneficial for 3. Improved partition of the drug, co-enhancer or solvent
reduction of local toxicity because of the lack of into the stratum corneum.
effective absorption of these enhancers into the lower
skin layers where irritation is likely to occur [50]. (4) STRATUM CORNEUM MODIFICATION
a) Hydration
(c) Urea Water is the most widely used and safest method to
Urea promotes transdermal permeation by facilitating increase skin penetration of both hydrophilic and
hydration of the stratum corneum and by the formation lipophilic permeants. The water content of the stratum
of hydrophilic diffusion channels within the barrier. corneum is around 15 to 20% of the dry weight but
Cyclic urea permeation enhancers are biodegradable and varies as per humidity of the external environment.
non-toxic molecules consisting of a polar parent moiety Additional water within the stratum corneum could alter
and a long chain alkyl ester group. As a result, permeant solubility and thereby modify partitioning
from the vehicle into the membrane. In addition,

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increased skin hydration may swell and open the intercalate between stratum corneum ceramides to create
structure of the stratum corneum leading to an increase spatial disruption [51].
in penetration, although it is yet to be demonstrated
experimentally. For example, Scheuplein and Blank CONCLUSION
showed that the diffusion coefficients of alcohols in Successful delivery of transdermal devices requires
hydrated skin were ten times that observed in dry skin. numerous considerations, one of them is the search for
Hydration can be increased by occlusion with plastic the ideal skin penetration enhancer. Over the years there
films, paraffins, oils, waxes as components of ointments has been an efforts to develop a better understanding of
and water-in-oil emulsions that prevent transepidermal the nature of the stratum corneum barrier and the effect
water loss; and oil-in-water emulsions that donate water. of penetration enhancer. So with the help of this article,
Of these, occlusive films of plastic or oily vehicle have we can conclude that the barrier function of skin can be
the most profound effect on hydration and penetration overcome to an extent by the use of above discussed
rate. A commercial example of this is the use of an methods. Still there is need to make efforts to develop
occlusive dressing to enhance skin penetration of such penetration enhancers which exhibit minimum side
lignocaine and prilocane from EMLA cream in order to effects and possible synergistic effect with the drug.
provide sufficient local anaesthesia within about 1 hour
[51]
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