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Department of pharmaceutics, SKIPS Page 1
TRANSDERMAL DRUG DELIVERY SYSTEMS
1. INTRODUCTION
At present, the most common form of delivery of drugs is the oral route. While it has
advantage of easy administration, it also has significant drawbacks namely poor
bioavailability due to hepatic metabolism and the tendency to produce rapid blood level
spikes, leading to a need for high and/or frequent dosing, which can be cost prohibitive and
inconvenient.[1]
To overcome these difficulties there is a need for the development of new drug
delivery system; which will improve the therapeutic efficacy and safety of drugs by more
precise (i.e site specific), spatial and temporal placement within the body thereby reducing
both the size and number of doses.
New drug delivery systems are also essential for the delivery of novel, genetically
engineered pharmaceuticals (i.e. peptides, proteins) to their site of action, without incurring
significant immunogenicity or biological inactivation. One of the methods most often utilized
has been transdermal delivery- meaning transport of therapeutic substances through the skin
for systemic effect. Closely related is percutaneous delivery, which is transport into target
tissues, with an attempt to avoid systemic effects.[2]
1.2 DRUG APPLICATION TO THE SKIN
Both topical and transdermal drug products are intended for external use. However,
topical dermatologic products are intended for localized action on one or more layers of the
skin (e.g., sunscreens, keratolytic agents, local anesthetics, antiseptics and anti-inflammatory
agents). Although some medication from these topical products may unintentionally reach
systemic circulation, it is usually in sub-therapeutic concentrations, and does not produce
effects of any major concern except possibly in special situations, such as the pregnant or
nursing patient. On the other hand, transdermal drug delivery systems use the percutaneous
route for systemic drug delivery, but the skin is not the primary target organ.
1.2.1 Percutaneous Drug Absorption
Percutaneous absorption of drug molecules is of particular importance in the case of
transdermal drug delivery systems because the drug has to be absorbed to an adequate extent
and rate to achieve and maintain uniform, systemic, therapeutic levels throughout the
Department of pharmaceutics, SKIPS Page 2
duration of use. In general, once drug molecules cross the stratum corneal barrier, passage
into deeper dermal layers and systemic uptake occurs relatively quickly and easily.
Generally, drug absorption into the skin occurs by passive diffusion. The rate of drug
transport across the stratum corneum follows Fick’s Law of Diffusion. In other words, the
rate of drug transport depends not only on its aqueous solubility, but is also directly
proportional to its oil/water partition coefficient, its concentration in the formulation vehicle,
and the surface area of the skin to which it is exposed; it is inversely proportional to the
thickness of the stratum corneum. The stratum corneum is thickest in the plantar (soles) and
palmar regions and thinnest in the postauricular, axillary, and scalp regions of the body. An
understanding of the transport behavior of drugs is vital for designing an effective topical or
transdermal product, as well as reasonably predicting and comparing drug behavior in various
formulations. The latter is of practical importance to the pharmacist who is required to
suggest one or more effective drug products out of the many commercial formulations
available or to counsel patients on proper use and handling transdermal products.
Fick’s Law of Diffusion as applied to drug transport across stratum corneum
dM = D.ΔC.K . . . . . . . . . . (1)
dt h
where dM/dt is the steady-state flux across stratum corneum
D is the diffusion coefficient or diffusivity of drug molecules
ΔC is the drug concentration gradient across the stratum corneum
K is the partition coefficient of the drug between skin and formulation medium, and
h is the thickness of the stratum corneum[3] [4]
1.2.2 Skin as a barrier
One of the major limitation to successful transdermal drug delivery is the skin itself
due to its property of being an excellent physical barrier. While transdermal patches, passive
or physically assisted, are limited by the dense tissue to deliver molecules of a certain size.
Understanding how patches interact with the tissue help in designing patches and to
understand penetration mechanisms.[5]
Department of pharmaceutics, SKIPS Page 3
Fig 1.2 (a): Stratum Corneum (topmost 15 μm layer) is the main barrier
1.2.3 Skin anatomy
The skin is made up of several layers including stratum corneum, viable epidermis and
dermis, and it contains appendages that include sweat glands, sebaceous glands, and hair
follicles. The skin can be considered to have four distinct layers of tissue.
i) Non-viable epidermis (stratum corneum)
ii) Viable epidermis
iii) Viable dermis
iv) Subcutaneous connective tissue (hypodermis)
i) Non-viable epidermis (stratum corneum)
Stratum corneum is the outer most layer of skin, which is the actual physical barrier to
most substance that comes in contact with the skin. The stratum corneum is 10 to 20 cell
layer thick over most of the body. Each cell is a flat, plate-like structure 34 - 44 μm long, 25-
36 μm wide, 0.5 to 0.20 μm thick with a surface area of 750 to 1200 μm2
stocked up to each
other in brick like fashion. It is the outermost desquamating ‘horny’ layer of skin, comprising
about 15-20 rows of flat, partially desiccated, dead, keratinized epidermal cells. Depending
upon the region of the body, the thickness of this layer ranges from 10-20 μm, with the
thickest layer on
Department of pharmaceutics, SKIPS Page 4
Fig 1.2 (b): Cross-sectional illustration of human skin
the palms of the hands and soles of the feet. Of the various skin layers, it is the stratum
corneum that is the rate-limiting barrier to percutaneous drug transport. In fact, the stratum
corneum is a remarkably more formidable barrier to drug transport than the epithelial barriers
of gastrointestinal, nasal, buccal, vaginal, or rectal delivery routes.
Fig 1.2 (c): Keratin structure
Department of pharmaceutics, SKIPS Page 5
1.3.1 Definition
Transdermal drug delivery systems (patches) are dosage forms designed to deliver a
therapeutically effective amount of drug across a patient’s skin[8]
also defined as medicated
adhesive patch that is placed on the skin to deliver a specific dose of medication through the
skin and into the bloodstream. Actually, transdermal drug delivery is a transport process of
drugs through a multi-laminar structure, e.g. from the patch to stratum corneum then to the
viable epidermis, and finally penetrating into the blood. [9][10]
Transdermal drug delivery means that a pharmaceutical compound is moved across
the skin the dermis for subsequent systemic distribution. Hence, strictly semantically this
does not only include the more commonly understood “patch”, but also traditional
subcutaneous administration by means of a hypodermic needle and a syringe. Common to all
methods of transdermal drug delivery, by this broad definition, is that the drug is passed
through an artificial route into the body. The main advantage of this approach is that the drug
is entered into the body undistorted without being passed through the body’s various defense
systems.[11]
In contrast to oral administration (e.g. swallowing a pill), the most convenient way of
drug administration, the transdermal route does not suffer from drug degradation in the
gastrointestinal tract and reduced potency through first-pass metabolism (i.e. in the liver). In
addition, oral-specific side-effects like liver damages are avoided, which are seen for example
with common drugs like estradiol (estrogen) [12]
or paracetamol.[13]
Fig 1.3 (a): Traditional vs. Transdermal Release
Department of pharmaceutics, SKIPS Page 6
1.3.2 Traditional transdermal patches
While infusion pumps are reliable in achieving a preferred therapeutic delivery
profile, the use of such a system (e.g. an insulin pump) is somewhat cumbersome, requires
training, is costly, and requires a hypodermic needle-based infusion set. Transdermal patches,
where the drug diffuses through the skin, offer a much more convenient way to administer a
drug while still having the benefits of continuous drug release. Transdermal patches were
introduced in the late 1970s, starting with a three-day patch to treat motion sickness. Since
then, the market for drug administration through patches has been steadily increasing and by
2004 the annual U.S. market value was more than 3 billion with several kinds of drug
formulations available.
In 2001, 51 of 129 drug delivery products under clinical evaluation in the U.S. were
transdermal or dermal systems. Still, only few drugs are presently available as transdermal
patches. The fundamental reason why so few drugs are used is that the barrier property of the
skin limits the use of patches to therapeutics where the molecule size is small enough to
diffuse through the skin at therapeutic rates.
The drugs presently used in patches have molecular masses ranging from 162 Da
(nicotine) to 357 Da (oxybutynin), giving a practical dose rate of 4–20 mg/day depending on
the patch size. As a comparison, the mass of the insulin molecule is 5808 Da and modern
DNA-based vaccines, built of vectors with thousands of base-pairs, may have molecular
weights in the order of hundreds of kilo Daltons (kDa).[15]
Table 1.3 (b): Transdermal patches developed as per USFDA
Drug Name Generic Name Approval Date
Catapres TTS Clonidine October 10, 1984
Flector Diclofenac epolamine January 31, 2007
Vivelle Estradiol October 28, 1994
Climara Estradiol December 22, 1984
Department of pharmaceutics, SKIPS Page 7
Vivelle-DOT Estradiol January 8, 1999
1.3.3 Pathways for a drug molecule to traverse stratum corneum
The stratum corneum of epidermis is the main barrier for traversing drug molecule from
TDDS.
i) Transappendageal transport (shunt route transport)
In this pathway the appendages (hair follicles, sweat ducts) offer pores that bypass
the barrier of the stratum corneum. However, these openings onto the skin surface occupy
only around 0.1% of the total skin surface area. The shunt routes may be important for ions
and large polar molecules that struggle to cross intact stratum corneum.[16]
ii) Intracellular route (Transcellular)
The pathway is directly across the stratum corneum and the molecule crossing the
intact stratum corneum faces numerous repeating hurdles. First, there is partitioning into the
keratinocyte, followed by diffusion through the hydrated keratin. In order to leave the cell,
the molecule must partition into the bilayer lipids before diffusing across the lipid bilayer to
the next keratinocyte. For highly lipophilic molecules the transcellular route may be
predominant.[17]
iii) Intercellular route
In this rout the pathway is via lipid matrix between the keratinocytes. It is now
accepted that this route provides the principle pathway by which most small, uncharged
molecules traverse stratum corneum and therefore many enhancing techniques aim to disrupt
or bypass its elegant molecular architecture.[10]
Fig 1.3 (c): Pathways of transdermal permeation
Department of pharmaceutics, SKIPS Page 8
Hydrophilic drugs permeate by Intercellular pathway and Lipophilic drugs permeates
by Intracellular (Transcellular) mechanism. Transport of hydrophilic or charged molecules is
especially difficult attributable to the lipid-rich nature of the stratum corneum and its low
water content; this layer is composed of about 40% lipids, 40% protein, and only 20% water.
Transport of lipophilic drug molecules is facilitated by their dissolution into intercellular
lipids around the cells of the stratum corneum. Absorption of hydrophilic molecules into skin
can occur through ‘pores’ or openings of the hair follicles and sebaceous glands, but the
relative surface area of these openings is barely 1% of the total skin surface. This small
surface area limits the amount of drug absorption.[3]
1.3.4 Process of drug permeation in transdermal delivery
Transdermal permeation of a drug involves the following steps:
i) Diffusion of drug from drug reservoir to the rate controlling membrane.
ii) Diffusion of drug from rate limiting membrane to stratum corneum.
iii) Sorption by stratum corneum and penetration through viable epidermis.
iv) Uptake of drug by capillary network in the dermal papillary layer.
v) Effect on target organ.[18][19]
Fig 1.3 (d): Process of drug permeation
1.3.5 Kinetics of transdermal permeation[20-25]
Knowledge of skin permeation kinetics is vital to the successful development of
transdermal therapeutic systems. This permeation can be possible only if the drug possesses
certain physiochemical properties.
The rate of permeation across the skin is given by
Department of pharmaceutics, SKIPS Page 9
dQ/dt = Ps (Cd – Cr) . . . . . . . . . . (1)
where Cd and Cr are the concentrations of the skin penetrant in the donor compartment i.e. on
the surface of stratum corneum and in the receptor compartment i.e. body respectively.
Ps is the overall permeability coefficient of the skin tissue to the penetrant. This permeability
coefficient is given by the relationship.
Ps = Ks. Dss/hs . . . . . . . . . . (2)
where Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule
from a solution medium or a transdermal therapeutic system on to the stratum corneum, Dss is
the apparent diffusivity for the steady state diffusion of the penetrant molecule through a
thickness of skin tissues and hs is the overall thickness of skin tissues. As Ks, Dss and hs are
constant under given conditions the permeability coefficient Ps for a skin penetrant can be
considered to be constant.
From equation (1) it is clear that a constantrate of drug permeation can be obtained
only when Cd >> Cr i.e. the drug concentration at the surface of the stratum corneum Cd is
consistently and substantially greater than the drug concentration in the body Cr. The
equation is
dQ/dt = Ps Cd . . . . . . . . . . (3)
And the rate of skin permeation is constant provided the magnitude of Cd remains
fairly constant throughout the course of skin permeation. For keeping Cd constant the drug
should be released from the device at a rate Rr i.e. either constant or greater than the rate of
skin uptake Ra
i.e. Rr >> Ra . . . . . . . . . . (4)
Since Rr >> Ra, the drug concentration on the skin surface Cd is maintained at a level equal
to or greater than the equilibrium solubility of the drug in the stratum corneum Cs .i.e.
Cd>>Cs. Therefore a maximum rate of skin permeation is obtained and is given by the
equation:
(dQ/dt)m = PsCs . . . . . . . . . . (5)
From the above equation it can be seen that the maximum rate of skin permeation
depends upon the skin permeability coefficient Ps and is equilibrium solubility in the stratum
corneum Cs. Thus skin permeation appears to be stratum corneum limited.
Department of pharmaceutics, SKIPS Page 10
Table 1.3 (e): Ideal properties of a transdermal drug delivery system[26]
Properties Comments
Shelf life Up to 2 years
Patch size < 40 cm2
Dose frequency Once a daily to once a week
Aesthetic
appeal
Clear, tan or white color
Packaging
Easy removal of release liner and minimum number of steps required to
apply
Skin reaction Non irritating and non sensitizing
Release Consistent pharmacokinetic and pharmacodynamic profiles over time
1.3.6 Factors affecting transdermal drug delivery[10]
i) Physicochemical properties of permeant
Partition coefficient
For molecules with intermediate partition coefficient (log K 1 to 3) and for highly
lipophilic molecules (log K > 3), the intercellular route will be almost the pathway used to
traverse the stratum corneum. However, for these molecules a further consideration is the
ability to partition out of the stratum corneum into the aqueous viable epidermal tissues. For
more hydrophilic molecules (log K < 1), the transcellular route probably predominates .
Molecular size
A second major factor in determining the flux of a material through human skin is the
size of the molecule. However, for simplicity, the molecular weight is generally taken as an
approximation of molecular size. It has been suggested that an inverse relationship existed
between transdermal flux and molecular weight of the molecule. However, most conventional
therapeutic agents that are selected as candidates for transdermal delivery tend to lie within
narrow range of molecular weight (100-500 Da).
Solubility/melting point
It is well known that most organic materials with high melting points have relatively low
Department of pharmaceutics, SKIPS Page 11
aqueous solubility at normal temperature and pressure. The lipophilic molecules tend to
permeate through the skin faster than more hydrophilic molecules. However, while
lipophilicity is a desired property of transdermal candidates, it is also necessary for the
molecule to exhibit some aqueous solubility since topical medicaments are generally applied
from an aqueous formulation.
Ionization
According to pH-partition hypothesis, only the unionized form of the drug can
permeate through the lipid barrier in significant amounts.
ii) Physiological factors
Skin barrier properties in the neonate and young infant
The skin of newborns is known to be relatively susceptible to irritants,[27]
other variables
related to stratum corneum function such as pH and stratum corneum hydration may enhance
the irritant potential to newborn skin.[28]
Skin surface pH values in newborns are significantly
higher in all body sites than those in adult skin, but stabilize at values similar to adults within
the first month. There are also significant changes in the metabolic capacity of infants,
whether full or preterm, and adult levels of cutaneous enzyme activity are not observed until
2 months or even 6–12 months of age which may additionally account for the sensitivity of
baby skin to irritants. The skin surface of the newborn is slightly hydrophobic and relatively
dry and rough when compared to that of older infants. Stratum corneum hydration stabilizes
by the age of 3 months.
Skin barrier properties in aged skin
There are changes in the physiology of aged skin (>65 years). The corneocytes are
shown to increase in surface area which may have implications for stratum corneum function
due to the resulting decreased volume of intercorneocyte space per unit volume of stratum
corneum. The moisture content of human skin decreases with age. There is a flattening of the
dermo-epidermal junction and, consequently, the area available for diffusion into the dermis
is diminished. Other age-related changes include reductions in the absolute number of hair
follicles, in the diameter of the hair, and pilosebaceous units are also expected.[27]
Race
Racial differences between black and white skins have been shown in some
anatomical and physiological functions of the skin although data is relatively sparse. In black
skin, increased intracellular cohesion, higher lipid content and higher electrical skin
Department of pharmaceutics, SKIPS Page 12
resistance levels compared to whites have been demonstrated. Black skin appears to have a
decreased susceptibility to cutaneous irritants, but this difference is not detected in stripped
skin, suggesting the stratum corneum modulates the different racial response to irritants.
Black skin responds with a decrease in blood flow and hence less erythematic than Hispanics
or Caucasians.[27]
Body site
It is readily apparent that skin structure varies to some degree over the human body.
However, the relative permeability of different skin sites is not simply a function of stratum
corneum thickness as different permeants exhibit varied rank orders through different skin
sites. It is apparent that genital tissue usually provides the most permeable site for
transdermal drug delivery. The skin of the head and neck is also relatively permeable
compared to other sites of the body such as the arms and legs. Intermediate permeability for
most drugs is found on the trunk of the body.
Other factors
The level of hydration of the stratum corneum may have a dramatic effect on drug
permeation through the tissue, and increasing hydration is well known to increase
transdermal delivery of most drugs. Indeed, occlusive dressings and patches are highly
effective strategies to increase transdermal drug delivery since they create elevated hydration
of the stratum corneum.The human body maintains a temperature gradient across the skin
from around 37 ºC to around 32 ºC at the outer surface. Since diffusion through the stratum
corneum is a passive process, elevation of the skin temperature can induce structural
alterations within the stratum corneum, and these modifications can also increase diffusion
through the tissue.
iii) Pathological disorders
Numerous disorders result in an eruption of the skin surface. In such cases, the barrier
properties of the stratum corneum are compromised, allowing the passage of drugs (and
potentially toxic materials) into and through the skin. Likewise, the erupted skin surface will
allow increased water loss from the body. Psoriasis is one of the most common skin diseases.
It is associated with reduced barrier skin function with transepidermal water loss (TEWL) up
to twenty times higher in active psoriasis. The reduced barrier function, which is correlated
with signs of scaling, enables increased percutaneous absorption of topically applied
compounds. The plaques are largely devoid of intracellular lipid, reducing the convoluted
lipid pathway to the dermoepidermal junction, thus enhancing permeation.[29]
Department of pharmaceutics, SKIPS Page 13
Eczema in the chronic stage is often characterized by lichenification, a dry thickened
leathery state, with increased cell markings caused by, repeated scratching and rubbing. In
such areas, where the skin is intact, absorption may be retarded, since the absorptive path is
increased. Non-eczematous skin of patients with a prior history of atopic eczema shows
abnormalities in lipid metabolism resulting in a decrease in stratum corneum lipids. In
addition to a reduced barrier function it is presumed that these compositional differences are
related to the decrease in water binding capacity of eczematous skin. Infections cause damage
to the skin barrier integrity varies depending on the severity of the infection. This is usually
favorable for topical treatment of infection, but it must be remembered that the barrier is
dynamic and will be restored as the condition improves, therefore, drug flux across the
repairing tissue will be expected to be slow.
1.3.7 Conditions in which Transdermal patches are used[10]
 When the patient has intolerable side effects (including constipation) and who is unable to
take oral medication (dysphagia) and is requesting an alternative method of drug delivery.
 Where the pain control might be improved by reliable administration. This might be
useful in
patients with cognitive impairment or those who for other reasons are not able to self-
medicate with their analgesia.
 It can be used in combination with other enhancement strategies to produce synergistic
effects.
1.3.8 Conditions in which Transdermal patches are not used[10]
 Cure for acute pain is required and where rapid dose titration is required.
 Where requirement of dose is equal to or less then 30 mg/24 hrs.
1.3.9 Merits of Transdermal drug delivery[10] [26] [30]
This approach to drug delivery offers many advantages over traditional methods.
 Enables the avoidance of gastrointestinal absorption, with its associated pitfalls of
enzymatic
and pH associated deactivation.
 This method also allows for reduced pharmacological dosaging due to the shortened
metabolization pathway of the transdermal route versus the gastrointestinal pathway.
Department of pharmaceutics, SKIPS Page 14
 The patch also permits constant dosing rather than the peaks and valleys in medication
level associated with orally administered medications.
 Multi-day therapy with a single application.
 It is of great advantage in patients who are nauseated or unconscious.
 First pass metabolism, an additional limitation to oral drug delivery, can be avoided.
 Controlled release over extended period
 Easily terminable means for systemic as well as topical drug delivery
 Improved patient compliance.
1.3.10 Demerits of Transdermal drug delivery [10] [26] [30]
However this system has its own limitations
 The drug that require high blood levels cannot be administered and may even cause
irritation or sensitization of the skin.
 The adhesives may not adhere well to all types of skin and may be uncomfortable to wear.
 The high cost of the product is also a major drawback for the wide acceptance of this
product.
 One of the greatest disadvantages is the possibility that a local irritation will develop at
the site of application.
 Erythema, itching, and local oedema can be caused by the drug, the adhesive, or other
excipients in the patch formulation. For most patients, site rotation can minimize
irritation.
 Another significant disadvantage is that the skin's low permeability limits the number of
drugs that can be delivered in this manner.
1.4 FORMULATION APPROACHES
1.4.1 Components of Transdermal Patch[1] [31]
The common ingredients which are used for the preparation of TDDS are as follows.
i) Drug - Drug solution in direct contact with release liner.
Ex: Nicotine, Methotrexate and Estrogen.
ii) Liner - Protects the patch during storage. The liner is removed prior to use.
Ex: polyester film.
Department of pharmaceutics, SKIPS Page 15
iii) Adhesive - Serves to adhere the components of the patch together along with adhering
the patch to the skin.
Ex: Acrylates, Polyisobutylene, Silicones.
iv) Membrane - Controls the release of the drug from the reservoir and multi-layer patches
containing permeation enhancers.
Ex: Terpenes, Terpenoids, Pyrrolidones.
Solvents like alcohol, Ethanol, Methanol.
Surfactants like Sodium Lauryl sulfate, Pluronic F127, Pluronic F68.
v) Backing - Protects the patch from the outer environment.
Ex: Cellulose derivatives, poly vinyl alcohol, Polypropylene Silicon rubber.
Fig 1.4 (a) Components of trandermal patch
1.4.2 Types of transdermal systems[31-40]
Four major transdermal systems
i) Single-layer Drug-in-Adhesive
Fig 1.4 (b): Single-layer Drug-in- Adhesive
It is characterized by the inclusion of the drug directly within the skin-contacting
adhesive. In this transdermal system design, the adhesive not only serves to affix the system
Department of pharmaceutics, SKIPS Page 16
to the skin, but also serves as the formulation foundation & responsible for the releasing of
the drug. The adhesive layer is surrounded by a temporary liner and a backing.
The rate of release of drug from this type of system is dependent on the diffusion
across the skin. The intrinsic rate of drug release from this type of drug delivery system is
defined by
dQ = Cr . . . . . . . . . . (1)
dT 1/Pm+ 1/Pa
where Cr is the drug concentration in the reservoir compartment and Pa and Pm are the
permeability coefficients of the adhesive layer and the rate controlling membrane , Pm is the
sum of permeability coefficients simultaneous penetrations across the pores and the
polymeric material. Pm and Pa , respectively, are defined as follows.
Pm = Km/r . D . . . . . . . . . . (2)
hm
Pa = Ka/m . D . . . . . . . . . . (3)
ha
where Km/r and Ka/m are the partition coefficients for the interfacial partitioning of drug from
the reservoir to the membrane and from the membrane to adhesive respectively; Dm and Da
are the diffusion coefficients in the rate controlling membrane and adhesive layer,
respectively; and hm and ha are the thicknesses of the rate controlling membrane and adhesive
layer, respectively.
ii) Multi-layer Drug-in-Adhesive
The Multi-layer Drug-in-Adhesive is similar to the Single-layer Drug-in-Adhesive in
that the drug is incorporated directly into the adhesive both adhesive layers are also
responsible for the releasing of the drug. One of the layers is for immediate release of the
drug and other layer is for control release of drug from the reservoir. However, is different
that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all
cases). The multi-layer encompasses either the addition of membrane between two distinct
Department of pharmaceutics, SKIPS Page 17
drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single
backing film. This patch also has a temporary liner.
Fig 1.4 (c): Multi-layer Drug-in-Adhesive
The rate of drug release in this system is defined by:
dQ = Ka/r . Da . . . . . . . . . . (4)
dt Cr ha
Where Ka/r is the partition coefficient for the interfacial partitioning of the drug from the
reservoir layer to adhesive layer.
iii) Drug Reservoir-in-Adhesive
The Reservoir transdermal system design is characterized by the inclusion of a liquid
compartment containing a drug solution or suspension separated from the release liner by a
semi-permeable membrane and adhesive. The adhesive component of the product responsible
for skin
Fig 1.4 (d): Drug Reservoir-in-Adhesive
adhesion can either be incorporated as a continuous layer between the membrane and the
release liner or in a concentric configuration around the membrane. Unlike the Single-layer
and Multi-layer Drug-in-adhesive systems the reservoir transdermal system has a separate
Department of pharmaceutics, SKIPS Page 18
drug layer. This patch is also backed by the backing layer. In this type of system the rate of
release is zero order.
The rate of drug release from this drug reservoir gradient controlled system is given by;
dQ = Ka/r . Da A ( ha) . . . . . . . . . . (5)
dt ha ( t )
The above equation, the thickness of the adhesive layer for drug molecules to
diffuse through increases with time ha (t). To compensate for this time dependent increase in
the diffusional path due to the depletion of drug dose by release, the drug loading level is also
increased with the thickness of diffusional path A (ha).
iv) Drug Matrix-in-Adhesive
The Matrix system design is characterized by the inclusion of a semisolid matrix
containing drug solution or suspension which is in direct contact with the release liner The
adhesive layer in this patch surrounds the drug layer partially overlaying it.. The component
responsible for skin adhesion is incorporated in an overlay and forms a concentric
configuration around the semisolid matrix. Matrix patches are not designed to provide true
zero-order release because as the drug closest to the skin is released, the drug deeper within
the patch must travel a longer distance to reach the skin. The longer diffusional path slows
the rate of absorption from the patch over time.
Fig 1.4 (e): Drug Matrix-in-Adhesive
Department of pharmaceutics, SKIPS Page 19
The rate of drug release from this type of system is defined as:
dQ = ACp Dp
½ . . . . . . . . . . (6)
dt 2t
where A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are
the solubility and diffusivity of the drug in the polymer respectively. Since, only the drug
species dissolved in the polymer can release, Cp is essentially equal to CR, where CR is the
drug concentration in the reservoir compartment.
v) Vapour Patch
In this type of patch the adhesive layer not only serves to adhere the various layers
together but also to release vapour. The vapour patches are new on the market and they
release essential oils for up to 6 hours. The vapours patches release essential oils and are used
in cases of decongestion mainly. Other vapour patches on the market are controller vapour
patches that improve the quality of sleep. Vapour patches that reduce the quantity of
cigarettes that one smokes in a month are also available on the market.
1.4.3 Methods for preparation of TDDS[31]
i) Asymmetric TPX membrane method[41]
A prototype patch can be fabricated for this a heat sealable polyester film (type 1009,
3m) with a concave of 1cm diameter will be used as the backing membrane. Drugsample is
dispensed into the concave membrane, covered by a TPX {poly(4-methyl-1-
pentene)}asymmetric membrane, and sealed by an adhesive.
Asymmetric TPX membrane preparation : These are fabricated by using the dry/wet
inversion process. TPX is dissolved in a mixture of solvent (cyclohexane) and nonsolvent
additives at 60°c to form a polymer solution. The polymer solution is kept at 40°C for 24 hrs
and cast on a glass plate to a pre-determined thickness with a gardner knife. After that the
casting film is evaporated at 50°C for 30 sec, then the glass plate is to be immersed
immediately in coagulation bath [maintained the temperature at 25°C]. After 10 minutes of
immersion, the membrane can be removed, air dry in a circulation oven at 50°C for 12 hrs].
ii) Circular teflon mould method[42]
Solutions containing polymers in various ratios are used in an organic solvent.
Calculated amount of drug is dissolved in half the quantity of same organic solvent.
Enhancers in different concentrations are dissolved in the other half of the organic solvent
and then added. Di-N-butylphthalate is added as a plasticizer into drug polymer solution. The
Department of pharmaceutics, SKIPS Page 20
total contents are to be stirred for 12 hrs and then poured into a circular teflon mould. The
moulds are to be placed on a leveled surface and covered with inverted funnel to control
solvent vaporization in a laminar flow hood model with an air speed of 0.5 m/s. The solvent
is allowed to evaporate for 24 hrs. The dried films are to be stored for another 24 hrs at
25±0.5°C in a desiccators containing silica gel before evaluation to eliminate aging effects.
The type films are to be evaluated within one week of their preparation.
iii) Mercury substrate method[43]
In this method drug is dissolved in polymer solution along with plasticizer. The
above solution is to be stirred for 10-15 minutes to produce a homogenous dispersion and
poured in to a leveled mercury surface, covered with inverted funnel to control solvent
evaporation.
iv) By using “IPM membranes” method[44]
In this method drug is dispersed in a mixture of water and propylene glycol
containing carbomer 940 polymer and stirred for 12 hrs in magnetic stirrer. The dispersion is
to be neutralized and made viscous by the addition of triethanolamine. Buffer pH 7.4 can be
used in order to obtain solution gel, if the drug solubility in aqueous solution is very poor.
The formed gel will be incorporated in the IPM membrane.
v) By using “EVAC membranes” method[45]
In order to prepare the target transdermal therapeutic system, 1% carbopol reservoir
gel, polyethelene (PE), ethylene vinyl acetate copolymer (EVAC) membranes can be used as
rate control membranes. If the drug is not soluble in water, propylene glycol is used for the
preparation of gel. Drug is dissolved in propylene glycol, carbopol resin will be added to the
above solution and neutralized by using 5% w/w sodium hydroxide solution. The drug (in gel
form) is placed on a sheet of backing layer covering the specified area. A rate controlling
membrane will be placed over the gel and the edges will be sealed by heat to obtain a leak
proof device.
vi) Aluminium backed adhesive film method[46]
Transdermal drug delivery system may produce unstable matrices if the loading dose
is greater than 10 mg. Aluminium backed adhesive film method is a suitable one. For
preparation of same, chloroform is choice of solvent, because most of the drugs as well as
adhesive are soluble in chloroform. The drug is dissolved in chloroform and adhesive
material will be added to the drug solution and dissolved. A custammade aluminium former
is lined with aluminium foil and the ends blanked off with tightly fitting cork blocks.
Department of pharmaceutics, SKIPS Page 21
vii) Preparation of TDDS by using Proliposomes[47-48]
The proliposomes are prepared by carrier method using film deposition technique.
From the earlier reference drug and lecithin in the ratio of 0.1:2.0 can be used as an optimized
one. The proliposomes are prepared by taking 5mg of mannitol powder in a 100 ml round
bottom flask which is kept at 60-70°c temperature and the flask is rotated at 80-90 rpm and
dried the mannitol at vacuum for 30 minutes. After drying, the temperature of the water bath
is adjusted to 20-30°C. Drug and lecithin are dissolved in a suitable organic solvent mixture,
a 0.5ml aliquot of the organic solution is introduced into the round bottomed flask at 37°C,
after complete drying second aliquots (0.5ml) of the solution is to be added. After the last
loading, the flask containing proliposomes are connected in a lyophilizer and subsequently
drug loaded mannitol powders (proliposomes) are placed in a desiccator over night and then
sieved through 100 mesh. The collected powder is transferred into a glass bottle and stored at
the freeze temperature until characterization.
viii) By using free film method[49]
Free film of cellulose acetate is prepared by casting on mercury surface. A polymer
solution 2% w/w is to be prepared by using chloroform. Plasticizers are to be incorporated at
a concentration of 40% w/w of polymer weight. Five ml of polymer solution was poured in a
glass ring which is placed over the mercury surface in a glass petri dish. The rate of
evaporation of the solvent is controlled by placing an inverted funnel over the Petri dish. The
film formation is noted by observing the mercury surface after complete evaporation of the
solvent. The dry film will be separated out and stored between the sheets of wax paper in a
desiccator until use. Free films of different thickness can be prepared by changing the volume
of the polymer solution.
1.5 PERMEABLITY ENHANCEMENT
1.5.1 Methods of enhancement[35] [50]
i) Chemical enhancement
ii) Physical enhancement
iii) Biochemical enhancement
iv) Supersaturation enhancement
v) Bioconvertable prodrug
Department of pharmaceutics, SKIPS Page 22
i) Chemical enhancement
The skin permeability of drugs can be greatly improved by treating the stratum
corneum surface with an appropriate skin permeation enhancer. Ideally penetrating enhancers
reversibly reduce the barrier resistance of the stratum corneum without damaging viable cell.
A synergistic effect in the skin permeation enhancement could be achieved by incorporating
two or more enhancers in the adhesive layer. Sometimes chemical penetration enhancers may
also provoke unwanted biochemical and metabolic events within skin but this is not their aim.
In the past two decades tremendous amount of work has been done to search specific
chemicals that can act as penetration enhancer with ideal properties as follows.
ii) Physical enhancement
Different physical approaches to increase percutaneous absorption have been utilized
but the most important approaches are iontophoresis, ultrasound, electroporation and heat.
These methods show most promising in the percutaneous delivery of large molecular weight
compounds but the major limitation is the input of energy to achieve their effects.
Fig 1.5 (a) : Enhanced permeation by ultrasound
Department of pharmaceutics, SKIPS Page 23
Fig 1.5 (b) : Enhanced permeation by electroporation
iii) Biochemical enhancement
This chemical provokes the biological and metabolic events within the skin and
significantly increases skin permeability.These types of enhancers reduce barrier properties
of the skin either by inhibiting enzymes responsible for synthesis of stratum corneum lipid or
by promoting metabolism of existing skin lipids that are responsible for barrier function.
iv) Supersaturation enhancement
The thermodynamic activity of drug can be increased by employing supersatured
systems that gives rise to unusually high thermodynamic properties. However topical vehicle
relying on supersaturation have the major limitation of formulation instability, both prior to
and during application to skin, unless the formulation can be stabilized with antinucleant and
anticrystal-growth agents.
v) Bioconvertable prodrug
The prodrug concept can be applied in transdermal controlled drug delivery by
altering skin permeability via modification of the physicochemical properties of the drug
molecules to enhance its rate of transdermal permeation. One example of this approach is the
Department of pharmaceutics, SKIPS Page 24
esterification of less skin permeable estradiol to form lipophilic estradiol ester (like estradiol-
17-acetate, estradiol-3, 17-diacetate and estradiol-17-cypiuonate etc.
1.5.2 Ideal characteristics of penetration enhancers[7]
Ideally, penetration enhancers reversibly reduce the barrier resistance of the
stratum corneum without damaging viable cells.[35] [51]
Some of the more desirable properties
for penetration enhancers acting within the skin have been given as:[52]
 They should be non-toxic, non-irritating and non-allergenic
 They would ideally work rapidly; the activity and duration of effect should be both
predictable and reproducible.
 They should have no pharmacological activity within the body.
 The penetration enhancers should work unidirectionally, i.e., they should allow
therapeutic agents into the body while preventing the loss of endogenous materials from
the body.
 When removed from the skin, barrier properties should return both rapidly and fully to
normal.
 They should be cosmetically acceptable with an appropriate skin feel. Not surprisingly,
no such material that possesses the above ideal properties has yet been discovered
although some chemicals demonstrate several of the above attributes.
1.5.3 Mechanism of penetration enhancement[7]
Penetration enhancers may act by one or more of three main mechanisms [52]
 Disruption of the highly ordered structure of stratum corneum lipid.
 Interaction with intercellular protein.
 Improved partition of the drug, co-enhancer or solvent into the stratum corneum.
Department of pharmaceutics, SKIPS Page 25
Fig 1.5 (c): Mechanisms of penetration enhancers
The enhancer act by altering one of three pathways. The key to altering the polar
pathway is to cause protein conformational change or solvent swelling. The fatty acid
enhancers increased the fluidity of the lipid protein portion of the stratum corneum. Some
enhancers act on both polar and nonpolar pathway by altering the multilaminate pathway for
penetration. Enhancers can increase the drug diffusivity through skin proteins. The type of
enhancer employed has a significant impact on the design and development of the product.[53]
A useful way to consider factors affecting drug permeation rate through the stratum
corneum is via the simple equation given below for steady state flux.[52]
If we plot the cumulative mass of diffusant, m, passing per unit area through the
membrane , at long time the graph approaches linearity and its slope its yield the steady flux ,
dm/dt
dm = D Co K . . . . . . . . . . (1)
dt h
Department of pharmaceutics, SKIPS Page 26
where Co is the constant concentration of drug in donor solution, K is the partition coefficient
of the solute between the membrane and the bathing solution, D is the diffusion coefficient
and h is thickness of membrane.
From the above equation (1), we deduce the ideal properties of a molecule that would
penetrating stratum corneum well. These are:
 Low molecular mass, preferably less than 600Da, when D tends to be high.
 Adequate solubility in oil and water so that membrane concentration gradient may be
high.
 High but balanced (optimal) K (if too large, may inhibit clearance by viable tissue)
 Low melting point, correlating with good solubility as predicted by ideal solubility
theory.
1.5.4 Chemical penetration enhancers[7]
Chemical substances temporarily diminishing the barrier of the skin and known as
accelerants or sorption promoters can enhance drug flux. Several types are known
i) Sulphoxides and similar chemicals
Dimethyl sulphoxides (DMSO) is one of the earliest and most widely studied
penetration enhancers. It is a powerful aprotic solvent which hydrogen bonds with itself
rather than with water. It is colourless, odourless and is hydroscopic and is often used in
many areas of pharmaceutical sciences as a universal solvent. DMSO alone has been applied
topically to treat systemic inflammation. DMSO works rapidly as a penetration enhancer -
spillage of the material onto the skin can be tasted in the mouth within a second. Although
DMSO is an excellent accelerant, it does create problems.
The effect of the enhancer is concentration-dependent and generally co-solvents
containing > 60% DMSO is needed for optimum enhancement efficacy. However, at these
relative high concentrations, DMSO can cause erythema and wheal of the stratum corneum.
Denaturing of some skin proteins results in erythema, scaling, contact uticaria, stinging and
Department of pharmaceutics, SKIPS Page 27
burning sensation.[54]
Since DMSO is problematic for use as a penetration enhancer,
researchers have investigated a similar chemically-related material as a accelerant. DMAC
and DMF are similarly powerful aprotic solvents.
However, South well and Barry, showing a 18-fold increase in the flux of caffeine
permeating across a DMF treated human skin, concluded that the enhancer caused
irreversible membrane damage.[55]
DMF irreversibly damages human skin membranes but
has been found in vivo to promote the bioavailability of betamethasone-17-benzoate as
measured by vasoconstrictor assay.[56][57]
DMSO may also extract lipids, making the horny
layer more permeable by forming aqueous channels.[58]
The mechanism of the sulphoxide
penetration enhancers is widely used to denature protein and, on application to human skin,
has been shown to change the intercellular keratin conformation, from helical to ß sheet.[59]
[60]
ii) Azone
Azone (1-dodecylazacycloheptan-2-one or laurocapran) was the first molecule
specifically designed as a skin penetration enhancer. Azone is a colourless, odourless liquid
with a melting point of -7ºC and it possesses a smooth, oily but yet non-greasy feel. Azone is
a highly lipophilic material with a log p-octanol / water of around 6.2 and it is soluble in and
compatible with most organic solvents including alcohol and propylene glycol. Azone
enhances the skin transport of a wide variety of drugs including steroids, antibiotics and
antiviral agents. Azone is most effective at low concentrations, being employed typically
between 0.1- 5% but more often between 1-3%.[35]
Azone partitions into a bilayer lipid to
disrupt their packing arrangement but integration into the lipid is unlikely to be
homogeneous. Azone molecules may exist dispersed within the barrier lipoid or separate
domains within the bilayer.[51]
iii) Pyrrolidones
Pyrrolidones have been used as permeation enhancers for numerous molecules
including hydrophilic (e.g. mannitol and 5-flurouracil) and lipophilic (progesterone and
hydrocortisone) permeants. N-methyl-2-pyrolidone was employed with limited success as a
penetration enhancer for captopril when formulated in a matrix-type transdermal patch.[61]
The pyrrolidones partition well into human stratum corneum within the tissue and they may
Department of pharmaceutics, SKIPS Page 28
act by altering the solvent nature of the membrane. Pyrrolidones have been used to generate
reservoirs within the skin membrane. Such a reservoir effect offers a potential for sustained
release of a permeant from the stratum corneum over extended time periods.[62]
iv) Fatty acids
Percutaneous drug absorption has been increased by a wide variety of long-chain fatty
acids, the most popular of which is oleic acid.
It is of interest to note that many penetration enhancers such as azone contain
saturated or unsaturated hydrocarbon chains and some structure - activity relationships have
been drawn from the extensive studies of Aungst who employed a range of fatty acids, acids,
alcohols, sulphoxides, surfactants and amides as enhancers for naloxone.[63][64]
Shin et al[65]
studied various penetration enhancers like glycols (diethylene glycol and tetraethylene
glycol), fatty acids (lauric acid, myristic acid and capric acid) and nonionic surfactant
(polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether) on the release of
triprolidone. Lauric acid in Propylene glycol enhanced the delivery of highly lipophilic
antiestrogen.[66]
Oleic acid greatly increased the flux of many drugs such as increasing the
flux of salicylic acid 28-fold and 5-flurouracil flux 56-fold through human skin membrane in
vitro.[57]
The enhancer interacts with and modifies the lipid domains of the stratum corneum as
would be expected for a long chain fatty acid with cis-configuration.[35]
v) Essential oil, terpenes and terpenoids
Terpenes are found in essential oils, and are compounds comprising of only carbon,
hydrogen and oxygen atoms, but which are not aromatic. Numerous terpenes have long been
used as medicines as well as flavoring and fragrance agents. The essential oils of eucalyptus,
chenopodium and ylang-ylang have been found to be effective penetration enhancers for 5-
flouorouracil transversing human skin in vivo.[67]
Cornwell et al.[68]
investigated the effect of 12 sesquiterpenes on the permeation of 5-
flurouracil in human skin. Pretreatment of epidermal membranes with sesquiterpene oil or
using solid sesquiterpenes saturated in dimethyl isosorbide increased the absorption of 5-
fluorouracil. L-menthol has been used to facilitate in vitro permeation of morphine
Department of pharmaceutics, SKIPS Page 29
hydrochloride through hairless rat skin as[69]
well as diffusion of imipramine hydrochloride
across rat skin and hydrocortisone through hairless mouse skin.[62] [63]
One mechanism by which this agent operates is to modify the solvent nature of the
stratum corneum, thus improving drug partitioning into the tissue. Many terpenes permeate
human skin well and large amounts of terpene have been found in the epidermis after
application from a matrix-type patch. Terpenes may also modify drug diffusivity through the
membrane. During steady state permeation experiments using terpenes as penetration
enhancers, the lag time for permeation was usually reduced, indicating some increase in drug
diffusivity through the membrane following terpene treatment.[35]
vi) Oxazolidinones
Oxazolidinones are a new class of chemical agents which have the potential for use in
many cosmetic and personal care product formulations. This is due to their ability to localize
co-administered drug in skin layers, resulting in low systemic permeation.[70] [71]
The
structural features of these permeation enhancers are closely related to sphingosine and
ceramide lipids which are naturally found in the upper skin layers. Oxazolidinones such as 4-
decyloxazolidin-2-one has been reported to localize the delivery of many active ingredients
such as retinoic acid and diclofenac sodium in skin layers.[72]
This compound has a higher
molecular weight and lipophilicity than other solvent-type enhancers, physical characteristics
that may be beneficial in terms of a reduction in local toxicity because of the lack of effective
absorption of these enhancers into the lower skin layers where irritation is likely to be occur.
vii) Urea
Urea promotes transdermal permeation by facilitating hydration of the stratum corneum
and by the formation of hydrophilic diffusion channels within the barrier. Cyclic urea
permeation enhancers are biodegradable and non-toxic molecules consisting of a polar parent
moiety and a long chain alkyl ester group. As a result, enhancement mechanism may be a
consequence of both hydrophilic activity and lipid disruption mechanism.[50]
1.6 SELECTION OF DRUG CANDIDATE [73-74]
The product development of a transdermal formulation generally includes the following
stages:
Department of pharmaceutics, SKIPS Page 30
 Selection of drug candidate
 Selection of the appropriate physical form (e.g., acid, base, or salt)
 Selection of the desired design (e.g., reservoir, matrix, etc.)
The transdermal route of administration cannot be employed for a large number of
drugs, only a small number of drug products are currently available via transdermal delivery.
In many cases, a drug's physical properties, including molecular size and polarity, have
limited its capacity to be delivered transdermally. Similarly, the biological properties of drug
molecules, including dermal irritation and insufficient bioavailability, have been problematic.
In the product development the focus must be on the rationality of drug selection based on
pharmacokinetic parameters and physicochemical properties of the drug. Physiochemical
factors such as solubility, crystallinity, molecular weight <400, polarity, melting point <200,
partition coefficient Log P (octanol-water) between -1.0 to 4 must be considered.
Table 1.6 (a) : Ideal Properties of drug candidate for transdermal drug delivery[26]
Parameter Properties
Dose Should be low
Half life in hr 10 or less
Molecular weight < 400
Partition coefficient Log P (Octanol-water) between 1.0 and 4
Skin permeability coefficient > 0.5 x10-3cm/hr
Skin reaction Non irritating and non sensitizer
Oral bioavailability Low
Therapeutic index Low
Biological factor should also be considered such as skin irritation, site of application
of the patch e.g. scopolamine patch for motion sickness is applied backside of the ear and
Transderm-Nitro is applied on the chest. When a pharmacologically active material has to be
Department of pharmaceutics, SKIPS Page 31
presented to the skin, an occlusive or allergic response is significant, limits have to be
determined for the acceptability of the undesired effect .The pharmacokinetic information of
the drug is a critical factor in deciding its suitability for delivery by the transdermal route as it
is suitable only for drugs whose daily dose is in few milligrams. The resulting plasma
concentration of active agent depends on the clearance; however, if one assumes a small
volume of distribution and relatively long half-life, plasma level in excess of few micrograms
per milliliter is very unlikely. Another important factor is the half-life, (e.g., nitroglycerin t 1/2
is 3 min) which provides information on the disposition of a drug in our body other
parameters such as effective plasma level; also determine whether a transdermal delivery can
be developed or not.
Department of pharmaceutics, SKIPS Page 32
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1. Chein YW. Novel Drug Delivery Systems. 2nd ed. New York: Marcel Dekker; 1992; 1-2.
2. Chien Yie W. Parenteral drug delivery and delivery systems. 2nd ed. New York:Marcel
Dekker Inc; 1992; 301-50.
3. Tyle P. Drug Delivery Devices. Fundamentals and Applications. New York:Marcel
Dekker; 1998; 385-417.
4. Desai BG, Annamalai AR, Divya B, Dinesh BM. Effect of enhancers on permeation
kinetics of captopril for transdermal system. Asian J Pharm 2008; 2: 35-7.
5. Langer R. Transdermal drug delivery: past progress, current status and future prospects.
Adv Drug Del Rev 2004; 56(5): 557-8.
6. Cleary GW, Beskar E. Transdermal and transdermals like delivery system opportunities;
Today and the Future. Pharmatech 2003; 82-8.
7. Ryan DG and Peterson TA. 4 Myths about transdermal drug delivery. Drug Del Tech
2003; 3(4): 1-7.
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9. Benson HAE., Transdermal drug delivery: Penetration enhancement techniques. Curr
Drug Deliv 2005;(2): 23-33.
10. Kanikkannan N, Kandimalla K, Lamba SS, Singh M. Structure-activity Relationship of
chemical penetration enhancers in transdermal drug delivery.Curr Med Chem 2000;7:
593, 608.
11. Barry BW. Drug delivery routes in skin: a novel approach. Adv Drug Deliv Rev2002;
54:s31-s40.
12. Hadgraft J. Skin deep. Eur J Pharm Biopharm 2004;58:291-9. Singh S, Singh J.
Transdermal drug delivery by passive diffusion and iontophoresis: a review. Med Res
Rev 1993; 13:569621.
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13. Ritschel WA, Hussain AS. The principles of permeation of substances across the skin.
Methods Find Exp Clin Pharmacol 1998;10(1); 39-56.
14. Shastri VP, Lee PJ, Ahmad N, Langer R, Mitragotri S. Evaluation of chemical enhancers
in the transdermal delivery of lidocaine. Int J Pharm 2006; 33:308.
15. Hardman JG, Limbird LE, editor. Goodman & Gilman’s-The pharmacological basis of
therapeutics. 10 ed. New York: McGraw Hill; 1996.
16. Barry BW, Novel mechanisms and devices to enable successful transdermaldrug delivery.
J Pharm Sci 2004; 21:371-7.
17. Jain NK. Advances in controlled and novel drug delivery.1st ed. Delhi: CBS Publishers;
2001. 426-48.
18. Rao YM ,Gannu R, Vishnu YV and Kishan V. Development of nitrendipine transdermal
patches for in vitro and ex vivo characterization. Curr Drug Deliv 2007;4: 69-76.
19. Mao Z, Zhan X, Tang G, Chen S. A new copolymer membrane controlling clonidine
linear release in a transdermal drug delivery system. Int J Pharm 2006; 332:1-5.
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tartrate: In vitro characterization. Acta Pharm 2003; 53: 119-25.
21. Vyas SP, Khar RK. Controlled drug delivery concepts and advances. 1st ed. New Delhi:
Vallabh Prakashan; 2002. 411-47.
22. Tiwary AK, Sapra B and Jain S. Innovations in transdermal drug delivery: formulations
and techniques. Recent Patents on Drug Delivery & Formulation 2007;1: 23-36.
23. Basak SC, Vellayan K. Transdermal drug delivery systems. The Eastern Pharmacist
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26. Murthy SN, Hiremath. Transdermal Drug Delivery systems. In: Hiremath SRR, editor.
Text book of industrial pharmacy. India: Orient longman private limited; 2008; 27-49.
27. Shin SC, Cho CW. Enhanced transdermal delivery of atenolol from the ethylene vinyl
acetate matrix. Int J Pharm 2004;287; 67-71.
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systemic agents. J Pharm Res 2007;6(2): 44-50.
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Transdermal drug delivary system

  • 1. Department of pharmaceutics, SKIPS Page 1 TRANSDERMAL DRUG DELIVERY SYSTEMS 1. INTRODUCTION At present, the most common form of delivery of drugs is the oral route. While it has advantage of easy administration, it also has significant drawbacks namely poor bioavailability due to hepatic metabolism and the tendency to produce rapid blood level spikes, leading to a need for high and/or frequent dosing, which can be cost prohibitive and inconvenient.[1] To overcome these difficulties there is a need for the development of new drug delivery system; which will improve the therapeutic efficacy and safety of drugs by more precise (i.e site specific), spatial and temporal placement within the body thereby reducing both the size and number of doses. New drug delivery systems are also essential for the delivery of novel, genetically engineered pharmaceuticals (i.e. peptides, proteins) to their site of action, without incurring significant immunogenicity or biological inactivation. One of the methods most often utilized has been transdermal delivery- meaning transport of therapeutic substances through the skin for systemic effect. Closely related is percutaneous delivery, which is transport into target tissues, with an attempt to avoid systemic effects.[2] 1.2 DRUG APPLICATION TO THE SKIN Both topical and transdermal drug products are intended for external use. However, topical dermatologic products are intended for localized action on one or more layers of the skin (e.g., sunscreens, keratolytic agents, local anesthetics, antiseptics and anti-inflammatory agents). Although some medication from these topical products may unintentionally reach systemic circulation, it is usually in sub-therapeutic concentrations, and does not produce effects of any major concern except possibly in special situations, such as the pregnant or nursing patient. On the other hand, transdermal drug delivery systems use the percutaneous route for systemic drug delivery, but the skin is not the primary target organ. 1.2.1 Percutaneous Drug Absorption Percutaneous absorption of drug molecules is of particular importance in the case of transdermal drug delivery systems because the drug has to be absorbed to an adequate extent and rate to achieve and maintain uniform, systemic, therapeutic levels throughout the
  • 2. Department of pharmaceutics, SKIPS Page 2 duration of use. In general, once drug molecules cross the stratum corneal barrier, passage into deeper dermal layers and systemic uptake occurs relatively quickly and easily. Generally, drug absorption into the skin occurs by passive diffusion. The rate of drug transport across the stratum corneum follows Fick’s Law of Diffusion. In other words, the rate of drug transport depends not only on its aqueous solubility, but is also directly proportional to its oil/water partition coefficient, its concentration in the formulation vehicle, and the surface area of the skin to which it is exposed; it is inversely proportional to the thickness of the stratum corneum. The stratum corneum is thickest in the plantar (soles) and palmar regions and thinnest in the postauricular, axillary, and scalp regions of the body. An understanding of the transport behavior of drugs is vital for designing an effective topical or transdermal product, as well as reasonably predicting and comparing drug behavior in various formulations. The latter is of practical importance to the pharmacist who is required to suggest one or more effective drug products out of the many commercial formulations available or to counsel patients on proper use and handling transdermal products. Fick’s Law of Diffusion as applied to drug transport across stratum corneum dM = D.ΔC.K . . . . . . . . . . (1) dt h where dM/dt is the steady-state flux across stratum corneum D is the diffusion coefficient or diffusivity of drug molecules ΔC is the drug concentration gradient across the stratum corneum K is the partition coefficient of the drug between skin and formulation medium, and h is the thickness of the stratum corneum[3] [4] 1.2.2 Skin as a barrier One of the major limitation to successful transdermal drug delivery is the skin itself due to its property of being an excellent physical barrier. While transdermal patches, passive or physically assisted, are limited by the dense tissue to deliver molecules of a certain size. Understanding how patches interact with the tissue help in designing patches and to understand penetration mechanisms.[5]
  • 3. Department of pharmaceutics, SKIPS Page 3 Fig 1.2 (a): Stratum Corneum (topmost 15 μm layer) is the main barrier 1.2.3 Skin anatomy The skin is made up of several layers including stratum corneum, viable epidermis and dermis, and it contains appendages that include sweat glands, sebaceous glands, and hair follicles. The skin can be considered to have four distinct layers of tissue. i) Non-viable epidermis (stratum corneum) ii) Viable epidermis iii) Viable dermis iv) Subcutaneous connective tissue (hypodermis) i) Non-viable epidermis (stratum corneum) Stratum corneum is the outer most layer of skin, which is the actual physical barrier to most substance that comes in contact with the skin. The stratum corneum is 10 to 20 cell layer thick over most of the body. Each cell is a flat, plate-like structure 34 - 44 μm long, 25- 36 μm wide, 0.5 to 0.20 μm thick with a surface area of 750 to 1200 μm2 stocked up to each other in brick like fashion. It is the outermost desquamating ‘horny’ layer of skin, comprising about 15-20 rows of flat, partially desiccated, dead, keratinized epidermal cells. Depending upon the region of the body, the thickness of this layer ranges from 10-20 μm, with the thickest layer on
  • 4. Department of pharmaceutics, SKIPS Page 4 Fig 1.2 (b): Cross-sectional illustration of human skin the palms of the hands and soles of the feet. Of the various skin layers, it is the stratum corneum that is the rate-limiting barrier to percutaneous drug transport. In fact, the stratum corneum is a remarkably more formidable barrier to drug transport than the epithelial barriers of gastrointestinal, nasal, buccal, vaginal, or rectal delivery routes. Fig 1.2 (c): Keratin structure
  • 5. Department of pharmaceutics, SKIPS Page 5 1.3.1 Definition Transdermal drug delivery systems (patches) are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin[8] also defined as medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Actually, transdermal drug delivery is a transport process of drugs through a multi-laminar structure, e.g. from the patch to stratum corneum then to the viable epidermis, and finally penetrating into the blood. [9][10] Transdermal drug delivery means that a pharmaceutical compound is moved across the skin the dermis for subsequent systemic distribution. Hence, strictly semantically this does not only include the more commonly understood “patch”, but also traditional subcutaneous administration by means of a hypodermic needle and a syringe. Common to all methods of transdermal drug delivery, by this broad definition, is that the drug is passed through an artificial route into the body. The main advantage of this approach is that the drug is entered into the body undistorted without being passed through the body’s various defense systems.[11] In contrast to oral administration (e.g. swallowing a pill), the most convenient way of drug administration, the transdermal route does not suffer from drug degradation in the gastrointestinal tract and reduced potency through first-pass metabolism (i.e. in the liver). In addition, oral-specific side-effects like liver damages are avoided, which are seen for example with common drugs like estradiol (estrogen) [12] or paracetamol.[13] Fig 1.3 (a): Traditional vs. Transdermal Release
  • 6. Department of pharmaceutics, SKIPS Page 6 1.3.2 Traditional transdermal patches While infusion pumps are reliable in achieving a preferred therapeutic delivery profile, the use of such a system (e.g. an insulin pump) is somewhat cumbersome, requires training, is costly, and requires a hypodermic needle-based infusion set. Transdermal patches, where the drug diffuses through the skin, offer a much more convenient way to administer a drug while still having the benefits of continuous drug release. Transdermal patches were introduced in the late 1970s, starting with a three-day patch to treat motion sickness. Since then, the market for drug administration through patches has been steadily increasing and by 2004 the annual U.S. market value was more than 3 billion with several kinds of drug formulations available. In 2001, 51 of 129 drug delivery products under clinical evaluation in the U.S. were transdermal or dermal systems. Still, only few drugs are presently available as transdermal patches. The fundamental reason why so few drugs are used is that the barrier property of the skin limits the use of patches to therapeutics where the molecule size is small enough to diffuse through the skin at therapeutic rates. The drugs presently used in patches have molecular masses ranging from 162 Da (nicotine) to 357 Da (oxybutynin), giving a practical dose rate of 4–20 mg/day depending on the patch size. As a comparison, the mass of the insulin molecule is 5808 Da and modern DNA-based vaccines, built of vectors with thousands of base-pairs, may have molecular weights in the order of hundreds of kilo Daltons (kDa).[15] Table 1.3 (b): Transdermal patches developed as per USFDA Drug Name Generic Name Approval Date Catapres TTS Clonidine October 10, 1984 Flector Diclofenac epolamine January 31, 2007 Vivelle Estradiol October 28, 1994 Climara Estradiol December 22, 1984
  • 7. Department of pharmaceutics, SKIPS Page 7 Vivelle-DOT Estradiol January 8, 1999 1.3.3 Pathways for a drug molecule to traverse stratum corneum The stratum corneum of epidermis is the main barrier for traversing drug molecule from TDDS. i) Transappendageal transport (shunt route transport) In this pathway the appendages (hair follicles, sweat ducts) offer pores that bypass the barrier of the stratum corneum. However, these openings onto the skin surface occupy only around 0.1% of the total skin surface area. The shunt routes may be important for ions and large polar molecules that struggle to cross intact stratum corneum.[16] ii) Intracellular route (Transcellular) The pathway is directly across the stratum corneum and the molecule crossing the intact stratum corneum faces numerous repeating hurdles. First, there is partitioning into the keratinocyte, followed by diffusion through the hydrated keratin. In order to leave the cell, the molecule must partition into the bilayer lipids before diffusing across the lipid bilayer to the next keratinocyte. For highly lipophilic molecules the transcellular route may be predominant.[17] iii) Intercellular route In this rout the pathway is via lipid matrix between the keratinocytes. It is now accepted that this route provides the principle pathway by which most small, uncharged molecules traverse stratum corneum and therefore many enhancing techniques aim to disrupt or bypass its elegant molecular architecture.[10] Fig 1.3 (c): Pathways of transdermal permeation
  • 8. Department of pharmaceutics, SKIPS Page 8 Hydrophilic drugs permeate by Intercellular pathway and Lipophilic drugs permeates by Intracellular (Transcellular) mechanism. Transport of hydrophilic or charged molecules is especially difficult attributable to the lipid-rich nature of the stratum corneum and its low water content; this layer is composed of about 40% lipids, 40% protein, and only 20% water. Transport of lipophilic drug molecules is facilitated by their dissolution into intercellular lipids around the cells of the stratum corneum. Absorption of hydrophilic molecules into skin can occur through ‘pores’ or openings of the hair follicles and sebaceous glands, but the relative surface area of these openings is barely 1% of the total skin surface. This small surface area limits the amount of drug absorption.[3] 1.3.4 Process of drug permeation in transdermal delivery Transdermal permeation of a drug involves the following steps: i) Diffusion of drug from drug reservoir to the rate controlling membrane. ii) Diffusion of drug from rate limiting membrane to stratum corneum. iii) Sorption by stratum corneum and penetration through viable epidermis. iv) Uptake of drug by capillary network in the dermal papillary layer. v) Effect on target organ.[18][19] Fig 1.3 (d): Process of drug permeation 1.3.5 Kinetics of transdermal permeation[20-25] Knowledge of skin permeation kinetics is vital to the successful development of transdermal therapeutic systems. This permeation can be possible only if the drug possesses certain physiochemical properties. The rate of permeation across the skin is given by
  • 9. Department of pharmaceutics, SKIPS Page 9 dQ/dt = Ps (Cd – Cr) . . . . . . . . . . (1) where Cd and Cr are the concentrations of the skin penetrant in the donor compartment i.e. on the surface of stratum corneum and in the receptor compartment i.e. body respectively. Ps is the overall permeability coefficient of the skin tissue to the penetrant. This permeability coefficient is given by the relationship. Ps = Ks. Dss/hs . . . . . . . . . . (2) where Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium or a transdermal therapeutic system on to the stratum corneum, Dss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through a thickness of skin tissues and hs is the overall thickness of skin tissues. As Ks, Dss and hs are constant under given conditions the permeability coefficient Ps for a skin penetrant can be considered to be constant. From equation (1) it is clear that a constantrate of drug permeation can be obtained only when Cd >> Cr i.e. the drug concentration at the surface of the stratum corneum Cd is consistently and substantially greater than the drug concentration in the body Cr. The equation is dQ/dt = Ps Cd . . . . . . . . . . (3) And the rate of skin permeation is constant provided the magnitude of Cd remains fairly constant throughout the course of skin permeation. For keeping Cd constant the drug should be released from the device at a rate Rr i.e. either constant or greater than the rate of skin uptake Ra i.e. Rr >> Ra . . . . . . . . . . (4) Since Rr >> Ra, the drug concentration on the skin surface Cd is maintained at a level equal to or greater than the equilibrium solubility of the drug in the stratum corneum Cs .i.e. Cd>>Cs. Therefore a maximum rate of skin permeation is obtained and is given by the equation: (dQ/dt)m = PsCs . . . . . . . . . . (5) From the above equation it can be seen that the maximum rate of skin permeation depends upon the skin permeability coefficient Ps and is equilibrium solubility in the stratum corneum Cs. Thus skin permeation appears to be stratum corneum limited.
  • 10. Department of pharmaceutics, SKIPS Page 10 Table 1.3 (e): Ideal properties of a transdermal drug delivery system[26] Properties Comments Shelf life Up to 2 years Patch size < 40 cm2 Dose frequency Once a daily to once a week Aesthetic appeal Clear, tan or white color Packaging Easy removal of release liner and minimum number of steps required to apply Skin reaction Non irritating and non sensitizing Release Consistent pharmacokinetic and pharmacodynamic profiles over time 1.3.6 Factors affecting transdermal drug delivery[10] i) Physicochemical properties of permeant Partition coefficient For molecules with intermediate partition coefficient (log K 1 to 3) and for highly lipophilic molecules (log K > 3), the intercellular route will be almost the pathway used to traverse the stratum corneum. However, for these molecules a further consideration is the ability to partition out of the stratum corneum into the aqueous viable epidermal tissues. For more hydrophilic molecules (log K < 1), the transcellular route probably predominates . Molecular size A second major factor in determining the flux of a material through human skin is the size of the molecule. However, for simplicity, the molecular weight is generally taken as an approximation of molecular size. It has been suggested that an inverse relationship existed between transdermal flux and molecular weight of the molecule. However, most conventional therapeutic agents that are selected as candidates for transdermal delivery tend to lie within narrow range of molecular weight (100-500 Da). Solubility/melting point It is well known that most organic materials with high melting points have relatively low
  • 11. Department of pharmaceutics, SKIPS Page 11 aqueous solubility at normal temperature and pressure. The lipophilic molecules tend to permeate through the skin faster than more hydrophilic molecules. However, while lipophilicity is a desired property of transdermal candidates, it is also necessary for the molecule to exhibit some aqueous solubility since topical medicaments are generally applied from an aqueous formulation. Ionization According to pH-partition hypothesis, only the unionized form of the drug can permeate through the lipid barrier in significant amounts. ii) Physiological factors Skin barrier properties in the neonate and young infant The skin of newborns is known to be relatively susceptible to irritants,[27] other variables related to stratum corneum function such as pH and stratum corneum hydration may enhance the irritant potential to newborn skin.[28] Skin surface pH values in newborns are significantly higher in all body sites than those in adult skin, but stabilize at values similar to adults within the first month. There are also significant changes in the metabolic capacity of infants, whether full or preterm, and adult levels of cutaneous enzyme activity are not observed until 2 months or even 6–12 months of age which may additionally account for the sensitivity of baby skin to irritants. The skin surface of the newborn is slightly hydrophobic and relatively dry and rough when compared to that of older infants. Stratum corneum hydration stabilizes by the age of 3 months. Skin barrier properties in aged skin There are changes in the physiology of aged skin (>65 years). The corneocytes are shown to increase in surface area which may have implications for stratum corneum function due to the resulting decreased volume of intercorneocyte space per unit volume of stratum corneum. The moisture content of human skin decreases with age. There is a flattening of the dermo-epidermal junction and, consequently, the area available for diffusion into the dermis is diminished. Other age-related changes include reductions in the absolute number of hair follicles, in the diameter of the hair, and pilosebaceous units are also expected.[27] Race Racial differences between black and white skins have been shown in some anatomical and physiological functions of the skin although data is relatively sparse. In black skin, increased intracellular cohesion, higher lipid content and higher electrical skin
  • 12. Department of pharmaceutics, SKIPS Page 12 resistance levels compared to whites have been demonstrated. Black skin appears to have a decreased susceptibility to cutaneous irritants, but this difference is not detected in stripped skin, suggesting the stratum corneum modulates the different racial response to irritants. Black skin responds with a decrease in blood flow and hence less erythematic than Hispanics or Caucasians.[27] Body site It is readily apparent that skin structure varies to some degree over the human body. However, the relative permeability of different skin sites is not simply a function of stratum corneum thickness as different permeants exhibit varied rank orders through different skin sites. It is apparent that genital tissue usually provides the most permeable site for transdermal drug delivery. The skin of the head and neck is also relatively permeable compared to other sites of the body such as the arms and legs. Intermediate permeability for most drugs is found on the trunk of the body. Other factors The level of hydration of the stratum corneum may have a dramatic effect on drug permeation through the tissue, and increasing hydration is well known to increase transdermal delivery of most drugs. Indeed, occlusive dressings and patches are highly effective strategies to increase transdermal drug delivery since they create elevated hydration of the stratum corneum.The human body maintains a temperature gradient across the skin from around 37 ºC to around 32 ºC at the outer surface. Since diffusion through the stratum corneum is a passive process, elevation of the skin temperature can induce structural alterations within the stratum corneum, and these modifications can also increase diffusion through the tissue. iii) Pathological disorders Numerous disorders result in an eruption of the skin surface. In such cases, the barrier properties of the stratum corneum are compromised, allowing the passage of drugs (and potentially toxic materials) into and through the skin. Likewise, the erupted skin surface will allow increased water loss from the body. Psoriasis is one of the most common skin diseases. It is associated with reduced barrier skin function with transepidermal water loss (TEWL) up to twenty times higher in active psoriasis. The reduced barrier function, which is correlated with signs of scaling, enables increased percutaneous absorption of topically applied compounds. The plaques are largely devoid of intracellular lipid, reducing the convoluted lipid pathway to the dermoepidermal junction, thus enhancing permeation.[29]
  • 13. Department of pharmaceutics, SKIPS Page 13 Eczema in the chronic stage is often characterized by lichenification, a dry thickened leathery state, with increased cell markings caused by, repeated scratching and rubbing. In such areas, where the skin is intact, absorption may be retarded, since the absorptive path is increased. Non-eczematous skin of patients with a prior history of atopic eczema shows abnormalities in lipid metabolism resulting in a decrease in stratum corneum lipids. In addition to a reduced barrier function it is presumed that these compositional differences are related to the decrease in water binding capacity of eczematous skin. Infections cause damage to the skin barrier integrity varies depending on the severity of the infection. This is usually favorable for topical treatment of infection, but it must be remembered that the barrier is dynamic and will be restored as the condition improves, therefore, drug flux across the repairing tissue will be expected to be slow. 1.3.7 Conditions in which Transdermal patches are used[10]  When the patient has intolerable side effects (including constipation) and who is unable to take oral medication (dysphagia) and is requesting an alternative method of drug delivery.  Where the pain control might be improved by reliable administration. This might be useful in patients with cognitive impairment or those who for other reasons are not able to self- medicate with their analgesia.  It can be used in combination with other enhancement strategies to produce synergistic effects. 1.3.8 Conditions in which Transdermal patches are not used[10]  Cure for acute pain is required and where rapid dose titration is required.  Where requirement of dose is equal to or less then 30 mg/24 hrs. 1.3.9 Merits of Transdermal drug delivery[10] [26] [30] This approach to drug delivery offers many advantages over traditional methods.  Enables the avoidance of gastrointestinal absorption, with its associated pitfalls of enzymatic and pH associated deactivation.  This method also allows for reduced pharmacological dosaging due to the shortened metabolization pathway of the transdermal route versus the gastrointestinal pathway.
  • 14. Department of pharmaceutics, SKIPS Page 14  The patch also permits constant dosing rather than the peaks and valleys in medication level associated with orally administered medications.  Multi-day therapy with a single application.  It is of great advantage in patients who are nauseated or unconscious.  First pass metabolism, an additional limitation to oral drug delivery, can be avoided.  Controlled release over extended period  Easily terminable means for systemic as well as topical drug delivery  Improved patient compliance. 1.3.10 Demerits of Transdermal drug delivery [10] [26] [30] However this system has its own limitations  The drug that require high blood levels cannot be administered and may even cause irritation or sensitization of the skin.  The adhesives may not adhere well to all types of skin and may be uncomfortable to wear.  The high cost of the product is also a major drawback for the wide acceptance of this product.  One of the greatest disadvantages is the possibility that a local irritation will develop at the site of application.  Erythema, itching, and local oedema can be caused by the drug, the adhesive, or other excipients in the patch formulation. For most patients, site rotation can minimize irritation.  Another significant disadvantage is that the skin's low permeability limits the number of drugs that can be delivered in this manner. 1.4 FORMULATION APPROACHES 1.4.1 Components of Transdermal Patch[1] [31] The common ingredients which are used for the preparation of TDDS are as follows. i) Drug - Drug solution in direct contact with release liner. Ex: Nicotine, Methotrexate and Estrogen. ii) Liner - Protects the patch during storage. The liner is removed prior to use. Ex: polyester film.
  • 15. Department of pharmaceutics, SKIPS Page 15 iii) Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin. Ex: Acrylates, Polyisobutylene, Silicones. iv) Membrane - Controls the release of the drug from the reservoir and multi-layer patches containing permeation enhancers. Ex: Terpenes, Terpenoids, Pyrrolidones. Solvents like alcohol, Ethanol, Methanol. Surfactants like Sodium Lauryl sulfate, Pluronic F127, Pluronic F68. v) Backing - Protects the patch from the outer environment. Ex: Cellulose derivatives, poly vinyl alcohol, Polypropylene Silicon rubber. Fig 1.4 (a) Components of trandermal patch 1.4.2 Types of transdermal systems[31-40] Four major transdermal systems i) Single-layer Drug-in-Adhesive Fig 1.4 (b): Single-layer Drug-in- Adhesive It is characterized by the inclusion of the drug directly within the skin-contacting adhesive. In this transdermal system design, the adhesive not only serves to affix the system
  • 16. Department of pharmaceutics, SKIPS Page 16 to the skin, but also serves as the formulation foundation & responsible for the releasing of the drug. The adhesive layer is surrounded by a temporary liner and a backing. The rate of release of drug from this type of system is dependent on the diffusion across the skin. The intrinsic rate of drug release from this type of drug delivery system is defined by dQ = Cr . . . . . . . . . . (1) dT 1/Pm+ 1/Pa where Cr is the drug concentration in the reservoir compartment and Pa and Pm are the permeability coefficients of the adhesive layer and the rate controlling membrane , Pm is the sum of permeability coefficients simultaneous penetrations across the pores and the polymeric material. Pm and Pa , respectively, are defined as follows. Pm = Km/r . D . . . . . . . . . . (2) hm Pa = Ka/m . D . . . . . . . . . . (3) ha where Km/r and Ka/m are the partition coefficients for the interfacial partitioning of drug from the reservoir to the membrane and from the membrane to adhesive respectively; Dm and Da are the diffusion coefficients in the rate controlling membrane and adhesive layer, respectively; and hm and ha are the thicknesses of the rate controlling membrane and adhesive layer, respectively. ii) Multi-layer Drug-in-Adhesive The Multi-layer Drug-in-Adhesive is similar to the Single-layer Drug-in-Adhesive in that the drug is incorporated directly into the adhesive both adhesive layers are also responsible for the releasing of the drug. One of the layers is for immediate release of the drug and other layer is for control release of drug from the reservoir. However, is different that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases). The multi-layer encompasses either the addition of membrane between two distinct
  • 17. Department of pharmaceutics, SKIPS Page 17 drug-in-adhesive layers or the addition of multiple drug-in-adhesive layers under a single backing film. This patch also has a temporary liner. Fig 1.4 (c): Multi-layer Drug-in-Adhesive The rate of drug release in this system is defined by: dQ = Ka/r . Da . . . . . . . . . . (4) dt Cr ha Where Ka/r is the partition coefficient for the interfacial partitioning of the drug from the reservoir layer to adhesive layer. iii) Drug Reservoir-in-Adhesive The Reservoir transdermal system design is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of the product responsible for skin Fig 1.4 (d): Drug Reservoir-in-Adhesive adhesion can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Unlike the Single-layer and Multi-layer Drug-in-adhesive systems the reservoir transdermal system has a separate
  • 18. Department of pharmaceutics, SKIPS Page 18 drug layer. This patch is also backed by the backing layer. In this type of system the rate of release is zero order. The rate of drug release from this drug reservoir gradient controlled system is given by; dQ = Ka/r . Da A ( ha) . . . . . . . . . . (5) dt ha ( t ) The above equation, the thickness of the adhesive layer for drug molecules to diffuse through increases with time ha (t). To compensate for this time dependent increase in the diffusional path due to the depletion of drug dose by release, the drug loading level is also increased with the thickness of diffusional path A (ha). iv) Drug Matrix-in-Adhesive The Matrix system design is characterized by the inclusion of a semisolid matrix containing drug solution or suspension which is in direct contact with the release liner The adhesive layer in this patch surrounds the drug layer partially overlaying it.. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix. Matrix patches are not designed to provide true zero-order release because as the drug closest to the skin is released, the drug deeper within the patch must travel a longer distance to reach the skin. The longer diffusional path slows the rate of absorption from the patch over time. Fig 1.4 (e): Drug Matrix-in-Adhesive
  • 19. Department of pharmaceutics, SKIPS Page 19 The rate of drug release from this type of system is defined as: dQ = ACp Dp ½ . . . . . . . . . . (6) dt 2t where A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are the solubility and diffusivity of the drug in the polymer respectively. Since, only the drug species dissolved in the polymer can release, Cp is essentially equal to CR, where CR is the drug concentration in the reservoir compartment. v) Vapour Patch In this type of patch the adhesive layer not only serves to adhere the various layers together but also to release vapour. The vapour patches are new on the market and they release essential oils for up to 6 hours. The vapours patches release essential oils and are used in cases of decongestion mainly. Other vapour patches on the market are controller vapour patches that improve the quality of sleep. Vapour patches that reduce the quantity of cigarettes that one smokes in a month are also available on the market. 1.4.3 Methods for preparation of TDDS[31] i) Asymmetric TPX membrane method[41] A prototype patch can be fabricated for this a heat sealable polyester film (type 1009, 3m) with a concave of 1cm diameter will be used as the backing membrane. Drugsample is dispensed into the concave membrane, covered by a TPX {poly(4-methyl-1- pentene)}asymmetric membrane, and sealed by an adhesive. Asymmetric TPX membrane preparation : These are fabricated by using the dry/wet inversion process. TPX is dissolved in a mixture of solvent (cyclohexane) and nonsolvent additives at 60°c to form a polymer solution. The polymer solution is kept at 40°C for 24 hrs and cast on a glass plate to a pre-determined thickness with a gardner knife. After that the casting film is evaporated at 50°C for 30 sec, then the glass plate is to be immersed immediately in coagulation bath [maintained the temperature at 25°C]. After 10 minutes of immersion, the membrane can be removed, air dry in a circulation oven at 50°C for 12 hrs]. ii) Circular teflon mould method[42] Solutions containing polymers in various ratios are used in an organic solvent. Calculated amount of drug is dissolved in half the quantity of same organic solvent. Enhancers in different concentrations are dissolved in the other half of the organic solvent and then added. Di-N-butylphthalate is added as a plasticizer into drug polymer solution. The
  • 20. Department of pharmaceutics, SKIPS Page 20 total contents are to be stirred for 12 hrs and then poured into a circular teflon mould. The moulds are to be placed on a leveled surface and covered with inverted funnel to control solvent vaporization in a laminar flow hood model with an air speed of 0.5 m/s. The solvent is allowed to evaporate for 24 hrs. The dried films are to be stored for another 24 hrs at 25±0.5°C in a desiccators containing silica gel before evaluation to eliminate aging effects. The type films are to be evaluated within one week of their preparation. iii) Mercury substrate method[43] In this method drug is dissolved in polymer solution along with plasticizer. The above solution is to be stirred for 10-15 minutes to produce a homogenous dispersion and poured in to a leveled mercury surface, covered with inverted funnel to control solvent evaporation. iv) By using “IPM membranes” method[44] In this method drug is dispersed in a mixture of water and propylene glycol containing carbomer 940 polymer and stirred for 12 hrs in magnetic stirrer. The dispersion is to be neutralized and made viscous by the addition of triethanolamine. Buffer pH 7.4 can be used in order to obtain solution gel, if the drug solubility in aqueous solution is very poor. The formed gel will be incorporated in the IPM membrane. v) By using “EVAC membranes” method[45] In order to prepare the target transdermal therapeutic system, 1% carbopol reservoir gel, polyethelene (PE), ethylene vinyl acetate copolymer (EVAC) membranes can be used as rate control membranes. If the drug is not soluble in water, propylene glycol is used for the preparation of gel. Drug is dissolved in propylene glycol, carbopol resin will be added to the above solution and neutralized by using 5% w/w sodium hydroxide solution. The drug (in gel form) is placed on a sheet of backing layer covering the specified area. A rate controlling membrane will be placed over the gel and the edges will be sealed by heat to obtain a leak proof device. vi) Aluminium backed adhesive film method[46] Transdermal drug delivery system may produce unstable matrices if the loading dose is greater than 10 mg. Aluminium backed adhesive film method is a suitable one. For preparation of same, chloroform is choice of solvent, because most of the drugs as well as adhesive are soluble in chloroform. The drug is dissolved in chloroform and adhesive material will be added to the drug solution and dissolved. A custammade aluminium former is lined with aluminium foil and the ends blanked off with tightly fitting cork blocks.
  • 21. Department of pharmaceutics, SKIPS Page 21 vii) Preparation of TDDS by using Proliposomes[47-48] The proliposomes are prepared by carrier method using film deposition technique. From the earlier reference drug and lecithin in the ratio of 0.1:2.0 can be used as an optimized one. The proliposomes are prepared by taking 5mg of mannitol powder in a 100 ml round bottom flask which is kept at 60-70°c temperature and the flask is rotated at 80-90 rpm and dried the mannitol at vacuum for 30 minutes. After drying, the temperature of the water bath is adjusted to 20-30°C. Drug and lecithin are dissolved in a suitable organic solvent mixture, a 0.5ml aliquot of the organic solution is introduced into the round bottomed flask at 37°C, after complete drying second aliquots (0.5ml) of the solution is to be added. After the last loading, the flask containing proliposomes are connected in a lyophilizer and subsequently drug loaded mannitol powders (proliposomes) are placed in a desiccator over night and then sieved through 100 mesh. The collected powder is transferred into a glass bottle and stored at the freeze temperature until characterization. viii) By using free film method[49] Free film of cellulose acetate is prepared by casting on mercury surface. A polymer solution 2% w/w is to be prepared by using chloroform. Plasticizers are to be incorporated at a concentration of 40% w/w of polymer weight. Five ml of polymer solution was poured in a glass ring which is placed over the mercury surface in a glass petri dish. The rate of evaporation of the solvent is controlled by placing an inverted funnel over the Petri dish. The film formation is noted by observing the mercury surface after complete evaporation of the solvent. The dry film will be separated out and stored between the sheets of wax paper in a desiccator until use. Free films of different thickness can be prepared by changing the volume of the polymer solution. 1.5 PERMEABLITY ENHANCEMENT 1.5.1 Methods of enhancement[35] [50] i) Chemical enhancement ii) Physical enhancement iii) Biochemical enhancement iv) Supersaturation enhancement v) Bioconvertable prodrug
  • 22. Department of pharmaceutics, SKIPS Page 22 i) Chemical enhancement The skin permeability of drugs can be greatly improved by treating the stratum corneum surface with an appropriate skin permeation enhancer. Ideally penetrating enhancers reversibly reduce the barrier resistance of the stratum corneum without damaging viable cell. A synergistic effect in the skin permeation enhancement could be achieved by incorporating two or more enhancers in the adhesive layer. Sometimes chemical penetration enhancers may also provoke unwanted biochemical and metabolic events within skin but this is not their aim. In the past two decades tremendous amount of work has been done to search specific chemicals that can act as penetration enhancer with ideal properties as follows. ii) Physical enhancement Different physical approaches to increase percutaneous absorption have been utilized but the most important approaches are iontophoresis, ultrasound, electroporation and heat. These methods show most promising in the percutaneous delivery of large molecular weight compounds but the major limitation is the input of energy to achieve their effects. Fig 1.5 (a) : Enhanced permeation by ultrasound
  • 23. Department of pharmaceutics, SKIPS Page 23 Fig 1.5 (b) : Enhanced permeation by electroporation iii) Biochemical enhancement This chemical provokes the biological and metabolic events within the skin and significantly increases skin permeability.These types of enhancers reduce barrier properties of the skin either by inhibiting enzymes responsible for synthesis of stratum corneum lipid or by promoting metabolism of existing skin lipids that are responsible for barrier function. iv) Supersaturation enhancement The thermodynamic activity of drug can be increased by employing supersatured systems that gives rise to unusually high thermodynamic properties. However topical vehicle relying on supersaturation have the major limitation of formulation instability, both prior to and during application to skin, unless the formulation can be stabilized with antinucleant and anticrystal-growth agents. v) Bioconvertable prodrug The prodrug concept can be applied in transdermal controlled drug delivery by altering skin permeability via modification of the physicochemical properties of the drug molecules to enhance its rate of transdermal permeation. One example of this approach is the
  • 24. Department of pharmaceutics, SKIPS Page 24 esterification of less skin permeable estradiol to form lipophilic estradiol ester (like estradiol- 17-acetate, estradiol-3, 17-diacetate and estradiol-17-cypiuonate etc. 1.5.2 Ideal characteristics of penetration enhancers[7] Ideally, penetration enhancers reversibly reduce the barrier resistance of the stratum corneum without damaging viable cells.[35] [51] Some of the more desirable properties for penetration enhancers acting within the skin have been given as:[52]  They should be non-toxic, non-irritating and non-allergenic  They would ideally work rapidly; the activity and duration of effect should be both predictable and reproducible.  They should have no pharmacological activity within the body.  The penetration enhancers should work unidirectionally, i.e., they should allow therapeutic agents into the body while preventing the loss of endogenous materials from the body.  When removed from the skin, barrier properties should return both rapidly and fully to normal.  They should be cosmetically acceptable with an appropriate skin feel. Not surprisingly, no such material that possesses the above ideal properties has yet been discovered although some chemicals demonstrate several of the above attributes. 1.5.3 Mechanism of penetration enhancement[7] Penetration enhancers may act by one or more of three main mechanisms [52]  Disruption of the highly ordered structure of stratum corneum lipid.  Interaction with intercellular protein.  Improved partition of the drug, co-enhancer or solvent into the stratum corneum.
  • 25. Department of pharmaceutics, SKIPS Page 25 Fig 1.5 (c): Mechanisms of penetration enhancers The enhancer act by altering one of three pathways. The key to altering the polar pathway is to cause protein conformational change or solvent swelling. The fatty acid enhancers increased the fluidity of the lipid protein portion of the stratum corneum. Some enhancers act on both polar and nonpolar pathway by altering the multilaminate pathway for penetration. Enhancers can increase the drug diffusivity through skin proteins. The type of enhancer employed has a significant impact on the design and development of the product.[53] A useful way to consider factors affecting drug permeation rate through the stratum corneum is via the simple equation given below for steady state flux.[52] If we plot the cumulative mass of diffusant, m, passing per unit area through the membrane , at long time the graph approaches linearity and its slope its yield the steady flux , dm/dt dm = D Co K . . . . . . . . . . (1) dt h
  • 26. Department of pharmaceutics, SKIPS Page 26 where Co is the constant concentration of drug in donor solution, K is the partition coefficient of the solute between the membrane and the bathing solution, D is the diffusion coefficient and h is thickness of membrane. From the above equation (1), we deduce the ideal properties of a molecule that would penetrating stratum corneum well. These are:  Low molecular mass, preferably less than 600Da, when D tends to be high.  Adequate solubility in oil and water so that membrane concentration gradient may be high.  High but balanced (optimal) K (if too large, may inhibit clearance by viable tissue)  Low melting point, correlating with good solubility as predicted by ideal solubility theory. 1.5.4 Chemical penetration enhancers[7] Chemical substances temporarily diminishing the barrier of the skin and known as accelerants or sorption promoters can enhance drug flux. Several types are known i) Sulphoxides and similar chemicals Dimethyl sulphoxides (DMSO) is one of the earliest and most widely studied penetration enhancers. It is a powerful aprotic solvent which hydrogen bonds with itself rather than with water. It is colourless, odourless and is hydroscopic and is often used in many areas of pharmaceutical sciences as a universal solvent. DMSO alone has been applied topically to treat systemic inflammation. DMSO works rapidly as a penetration enhancer - spillage of the material onto the skin can be tasted in the mouth within a second. Although DMSO is an excellent accelerant, it does create problems. The effect of the enhancer is concentration-dependent and generally co-solvents containing > 60% DMSO is needed for optimum enhancement efficacy. However, at these relative high concentrations, DMSO can cause erythema and wheal of the stratum corneum. Denaturing of some skin proteins results in erythema, scaling, contact uticaria, stinging and
  • 27. Department of pharmaceutics, SKIPS Page 27 burning sensation.[54] Since DMSO is problematic for use as a penetration enhancer, researchers have investigated a similar chemically-related material as a accelerant. DMAC and DMF are similarly powerful aprotic solvents. However, South well and Barry, showing a 18-fold increase in the flux of caffeine permeating across a DMF treated human skin, concluded that the enhancer caused irreversible membrane damage.[55] DMF irreversibly damages human skin membranes but has been found in vivo to promote the bioavailability of betamethasone-17-benzoate as measured by vasoconstrictor assay.[56][57] DMSO may also extract lipids, making the horny layer more permeable by forming aqueous channels.[58] The mechanism of the sulphoxide penetration enhancers is widely used to denature protein and, on application to human skin, has been shown to change the intercellular keratin conformation, from helical to ß sheet.[59] [60] ii) Azone Azone (1-dodecylazacycloheptan-2-one or laurocapran) was the first molecule specifically designed as a skin penetration enhancer. Azone is a colourless, odourless liquid with a melting point of -7ºC and it possesses a smooth, oily but yet non-greasy feel. Azone is a highly lipophilic material with a log p-octanol / water of around 6.2 and it is soluble in and compatible with most organic solvents including alcohol and propylene glycol. Azone enhances the skin transport of a wide variety of drugs including steroids, antibiotics and antiviral agents. Azone is most effective at low concentrations, being employed typically between 0.1- 5% but more often between 1-3%.[35] Azone partitions into a bilayer lipid to disrupt their packing arrangement but integration into the lipid is unlikely to be homogeneous. Azone molecules may exist dispersed within the barrier lipoid or separate domains within the bilayer.[51] iii) Pyrrolidones Pyrrolidones have been used as permeation enhancers for numerous molecules including hydrophilic (e.g. mannitol and 5-flurouracil) and lipophilic (progesterone and hydrocortisone) permeants. N-methyl-2-pyrolidone was employed with limited success as a penetration enhancer for captopril when formulated in a matrix-type transdermal patch.[61] The pyrrolidones partition well into human stratum corneum within the tissue and they may
  • 28. Department of pharmaceutics, SKIPS Page 28 act by altering the solvent nature of the membrane. Pyrrolidones have been used to generate reservoirs within the skin membrane. Such a reservoir effect offers a potential for sustained release of a permeant from the stratum corneum over extended time periods.[62] iv) Fatty acids Percutaneous drug absorption has been increased by a wide variety of long-chain fatty acids, the most popular of which is oleic acid. It is of interest to note that many penetration enhancers such as azone contain saturated or unsaturated hydrocarbon chains and some structure - activity relationships have been drawn from the extensive studies of Aungst who employed a range of fatty acids, acids, alcohols, sulphoxides, surfactants and amides as enhancers for naloxone.[63][64] Shin et al[65] studied various penetration enhancers like glycols (diethylene glycol and tetraethylene glycol), fatty acids (lauric acid, myristic acid and capric acid) and nonionic surfactant (polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly ether) on the release of triprolidone. Lauric acid in Propylene glycol enhanced the delivery of highly lipophilic antiestrogen.[66] Oleic acid greatly increased the flux of many drugs such as increasing the flux of salicylic acid 28-fold and 5-flurouracil flux 56-fold through human skin membrane in vitro.[57] The enhancer interacts with and modifies the lipid domains of the stratum corneum as would be expected for a long chain fatty acid with cis-configuration.[35] v) Essential oil, terpenes and terpenoids Terpenes are found in essential oils, and are compounds comprising of only carbon, hydrogen and oxygen atoms, but which are not aromatic. Numerous terpenes have long been used as medicines as well as flavoring and fragrance agents. The essential oils of eucalyptus, chenopodium and ylang-ylang have been found to be effective penetration enhancers for 5- flouorouracil transversing human skin in vivo.[67] Cornwell et al.[68] investigated the effect of 12 sesquiterpenes on the permeation of 5- flurouracil in human skin. Pretreatment of epidermal membranes with sesquiterpene oil or using solid sesquiterpenes saturated in dimethyl isosorbide increased the absorption of 5- fluorouracil. L-menthol has been used to facilitate in vitro permeation of morphine
  • 29. Department of pharmaceutics, SKIPS Page 29 hydrochloride through hairless rat skin as[69] well as diffusion of imipramine hydrochloride across rat skin and hydrocortisone through hairless mouse skin.[62] [63] One mechanism by which this agent operates is to modify the solvent nature of the stratum corneum, thus improving drug partitioning into the tissue. Many terpenes permeate human skin well and large amounts of terpene have been found in the epidermis after application from a matrix-type patch. Terpenes may also modify drug diffusivity through the membrane. During steady state permeation experiments using terpenes as penetration enhancers, the lag time for permeation was usually reduced, indicating some increase in drug diffusivity through the membrane following terpene treatment.[35] vi) Oxazolidinones Oxazolidinones are a new class of chemical agents which have the potential for use in many cosmetic and personal care product formulations. This is due to their ability to localize co-administered drug in skin layers, resulting in low systemic permeation.[70] [71] The structural features of these permeation enhancers are closely related to sphingosine and ceramide lipids which are naturally found in the upper skin layers. Oxazolidinones such as 4- decyloxazolidin-2-one has been reported to localize the delivery of many active ingredients such as retinoic acid and diclofenac sodium in skin layers.[72] This compound has a higher molecular weight and lipophilicity than other solvent-type enhancers, physical characteristics that may be beneficial in terms of a reduction in local toxicity because of the lack of effective absorption of these enhancers into the lower skin layers where irritation is likely to be occur. vii) Urea Urea promotes transdermal permeation by facilitating hydration of the stratum corneum and by the formation of hydrophilic diffusion channels within the barrier. Cyclic urea permeation enhancers are biodegradable and non-toxic molecules consisting of a polar parent moiety and a long chain alkyl ester group. As a result, enhancement mechanism may be a consequence of both hydrophilic activity and lipid disruption mechanism.[50] 1.6 SELECTION OF DRUG CANDIDATE [73-74] The product development of a transdermal formulation generally includes the following stages:
  • 30. Department of pharmaceutics, SKIPS Page 30  Selection of drug candidate  Selection of the appropriate physical form (e.g., acid, base, or salt)  Selection of the desired design (e.g., reservoir, matrix, etc.) The transdermal route of administration cannot be employed for a large number of drugs, only a small number of drug products are currently available via transdermal delivery. In many cases, a drug's physical properties, including molecular size and polarity, have limited its capacity to be delivered transdermally. Similarly, the biological properties of drug molecules, including dermal irritation and insufficient bioavailability, have been problematic. In the product development the focus must be on the rationality of drug selection based on pharmacokinetic parameters and physicochemical properties of the drug. Physiochemical factors such as solubility, crystallinity, molecular weight <400, polarity, melting point <200, partition coefficient Log P (octanol-water) between -1.0 to 4 must be considered. Table 1.6 (a) : Ideal Properties of drug candidate for transdermal drug delivery[26] Parameter Properties Dose Should be low Half life in hr 10 or less Molecular weight < 400 Partition coefficient Log P (Octanol-water) between 1.0 and 4 Skin permeability coefficient > 0.5 x10-3cm/hr Skin reaction Non irritating and non sensitizer Oral bioavailability Low Therapeutic index Low Biological factor should also be considered such as skin irritation, site of application of the patch e.g. scopolamine patch for motion sickness is applied backside of the ear and Transderm-Nitro is applied on the chest. When a pharmacologically active material has to be
  • 31. Department of pharmaceutics, SKIPS Page 31 presented to the skin, an occlusive or allergic response is significant, limits have to be determined for the acceptability of the undesired effect .The pharmacokinetic information of the drug is a critical factor in deciding its suitability for delivery by the transdermal route as it is suitable only for drugs whose daily dose is in few milligrams. The resulting plasma concentration of active agent depends on the clearance; however, if one assumes a small volume of distribution and relatively long half-life, plasma level in excess of few micrograms per milliliter is very unlikely. Another important factor is the half-life, (e.g., nitroglycerin t 1/2 is 3 min) which provides information on the disposition of a drug in our body other parameters such as effective plasma level; also determine whether a transdermal delivery can be developed or not.
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