assembled into
multi-lamellar bilayers. This unusual extracellular
matrix of lipid bilayers serves the primary barrier
function of the stratum corneum.
Molecules are
believed to diffuse across skin following a tortuous pathway in which transport
between bilayers can occur at bilayer-bilayer
interfaces or other sites of structural disorganization. Ablation of stratum corneum increases permeability of skin several hundred
folds.
Consequently the
daily dose of drug that can be delivered from a transdermal
patch is less than 20 mg, effectively limiting this route of administration to
potent drugs.1,2,15
Today’s transdermal drug delivery systems are technically limited
by the size (e.g., molecular weight) of the molecule that can be successfully
moved through the skin and into the body. This "limiting" molecular
weight that can be successfully delivered transdermally
is therefore a measure of the progress of development of transdermal
delivery systems. As transdermal systems evolve, it
is expected that they will become capable of delivering drug molecules of
ever-increasing size and complexity. If this "limiting molecular
size" is plotted against time, the resulting profile would be expected to
assume the shape of an "S" curve.
This S-curve for transdermal drug delivery systems addresses only one system
function (although it is a very important one): the capability of the system to
deliver higher-molecular weight molecules. The "X" point on the
S-curve indicates that the transdermal systems of
today are in the "infancy" stage of their possible evolution (Graph
1). A major challenge for designers, scientists and researchers to discover how
to deliver an entire range of larger-molecule therapeutic agents through the
skin, in a manner that adds value for users of transdermal
patches and similar devices.7
Graph.1 Functinal Performance of transdermal drug delivery
system
LIMITATIONS
OF RESEARCH, EXPERIMENTATION AND MODELING
The conduct of research,
scientific experimentation and process modeling to resolve the conflict
described above ("Large molecules cannot, yet must, enter the skin")
have been historically ineffective, and are rarely responsible for major
product breakthroughs. There is a lack of understanding of how transdermal delivery really works. Modeling
approaches for predicting transdermal drug delivery
have had generally poor predictive power.
The skin itself is a rather
complex, heterogeneous membrane; its penetration pathways and skin
lipid-structure are not well understood. In many current delivery systems,
penetration enhancers increase drug transport through the skin. An important
step would be to develop a better understanding of the functioning of
penetration enhancers in the stratum corneum lipid
structure and in the drug penetration pathway.
The researcher’s aim is to
develop models that incorporate all these factors and effects, and to use the
models to predict systemic drug levels likely to result from a given drug
delivery system. Unfortunately, research in this area has proven to be slow and
relatively ineffective, and it does not effectively support the conception and
development of next-generation delivery systems.8
Selection of Drug Candidate for Transdermal
Drug Delivery:
Judicious choice of drug substance is the most
important decision in the successful development of a transdermal
product.3,5
·
The
effective concentration (dose) of the drug should be low (≤ 20mg).
·
A drug
with short biological half life is a much better candidate for transdermal delivery.
·
Melting
point: - should be < 200 şC.
·
The
drug should have reasonably wide therapeutic index so that individual
variability in skin absorption would not pose too much problem for dosage
adjustment.
·
The drug should have an extensive
pre-systemic metabolism.
·
The drug as well as other additives
should be essentially free from skin irritation.
·
Immunogenicity:-the drug should not
stimulate an immune reaction in the skin.
·
More is the molecular weight less will
be the diffusion rate hence low molecular weight drugs are preferable
(< 1000 Daltons).
·
The drug should not be irreversibly
bound in the subcutaneous tissues.
·
A lipid water partition coefficient (log
Kp) should be in the range -1.0-4.0 for optional transdermal permeability.
·
The free acid or base should be chosen
so that partitioning into the skin is optimized otherwise ionized drug
generally penetrate the skin poorly where as unionized form penetrates rapidly
(Table 1).
Table
1: Ideal Properties of Drug candidate for Tdds
|
PARAMETER |
IDEAL
PROPERTIES |
|
Dose |
Should be low (< 20 mg/day) |
|
Half life |
10 hour or less |
|
Molecular weight |
< 1000 |
|
Partition coefficient |
log P (octanol-water)
between -1.0 and 4.0 |
|
Skin permeability coefficient |
> 0.5×
10-3 cm/hr |
|
Skin reaction |
Non irritating and non-sensitizing |
|
Oral bioavailability |
Low |
|
Therapeutic index |
Low |
ANATOMY AND PHYSIOLOGY OF SKIN:
It is necessary
to understand the
anatomy, physiology, physicochemical and biochemical properties
of the skin
to utilize the
phenomenon of percutaneous
absorption successfully. The skin of an average adult human covers a surface
area of nearly 2.0 m2 and receives about one-third of the blood
circulating through the body.
Microscopically skin is composed of three main
histological layers: epidermis, dermis and subcutaneous tissues (Fig. 1). The
epidermis is further divided into two parts; the non-viable epidermis (stratum corneum) and
the viable epidermis.
The viable epidermis is
divided into four
layers, viz., stratum
lucidium,
stratum granulosum,
stratum spinosum and stratum germinativum.
Fig.1:
Cross-section of human skin
Stratum corneum (SC) and
epidermis: the main barrier to percutaneous absorption:
The SC consists of multiple layers of horny dead cells,
which are compacted, flattened, dehydrated and
keratinized. The horny
cells are stacked
in highly inter digitated columns
with 15-25 cells in
the stack over most of the body.
It has a density of 1.55 gm/cc. The SC has a water content of only 20%
as compared to 70% in physiologically active stratum germinativum. It exhibits regional differences over most of
the body and is approximately 10-15 µm in thickness. However the thickness may
be 300-400 µm on friction surfaces such as the palms of hand and soles of
feet.
The viable epidermis is an aqueous solution of protein
encapsulated into cellular compartments by thin cell membranes, which are fused
together by tonofibrils. The viable epidermis has a
density near that of water. The germinal (proliferative) layer above dermis
undergoes cell divisions producing an outward displacement of the cell towards
the surface. As the germinal layer moves upwards,
it changes shape
into a more rounded form with
spiny projections and appears as a stratum spinosum.
After the germinal layer
has raised 12-15
layers above its
point of origin,
it becomes flattened and
the basophilic nuclear
material is dispersed
throughout the cells
as granules. The layer is referred to as stratum granulosum.
The stratum lucidium layer, which
lies just below the
stratum corneum, is the
site where nuclei
disintegrate and keratinization and sulphahydryl
rich matrix formation takes place. Eventually it moves upwards to
form the stratum corneum. It
should be pointed
out that the
epidermis contains no
vascular elements. The cells receive their nourishment from the
capillary beds located in the papillary layers of the dermis by diffusion of
plasma and serum components (Fig.2).16
Fig. 2: Stratum Corneum
Dermis: The site
of systemic absorption :
The dermis is
0.2-0.3 cm thick
and is made of
a fibrous protein matrix, mainly collagen, elastin and reticulum embedded in an amorphous colloidal
ground substance. It is divided into
two distinct zones:
a superficial finely
structured thin papillary
layer adjacent to the epidermis and a deeper coarse reticular layer (the
main structural layer of skin). The dermis is also the locus of the blood
vessels, sensory nerves segments of the sweat glands and pilosebaceous units. The
blood vessels supply
blood to the
hair follicles, the
glandular skin appendages
and the subcutaneous
fat as well as the
dermis itself. It protects the body from injury, provides flexibility with
strength, and serves as a barrier to infection and functions as a
water-storage.14,16
Subcutaneous fatty tissue:
Cushioning the epidermis and dermis is the subcutaneous
tissue or fat layer where fat is manufactured and stored. It acts as a heat insulator and a shock
absorber. It essentially has no effect
on the percutaneous absorption of drugs because it
lies below the vascular system.18
Skin appendages:
The skin has several types of appendages. These
include hair follicles
with sebaceous, eccrine and apocrine sweat
glands and the
nails. An average human skin surface is known to contain on the
average 40-70 hairs follicles and 200-250 sweat ducts per square centimeter
area. These skin appendages occupy only 0.1% of the total human skin surface.
The eccrine sweat glands (2-5 million) produce sweat
(pH 4.0-6.8) and may also secrete drugs, protein, or antibodies. Their
principal function is to
aid heat control; approximately 400 glands
per square centimeter
are particularly concentrated
in the palms and soles.
Sebaceous glands are most numerous and largest on the
face, forehead, ear, on the midline of the back and on anogenital
surfaces. The palms and soles usually lack them. The glands vary in size from
200-2000 m in diameter. The larger ones are found on the nose. They secrete an
oily material known as sebum from cell disintegration. Its principal components
are glycerides, free fatty acids, cholesterol,
cholesterol esters and squalene. It acts as a skin
lubricant and a source of stratum corneum
plasticizing lipid and maintains an acidic condition on the skins outer surface
(pH-5).18
PATHWAYS OF TRANSDERMAL PERMEATION:
Permeation can occur by diffusion via:
1 Transcellular/intracellular
permeation, through the stratum corneum
2 Intercellular permeation, through the stratum corneum
3 Trans-appendageal permeation via the
hair follicles, sebaceous and sweat glands.
The first two mechanisms require further diffusion
through the rest of the epidermis and dermis. The third mechanism allows diffusional leakage into the epidermis and direct
permeation into dermis. For drugs penetrating directly across the intact
stratum corneum, entry may be Transcellular
or intracellular. The relative importance of these alternatives depends on many
factors, which include the time scale of permeation (steady state Vs. transient
diffusion), the physiochemical properties of penetrant
(pKa, molecular size, stability and binding affinity,
and its solubility and partition coefficient), integrity and thickness of stratum corneum,
density of sweat glands and follicles, skin hydration, metabolism and vehicle
effects (Fig. 3).17
Fig.
3:Simplified diagram of stratum corneum and two micro
routes of drug Penetration
MECHANISMS OF
TRANSDERMAL: PERMEATION:
For a systemically active drug to reach a target
tissue, it has to possess some physicochemical properties which facilitate the
sorption of the drug through the skin and enter the microcirculation. The rate of permeation, dq/dt, across various layers of skin tissues can be expressed
as :
Where, Cd and Cr are
respectively, the concentrations of a skin penetrant
in the donor phase (stratum corneum) and in the
receptor phase (systemic circulation), and Ps is the overall permeability
coefficient of the skin and is defined by :
Where , Ks = partition coefficient of the penetrant.
Dss
= apparent diffusivity of penetrant,
hs
= thickness of skin
Thus, permeability coefficient (Ps) may be a constant,
if Ks, Dss and hs terms in
equation (2) are constant under a given set of conditions. A constant rate of
drug permeation is achieved if Cd >> Cr, then
the equation (1) may be reduced to:
Molecular penetration through the various regions of
the skin is limited by the diffusional resistances
encountered. The total diffusional resistance (Rskin) to
permeation through the skin has been described by Chien
as:
Where, R is the diffusional
resistance and subscripts sc , e , pd
refer to stratum corneum, epidermis and papillary
layer of the dermis respectively. Of these layers, the greatest resistance is
put up by the stratum corneum and tends to be the
rate –limiting step in percutaneous absorption.When more than one phase of the membrane is
capable of supporting separate diffusional currents
through each. In this instance, the pathways are configured in parallel to one
another and the total fluxes of matter across the membrane is the sum of the
fluxes of each route and is expressed by :
Where, J = diffusional
flux and the term f1p1 + f2p2 + .fnpn, defines the overall permeability coefficient, ∆C
being the concentration drop.2,13
FACTORS
AFFECTING TRANSDERMAL: PERMEABILITY:
The principal transport mechanism across mammalian skin
is by passive diffusion through, primarily, the trans-epidermal route at steady
state or through trans appendageal route at initial
non-steady state. The factors controlling
transdermal
permeability can be
broadly placed in the
following classes.1,11,12
i.
Physicochemical properties of the penetrant
molecule
(a) Partition coefficient:
Drugs possessing lipid and water solubility are
favorably absorbed through the skin. Transdermal
permeability coefficient shows a linear dependency on partition coefficient. A
lipid/water partition coefficient of 1 or greater is generally required for
optimal transdermal permeability.
(b) pH conditions:
Application of solutions whose pH values are very high or
very low can be destructive to the skin. With moderate pH values, the flux of ionizable drugs can be affected by changes in pH that alter
the ratio of charged and uncharged species and their transdermal
permeability.
(c) Penetrant
concentration:
Assuming
membrane limited transport,
increasing concentration of dissolved
drug causes a
proportional increase in
flux. At concentrations higher
than the solubility, excess solid drug functions as a reservoir and helps to
maintain a constant drug concentration for a prolonged period of time.
ii. Physicochemical properties of drug delivery system: Generally, the drug delivery system
vehicles do not increase the rate of penetration of a drug into the skin but
serve as carriers for the drug.
(a) Release characteristics:
Solubility of the drug in the vehicle determines the
release rate.
The mechanisms of drug release depend on the following
factors.
(i) Whether the drug
molecules are dissolved or suspended in the delivery systems.
(ii) The interfacial partition coefficient of the drug
from the delivery systems to the skin tissue.
(iii) pH of the vehicle.
(b) Composition of drug delivery systems:
The composition of
the drug delivery system not only
affects the rate of drug release, but also the permeability of stratum corneum by means
of hydration, mixing
with skin lipids
or other sorption
promoting effects. Permeation
decreases with polyethylene glycols of low molecular weight. Similarly, methyl salicylate is
more lipophilic than
its parent acid
and when applied to
the skin, from
fatty vehicles, the methyl salicylate yielded
a higher percutaneous absorption than salicylic acid.
(c) Enhancement of transdermal
permeation:
Majority of drugs will not penetrate the skin at rates
sufficiently high for therapeutic efficacy.
In order to allow clinically useful transdermal permeation of most drugs, the permeation can
be improved by the addition of a sorption or permeation promoter into the drug
delivery systems. Such promoters can be of following types:
(i) Organic solvents:
These
agents cause an
enhancement in the
absorption of oil-soluble
drugs, due to
the partial leaching
of the epidermal
liquids, resulting in
the improvement of
the skin conditions
for wetting and
for transepidermal and transfollicular
penetration. e.g. dimethyl acetamide, dimethyl formamide, dimethyl sulphoxide,
cineole, propylene glycol,
polyethylene glycol, ethanol,
tetrahydro furfuryl alcohol,
cyclohexane,
acetone, ethyl ether,
benzene, and chloroform.
Dimethyl
sulphoxide has shown permeation promoting
effect on a variety of drugs, such as steroids, dyes, iodine, local
anesthetics, antibiotics, quaternary ammonium compounds, etc.
(ii) Surface active agents:
The permeation promoting activity of surfactants is assumed to be due to action
to decrease the surface
tension, to improve
the wetting of the skin, and
to enhance the
distribution of the
drugs. Anionic surfactants are
the most effective. Their action
may be due
to their modification
of the stratum
germinativum and/or to
their denaturation of the epidermal proteins. Ex. Sodium lauryl sulfate
and sodium dioctyl
sulfo-succinate.
iii. Physiological and pathological conditions of the
skin
(a) Lipid Film:
The lipid film on the skin surface acts as a protective
layer to prevent the removal of moisture from the skin and helps in maintaining the barrier function of the stratum
corneum.
Defatting
of this film
was found to
decrease transdermal
absorption.
(b) Skin Hydration:
Hydration
of the stratum
corneum
can enhance transdermal
permeability, although the degree of
penetration enhancement varies from
drug to drug. Simply covering
or occluding the
skin with plastic
sheeting, leading to the
accumulation of sweat
and condensed water
vapor can achieve
skin hydration. Increased hydration
appears to open
up the dense,
closely packed cells
of the skin
and increase its porosity.
(c) Skin Temperature:
Raising skin temperature results in an increase in the
rate of skin permeation. This may be due to:
(i) Thermal energy required
for diffusivity.
(ii) Solubility of drug in skin tissues.
(iii) Increased vasodilatation of skin vessels
(d) Regional Variation:
Differences in the nature and thickness of the barrier
layer of the skin causes variation in permeability.
(e) Traumatic / Pathological injuries to the skin:
Injuries that disrupt the continuity of the stratum corneum,
increase permeability due to increased vasodilatation caused by removal of
the barrier.
(f) Cutaneous drug
metabolism:
Catabolic enzymes present in the viable epidermis may
render a drug inactive by metabolism and thus affect the topical
bioavailability of the drug.
(g) Reservoir effect of the horny layer:
The horny layer, especially its deeper layers, can
sometimes act as a depot and modify the transdermal
permeation characteristics of some drugs. The reservoir effect is due to the
irreversible binding of part of the applied drug with the skin. This binding
can be reduced by the pretreatment of the skin surface with anionic
surfactants.
REGULATORY ISSUES:
The role of any regulatory authority is to ensure a
safe and effective medicine. In the case
of transdermal drug
delivery a number
of issues need
to be considered. They have to take into account
the drug, the excipients, and the device. The active
has to be delivered
at an adequate
rate through the
skin and it
should have no
adverse effects on the skin. It is surprising how many chemical entities
have some degree of skin toxicity, irritancy, or allergenicity.
This can be exacerbated by
solvents in the delivery
system such as those present
to solubilize the medicine
or to enhance
its passage through the skin.
It is essential to
choose Enhancers that are
toxicologically safe and
do not alter
the barrier function of the
skin in an
irreversible way. It is possible for solvents to leach
components of the patch, such as plasticizers present in the
polymers/adhesives. The safety of these issues needs to be tested
carefully. For active
delivery systems it is
important to ensure
that the devices
are capable of
delivering the drug
in a reproducible way to skin
sites that may
vary considerably in
permeability characteristics.
Stability is also an area of interest. Often transdermal
patches have high drug loads to minimize their surface area. The active is
often close to saturation; care
needs to be
taken that crystallization on
storage does not
influence the effectiveness of the
medication. In the
case of iontophoresis, the
drug flux will be proportional to the
current. Tests will need to show that constant current is provided over a range
of conditions and after storage of the devices.
REFERENCES:
1. Barry
BW Novel mechanisms and devices to enable successful transdermal
drug delivery. J Pharm Sci. 21; 2004: 371-377.
2. Barry
B. Transdermal Drug Delivery. In: Aulton
ME, Pharmaceutics. The science of dosage form design. 2nd ed,
Churchill Livingstone, 2002.499-543.
3. Berner B.,
John V.A. "Pharmacokinetic characterisation of transdermal delivery systems". Clinical pharmacokinetics.
26(2); 1994:121–34
4. Boylan J. “Transdermal Drug Delivery Devices: System Design and Composition” In Swarbrick J. (Ed.) Encyclopedia of Pharmaceutical
Technology: Volume 18, New York : Informa healthcare,
309 – 337
5. Chandrashekhar NS, Shobha Rani R H. Physicochemical and Pharmacokinetic Parameters in Drug Selection and Loading of Transdermal Drug Delivery. Indian Journal of Pharmaceutical Sciences. 70(1);
2008: 94‐96
6. Chien Yie.W. Development of Transdermal
drug delivery systems. Drug Dev Ind
Pharm.13;1987,589-651
7. Gaur PK, Mishra S, Purohit S, Dave
K. Transdermal
Drug Delivery System:
A Review. Asian Journal of
Pharmaceutical and Clinical Research.2 (1); 2009: 14‐20.
8. Jalwal P, Jangra1 A, Dahiya L. Sangwan Y, Saroha R. A Review on Transdermal Patches. The Pharma Research. 3;2010:
139‐ 149
9. Loyd, V.,
Allen, Jr., Nicholas, G., Howard. C, Transdermal Drug
Delivery Systems, In Ansel‟s Pharmaceutical Dosage Forms and Drug Delivery Systems, Chapter 11 :.
Churchill Livingstone, pp. 298 – 315
10. Misra, AN, Transdermal drug delivery. In: Jain NK, editor. Controlled
and novel drug delivery. New Delhi: CBS Publishers and Distributors; 2004. pp
101-17.
11. Murthy,
S.N. Hiremath. Transdermal
Drug Delivery systems. In: Hiremath SRR,editor. Text book of
industrial pharmacy. India; Orient longman private
limited, 2008, Pp. 27-49,
12. Robert.L.B.
& Howard.I.M.. Percutaneous
Absorptions. 2nd ed., 1989, New York: Marcel Dekker Inc
13. Tortora G.J.
The Integumentary system. In: Tortora
G.J and Grabowski SR. Principle of Anatomy and Physiology, Harpercollins
College Publishers, USA 10th ed.:1996, pp140-145.
14. Wadher K, Kalsail R, Umekar M. Alternate
Drug Delivery System:
Recent Advancement and Future
Challenges. Arch Pharm Sci& Res 2009; 1: 297.
15. Waugh
A and Grant A. The Skin. In: Ross and Wilson Anatomy and Physiology in health
and illness, Churchill Livingstone, 10th ed.; 2006, pp 358-367,
16. William
AC and Barry BW. Penetration enhancers. Adv Drug Deliv
Rev 2004; 603-618 Available at http://en. wikipedia.org/ wiki/skin.
Received on 11.09.2012
Modified on 02.10.2012
Accepted on 09.10.2012
© A&V Publication all right reserved
Research J. Science and Tech. 4(5):
September –October, 2012:
213-219