Nikhil Patel*, Chetan Patel, Savan Vachhani, ST Prajapati and CN Patel
Department of
Pharmaceutics and Pharmaceutical Technology, Shri Sarvajanik Pharmacy College, Near Arvind
Baug, Mehsana-384 001, India
ABSTRACT:
Human skin serves a
protective function by imposing physicochemical limitations. For a drug to be
delivered passively via the skin it needs to have a
suitable lipophilicity and a molecular weight <
500 Da. The number of commercially available products based on transdermal or
dermal delivery has been limited by these requirements. In recent years various
passive and active strategies have emerged to optimize delivery. The passive
approach entails the optimization of formulation or drug carrying vehicle to
increase skin permeability. However, passive methods do not greatly improve the
permeation of drugs with molecular weights >500 Da. In contrast, active
methods, normally involving physical or mechanical methods of enhancing
delivery, have been shown to be generally superior. The delivery of drugs of
differing lipophilicity and molecular weight,
including proteins, peptides and oligonucletides, has
been shown to be improved by active methods such as iontophoresis,
electroporation, mechanical perturbation and other energy-related
techniques such as ultrasound and needleless injection
KEYWORDS:
Techniques
for transdermal delivery, microneedle, radiofrequency drug delivery system, iontophoresis.
INTRODUCTION:
The potential of
transdermal drug delivery systems has been demonstrated in recent years with
the approval of several medicines for use by patients who are unable to use
conventional dosage routes, like oral administration or injection. To enhance
the TDDS (Transdermal Drug Delivery System) potential to include other drug
candidates, many researchers have been exploring enhancement approaches to
increase the permeability of various drugs through the skin. One classic
method, chemical enhancers, is of practical use in some formulations that are
available in the market. On top of these, recently, physical enhancement
systems are being reported as having more potential by many researchers. In
particular, iontophoresis is a very attractive way of
delivering ionized drugs by the application of an electric field to the skin.
This has been marketed with some topical and systemic drugs (lidocaine and fentanyl). Sonophoresis is also an attractive method to deliver a drug
through the skin using ultrasound. Besides these technologies, various physical
approaches are under study. Such technologies can be expected to deliver not
only small MW compounds but also macromolecules like peptides. In this session,
after looking back through the history of TDDS development,
As
reviewed in the previous chapter, one of the major limitation to successful
transdermal drug delivery stem from the skin itself and 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, methods that circumvent the skin barrier (i.e. ablative methods, jet
injectors or microneedles) are not restricted by the
size of the drug molecule. .
Nevertheless,
the barrier property of the skin poses a challenge for these methods as well;
less from an intercellular or chemical point of view, but instead from a
mechanical perspective
SKIN
ANATOMY:2
The
skin is the largest organ of the human body and has several functions. It is a
physical barrier towards the environment, it regulates body temperature and
fluid loss, it conveys sensory information to the nervous system, and it
processes immunologic information to the immune system. The skin can be divided
into three main layers: the superficial epidermis, dermis and hypodermis
(Figure 1).
Figure1.
Anatomy
of skin
Figure 2: Iontophoresis
Iontophoresis is the ability of an
electric current to cause charges particles to move (Figure 2). Iontophoresis delivers medication transdermally
(both locally and systemically) using electric current to ionize drug molecules
and propel them through the skin. In a patch form, two adjacent electrodes set
up an electrical potential to drive charged compounds through the skin. This is
particularly important for the transdermal delivery of peptides
and oligonucleotides, due to the polar groups associated with
these molecules. The real attraction of iontophoresis
is that is does not rely on a concentration gradient and is not affected by
individual differences in skin permeability. The technology also has the
potential to deliver pulses, for example, hormonal treatments, simply by
switching the current on or off. Iontophoresis is
used for treatment in the areas of pain management and rehabilitation,
administration of medications to treat numerous conditions including diabetes,
reduction of excessive bodily perspiration, and throughout the cosmetic
industry. Iontophoresis products are positioned to
make a significant impact in selected therapeutic areas. New wearable
designs that are user-friendly and conform to the user’s physique are improving
outcomes in pain management. Prefilled disposable devices are user-friendly and
improve compliance.
TYPES OF
TRANSDERMAL PATCH:4,14
The adhesive layer of
this system also contains the drug. In this type of patch the adhesive layer
not only serves to adhere the various layers together,
along with the entire system to the skin, but is also responsible for the
releasing of the drug. The adhesive layer is surrounded by a temporary liner
and a backing.
The multi-layer
drug-in adhesive patch is similar to the single-layer system in that both
adhesive layers are also responsible for the releasing of the drug. The
multi-layer system is different however that it adds another layer of
drug-in-adhesive, usually separated by a membrane (but not in all cases). This
patch also has a temporary liner-layer and a permanent backing.
Unlike the
Single-layer and Multi-layer Drug-in-adhesive systems the reservoir transdermal
system has a separate drug layer. The drug layer is a liquid compartment
containing a drug solution or suspension separated by the adhesive layer. This
patch is also backed by the backing layer. In this type of system the rate of
release is zero order.
The Matrix system has
a drug layer of a semisolid matrix containing a drug solution or suspension.
The adhesive layer in this patch surrounds the drug layer partially overlaying
it.
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.
The first prototype
patch measures about 1cm2 and is made using polymers and thin metallic films.
The 5×5 sampling array can be clearly seen, as well as their metallic
interconnections (Figure 3). When the seal is compromised, the interstitial
fluid, and the biomolecules contained therein,
becomes accessible on the skin surface. Utilizing micro-heating elements
integrated into the structural layer of the patch closest to the skin surface,
a high-temperature heat pulse can be applied locally, breaching the stratum corneum. During this ablation process, the skin surface
experiences temperatures of 130°C for 30ms duration. The temperature diminishes
rapidly from the skin surface and neither the living tissue nor the nerve
endings are affected. This painless and bloodless process results
in disruption of a 40–50μm diameter region of the dead skin layer,
approximately the size of a hair follicle, allowing the interstitial fluid to
interact with the patch's electrode sites.
Figure 3. pain free diabetic
monitoring using transdermal patch
In premenopausal
women, the daily testosterone production is approximately 300 µg, of which
approximately half is derived from the ovaries and half from the adrenal glands.(Figure 4) Young women with spontaneous premature ovarian
failure (sPOF) may have lower androgen levels,
compared with normal ovulatory women. Testosterone
transdermal patch (TTP) was designed to deliver the normal ovarian production
rate of testosterone. The addition of TTP to cyclic E2/MPA therapy in women
with sPOF produced mean free testosterone levels that
approximate the upper limit of normal.
Figure 4. transdermal patch
for postmenstrual syndrome
The product is a
transdermal patch containing Oxybutynin HCl and is approved in US under the brand name of Oxytrol and in Europe under the brand name of Kentera. OXYTROL
is a thin, flexible and clear patch that is applied to the abdomen, hip or
buttock twice weekly and provides continuous and consistent delivery of oxybutynin over a three to four day interval. OXYTROL
offers OAB patient’s continuous effective bladder control with some of the side
effects, such as dry mouth and constipation encountered with and oral
formulation. In most patients these side effects however are not a troublesome.
The patch is 4.5
square centimeters in size and has three layers: the inner release liner which
should be removed before application, a layer containing hormones, and an outer
polyester protective layer. The patch contains 6 milligram of progestin, Norelgestromin 0.75 milligram of Ethinyle
Estradiol. The patch is applied on the skin through
which the hormones are absorbed in order to provide continuous flow of hormones
during menstrual cycle. The patch is marketed by Ortho McNeil Pharmaceutical
with the brand name Ortho Evra.
The rotigotine transdermal patch is used for symptom control in
Parkinson’s disease. The patches are effective in reducing the symptoms of
early Parkinson’s disease, and in reducing “off” time in advanced Parkinson’s
disease. It is available in market under the brand name of NeuproR.
JET
INJECTOR:2
Jet
injectors are hand-held devices that deliver a high-pressure liquid stream
through a small nozzle orifice. (Figure 5)The impact of the stream is high
enough to penetrate the skin tissue and by controlling the magnitude, the
liquid can be delivered to specific tissue depths, e.g. intradermal,
subcutaneous or intramuscular. The major advantage of jet injectors is the
extremely efficient way of drug administration where drug doses can be fired
off sequentially, allowing up to 1000 subjects to be medicated per hour . Jet
injectors have been used in military and mass vaccination campaigns since the
1950s but their use was discontinued after an outbreak of hepatitis B in 1985
was linked to the use of jet injectors. During recent years, with renewed
interest due to bioterror threats, a new generation
of safer jet injectors have been developed which use single-dose cartridges
and, for example disposable caps to eliminate the risk of cross-contamination
between injections. Several systems are commercially available, e.g. Bioject, Injex, Intraject and J-Tip. A similar system called PMED also
exists where the jet-injected substance has the form of a dry powder (Powder
Med Ltd, a Pfizer Inc. subsidiary) and where the delivery specifically targets immuno-competent cells in the skin layer. Due to this
efficient location of vaccine delivery, immune response has been achieved with
20–2500-fold lower doses as compared to conventional intramuscular delivery
(using a needle and syringe).
Figure 5: jet injector
ULTRASOUND
TRANSEDERMAL DRUG DELIVERY SYSTEM:8,13
Low
frequency (20 kHz) ultrasound can increase the permeability of human skin to
high-molecular-weight -drugs.(figure 6) Ultrasound
causes cavitation, or growth and oscillation of the
air pockets in the skin's keratin fibers. The stratum corneum
(outer skin layer) consists of cells called Keratinocites
surrounded by lipid bilayers. Low frequency ultrasound
generates micro bubbles in the tissue. Researchers suggest the bubbles disrupt
the lipid bilayer and allow water channels to be
produced within the bilayer. The disorder in the
stratum corneum facilitates the crossing of a larger
molecule. This process is of particular significance to the delivery of insulin
to diabetics. Insulin protein is too large to permeate the skin without use of
the active transdermal system. A team of researchers completed an Insulin patch
prototype in October of last year. This device provides needle free delivery of
insulin via a wearable patch. It has been tested to safely administer effective
dosages of insulin in rats. Down the road researchers hope to devise a patch
delivery system that will detect glucose and administer insulin.
Figure 6.ultrasound
transdermal system
GENERAL
ASPECTS ON MICRONEEDLES:2
Following
conventional terminology, a microneedle is a needle with representative parts
(e.g. diameter) on the micrometer length scale. However, this definition is
rather bold as it includes most of the standard hypodermic needles used in
medical practice. Although there are many examples of “microneedles”
with lengths of a few millimeters described in the literature, a common
understanding of microneedles is that the length of
the needle is shorter than 1 mm. What can be said is that microneedles
are significantly smaller than ordinary needles, especially concerning the
length.
The
device contains microneedles, a drug reservoir,
adhesives and optionally a rate-controlling membrane. (i.e.
microneedles) and a drug reservoir is claimed. The
needles are small enough to penetrate only the stratum corneum
and can be either solid or hollow. Delivery from the device may occur through
diffusion or through convection by applying a force to the backing of the
reservoir. shows a drawing from the original document
illustrating the device. Although the concept of miniaturized needles for drug
delivery was presented earlier, it was not until the 1990s that the technique
was tested experimentally. A reason for this was that microfabrication
techniques, evolving strongly at that time, enabled these micrometer-sized
needles to be precisely fabricated in a potentially cost-effective manner. The
first reported study on microneedles for transdermal
drug delivery came 1998. This work led by Allen, with a background in microfabrication and MEMS (Microelectromechanical
systems), and Prausnitz, with a background at Alza corp. and in drug delivery research, demonstrated a
four orders of magnitude increase in permeability of human skin after insertion
of an array of 150 micrometer long, solid silicon, out-of-plane microneedles. Given the governing goal to deliver a
substance across the skin for subsequent systemic distribution, and the means (microneedles), several possible strategies can be employed
to accomplish this. The simplest way, as also proposed by the early
vaccinations strategies mentioned above, is to perforate the skin with microneedles and then apply the drug onto the skin for
subsequent diffusive spread into the body. The drug can be applied to the skin
surface as a gel or through a medicated patch to achieve prolonged release.
Another way is to precoat the microneedles
with the drug before they are inserted into the skin. A third option is to
fabricate the microneedles in a biodegradable
material that incorporates the drug. When the needles are inserted into the
skin, the needles dissolve and the drug is subsequently released. If the microneedles are hollow, the drug can be actively injected
into the tissue. Hollow needles can also be used with passive,
diffusion-driven, delivery. In that case, the needles merely functions as
controlled and sustained paths (channels) into the body. The achievable dose
for precoated and drug-embedded needles is naturally
limited to the amount that the needles can bear. For moderately sized microneedle arrays, it is difficult to embed more than 1
mg. This may be sufficient for certain highly potent drugs (e.g. vaccines) but
requires tailored drug formulations to be used.
This method involves
the application of high voltage pulses to the skin which has been suggested to
induce the formation of transient pores. Other electrical parameters that
affect delivery include pulse properties such as waveform, rate and number. The
technology has been successfully used to enhance the skin permeability of
molecules with differing lipophilicity and size (i.e.
small molecules, proteins, peptides and oligonucleotides)
including biopharmaceuticals with molecular weights greater that 7kDA. As electroporation improves the diffusion of such a wide range
of compounds, it is thought that the pores created in the superficial layers of
the skin are directly responsible for the increase in skin permeability. Genetronics, Inc. has developed a prototype electroporation transdermal device, which has been tested
with various compounds with a view to achieving gene delivery, improving drug
delivery and aiding the application of cosmetics
MICROSCISSUINING:9
It is a process which
creates microchannels in the skin by eroding the
impermeable outer layers with sharp microscopic metal granules. In
addition, MedPharm Ltd. has recently developed a
novel dermal abrasion device (D3S) for the delivery of difficult to formulate
therapeutics ranging from hydrophilic low molecular weight compounds to
biopharmaceuticals. In vitro data has shown that the application of the device
can increase the penetration of angiotensin into the
skin 100-fold compared to untreated human skin. This device is non-invasive and
histological studies on human skin show that the effects on the stratum corneum are reversible and non-irritating.
This is reported to
involve a pain-free method of administering drugs to the skin. Over the years,
there have been numerous examples of both liquid (Ped-O-Jet,
Iject, Biojector2000, Medi-jector
and Intraject) and powder (PMED device formerly known
as Powderject injector) systems. The latter
device has been reported to successfully deliver testosterone, lidocaine hydrochloride and macromolecules such as calcitonin and insulin. This method of administering drugs
circumvents issues of safety, fear and pain associated with the use of
hypodermic needles. Transdermal delivery is achieved by firing the liquid or
solid particles at supersonic speeds through the outer layers of the skin using
a suitable energy source. The PMED device consists of a helium gas cylinder,
drug powder sealed in a cassette made of plastic membrane, a specially designed
convergent-divergent supersonic nozzle and a silencer to reduce the noise
associated with the rupturing of the membrane when particles are fired. The
mechanism involves forcing compressed gas (helium) through the nozzle, with the
resultant drug particles entrained within the jet flow reportedly traveling at
sufficient velocity for skin penetration. An essential difference between
administration of a DNA vaccine by needle injection or by PMED is the
efficiency with which the administered DNA generates the encoded protein for
presentation on the surface of antigen-presenting cells (APCs). Using PMED, it
is possible to deliver the DNA directly to the intracellular compartment of
cells within the epidermis, and because the epidermis is rich in APCs,
significant numbers can potentially be targeted with each administration. This
is supported by non-clinical studies in pigs that have included histological
examination of PMED administration sites.
This method involves
direct and controlled exposure of a laser to the skin which results in the
ablation of the stratum corneum without significantly
damaging the underlying epidermis. Removal of the stratum corneum
using this method has been shown to enhance the delivery of lipophilic
and hydrophilic drugs. A handheld portable laser device has been developed by
Norwood Abbey Ltd. (Victoria, Australia), which, in a study involving human
volunteers, was found to reduce the onset of action of lidocaine
to 3 to 5 minutes, while 60 minutes was required to attain a similar effect in
the control group. Laser systems are also being developed to ablate the stratum
corneum from the epidermal layer. As with microneedles, the ablated regions offer lower resistance to
drug diffusion than non-ablated skin. One company has recently received FDA
approval to market this device with a lidocaine
cream.
3M core pop-up
dispensing technology is being
used to develop compact transdermal patch dispensers. The
patented dispenser is designed to dispense patches in a manner that makes the
patches convenient to apply. The dispenser appearance, size, shape and quantity
of patches stored can be customized to meet patients
needs.
MAGNETOPHORESIS:9
Which is still in the
research phase, enhances skin permeability by applying a magnetic field. The
research data on animal models suggests that skin penetration can be enhanced
by applying a magnetic field to therapeutic molecules that are diamagnetic or
paramagnetic in nature.
MICROSTRUCTURED
3M DRUG DELIVERY SYSTEM:10
3M Drug Delivery Systems Division's other key
technology platform is transdermal drug delivery (TDD), and micro needle or
micro structured transdermal systems for vaccines is an emerging area of
interest here. Other advances include improvement in liners, films, and
adhesives used as components within TDD systems. Drug-in-adhesive (DIA) systems
are the most prevalent of established TDD designs. DIA systems offer advantages
in simplicity, reduced size and thickness, and improved conformability to the
application site. Modified versions of the DIA design, reservoir designs, and,
more rarely, matrix patches are other examples of TDD system designs. "For
drugs with a narrower therapeutic window or for which there is need for more temporal
control of the delivery profile, systems with a rate-moderating membrane such
as the multilaminate DIA or reservoir design are the
best option," 3M Drug Delivery
Systems Division. "The multilaminate DIA
combines most of the patient friendliness of the simple DIA design with added
control over the drug delivery profile,"Another
transdermal drug delivery type, matrix patches, are seldom used because they
require an additional peripheral adhesive to hold the system in place, which in
turn increases the overall patch size and thickness. 3M recently developed new
components for transdermal drug delivery. These include fluoropolymer-coated
release liners for use with new soft adhesives and formulations, ultraviolet
blocking films for light-sensitive formulations, and micro layered films that
are designed to be soft and occlusive.
Microstructured transdermal system:10
3M also is
actively developing alternative transdermal delivery methods such as microstructured transdermal systems or micro needles. Micro
structured transdermal systems may be used in vaccine delivery, replacing the
common approach of using a needle and syringe or in delivering other
macromolecules. (Figure 7)A microstructured
transdermal system consists of an array of microstructured
projections coated with a drug or vaccine that is applied to the skin to
provide intradermal delivery of active agents, which
otherwise would not cross the stratum corneum,
explains Peterson. The mechanism for delivery, however, is not based on
diffusion as it is in other trandsermal drug delivery
products. Instead, it is based on the temporary mechanical disruption of the
skin and the placement of the drug or vaccine within the epidermis, where it
can more readily reach its site of action. Much of the work on microstructured transdermal systems is focused on vaccine
delivery, in which the system targets the antigen-presenting cells within the
skin to reduce pain in administering the vaccine and a more efficient method of
vaccination, explains Peterson. Microstructured
transdermal systems also may be used for systemic delivery of potent proteins
and peptides.3M's program in microstructured
transdermal systems also has provided a basis for the company to develop
expertise in coating biomolecules such as proteins
and peptides on patch structures.
Figure 7. Photomicrographs
of MTS Arrays Coated with Fluorescent Nanobeads
before (top) and after application (bottom).
A microelectronic system based on
radio-frequency (RF) cell ablation addresses limitations of other transdermal
drug-delivery methods. This system expands the transdermal spectrum to include
the delivery of water-soluble molecules, peptides, proteins, and other
macromolecules
RF ablation is a well-known medical technology to
eliminate living cells. It is widely used to cut through tissues in minimally
invasive operations or to destroy small tumors in the kidney and liver (1–5).
RF ablation is performed by placing a conducting wire on a body area and
passing an alternating electrical current at a frequency above 100 KHz (radio
frequency) through the area. The ions in the cells adjacent to the electrodes
vibrate as they try to follow the change in electrical current direction. These
vibrations cause heat, which results in water evaporation and cell ablation.(Figure 8) RF microchannels are
created by placing a closely spaced array of tiny electrodes with very precise
dimensions against the skin. The alternating electrical current is transferred
through each of the microelectrodes, ablates the cells underneath each
electrode, and forms microscopic passages in the stratum corneum
and outer dermis. These RF microchannels penetrate
only the outer layers of the skin, where there are no blood vessels or nerve
endings. This action minimizes skin trauma and unpleasant sensations. The
process is performed in seconds. Immediately after formation, the microchannels fill with interstitial fluid, which is
responsible for the hydrophilic nature of the microchannels.
As a result, microchannels serve as aquatic channels
into the inner layers of the skin. They are embedded in the surrounding of the
hydrophobic stratum corneum. For drug delivery, the microchannels may last up to 24 h. At 36 h, the delivery
through treated skin returns to the values of intact skin.
Figure 8. RF cell ablation
technology
DRUG DELIVERY DEVICE:11
The "ViaDerm" (TransPharma Medical Ltd., Lod,
Israel) system is an example of a microelectronic system based on RF cell
ablation for transdermal drug delivery(Figure 9). The
system consists of the device, which is used to pretreat
the skin and form the RF microchannels in the outer
layers of the skin, and a patch containing the drug, which is placed on top of
the pretreated skin. “Intra derm “ consists of a handheld electronic control unit and a
microelectrode array (Figure 10). The control unit is battery-operated,
rechargeable, and reusable for at least 1000 applications. This particular
device is available in three sizes (treatment area of 1, 2.5, or 5 cm2 ), depending on the desired dose of drug to
be delivered. The microelectrode arry contains
hundreds of microelectrodes. The microelectrode array is disposable, low-cost
and intended for one use only. The array is based on a proprietary design and
made of biocompatible materials that are well-established in medical devices.
Within a few seconds, the control unit and the array create an array of RF microchannels, thereby preparing the treatment site for the
patch containing the drug. After application of the patch on the pretreated area, the drug
passively diffuses from the patch through the RF microchannels
into the inner layers of the skin and into systemic circulation.
figure 9. “via
derm” system depending on Rf
cell ablation technology
Figure 10. “intra derm “system depending on Rf cell
ablation technology
CHEMICAL
PENETRATION ENHANCERS:2
The
delivery rate of conventional transdermal patches can be increased
significantly by using chemical penetration enhancers in combination with the
patch. The simplest form of penetration enhancement is the use of water.
Hydration of skin tissue progressively increases permeability as water opens up
the compact structure of the outer most skin layer The layer is also extremely
hygroscopic as up to 500% of the dry weight can be absorbed within 1 h (by
immersion) causing the layer thickness to increase 4–5 times Consequently,
moisturizing factors like occlusive films or hydrophobic ointments (e.g. oily
creams) also lead to increased skin permeability. Other penetration-enhancing
chemicals work by diminishing the barrier property of the outermost skin layer.
A great variety of chemicals are known to posses this capability. Some of the
more common ones are surfactants (like Tween), fatty acids (like oleic acid), terpenes (e.g. eucalyptus oil) and solvents (e.g. ethanol)
CONCLUSION:
Among
all the method, Iontophoresis delivers medication transdermally (both locally and systemically) using
electric current to ionize drug molecules and propel them through the skin. jet
injectors is the extremely efficient way of drug administration where drug
doses can be fired off sequentially, RF cell ablation technology expands the
transdermal spectrum to include the delivery of water-soluble molecules,
peptides, proteins, and other macromolecules.3M Drug Delivery Systems
Division's other key technology platform is transdermal drug delivery (TDD),
and micro needle or micro structured transdermal systems for vaccines is an
emerging area of interest here. Needle less injection reported to involve a
pain-free method of administering drugs to the skin. For microneedles
to function properly, the needles need to have a certain length and certain
sharpness, and they should be fabricated in a material which can withstand the
forces of matter. Ultrasound can increase the permeability of human skin to
high-molecular-weight -drugs.
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Received on 08.12.2009
Accepted on 12.02.2010
© A&V Publication
all right reserved
Research
Journal of Pharmaceutical Dosage Forms and Technology. 2(2): March –April.
2010, 113-119