INTRODUCTION TO TRANSDERMAL DRUG DELIVERY SYSTEM:

Transdermal drug delivery systems encompass a wide array of non-invasive or minimally invasive technologies for delivering drugs and vaccines across the skin without needles¹. Active methods of skin permeation enhancement include jet injectors, iontophoresis, electroporation, ultrasound, microneedles, powder injection, ablation and tape stripping². Active methods increase transport across the skin typically by using an added driving force for drug transport or by physically disrupting the barrier. This enables delivery of many hydrophilic drugs and macromolecules. In addition, active methods also offer more control over delivery profile, thus resulting in shorter delays between application and drug reaching systemic circulation compared to passive methods. Also, the device and application parameters can be adjusted to better match individual’s skin properties³. For the same reasons, devices using active methods can have additional requirements including power supply, possible feedback/ sensor mechanism to adjust the rate of delivery and user interface for parameter control⁴. This stretches the challenges of active device development beyond simply breaching the permeability barrier of skin and into varying engineering fields of microelectromechanical systems (MEMS), micro fluidics and embedded software⁵.

Operation at micron scale is important because micron-sized breaches in the stratum corneum barrier are large enough to let most drugs through, since most drugs are of nanometer dimensions. At the same time, they are small enough that they appear to be safe, well tolerated by patients and allow rapid skin recovery post-administration. Such micro-scale devices include liquid jet injectors, solid powder injectors, microneedles and thermal microporation devices.

Fig-1Human Skin shows the potential targets or site of action for cosmetics and drugs⁶

Advantages of TDDS:⁷

1. Delivers a steady infusion of a drug over an extended period of time.

2. It can increase the therapeutic value of many drugs by avoiding specific problems associated with drug like GI irritation, low absorption, decomposition due to hepatic first pass effect, formation of metabolites that cause adverse effects, short half life necessitating frequent dosing etc.

3. Due to above advantages, it is possible to get equivalent therapeutic effect with a lower daily dose.

4. Leads to improved patient compliance and reduced inter and intra patient variability.

5. Self administration is possible

6. The drug input can be terminated at any point of time by removing the patch.

Disadvantages of TDDS:⁷

1. The drug must have some desirable physicochemical properties for penetration through stratum corneum and if the drug dosage required for therapeutic value is more than 10 mg/day, the transdermal delivery will be very difficult or not possible. Daily doses of less than 5 mg/day are preferred.

2. Skin irritation or contact dermatitis due to the drug, excipient and enhancers of the drug used to increase percutaneous adsorption is another limitation.

3. The barrier function of the skin changes from one site to another on the same person, from person to person and with age.

THE EFFECT OF HEAT ON SKIN PERMEABILITY:⁸

Although the effects of long exposure (>>1s) to moderate temperatures (< or =100 C) have been well characterized, recent studies suggest that shorter exposure (<1s) to higher temperatures (>100 C) can dramatically increase skin permeability. Research suggests that by keeping exposures short, thermal damage can be localized to the stratum corneum without damaging deeper tissue. Initial clinical trials have progressed to Phase II (http://clinicaltrials.gov), which indicates the procedure can be safe. Because the effect of heating under these conditions has received little systematic or mechanistic study, heated full-thickness skin, epidermis and stratum corneum samples from human and porcine cadavers to temperatures ranging from 100 to 315 degrees C for times ranging from 100ms to 5s.

(1) By a few fold after heating to approximately 100-150 C,

(2) By one to two orders of magnitude after heating to approximately 150-250 C

(3) By three orders of magnitude after heating above 300 C.

These permeability changes were attributed to

(1) Disordering of stratum corneum lipid structure,

(2) Disruption of stratum corneum keratin network structure and

(3) Decomposition and vaporization of keratin to create micron-scale holes in the stratum corneum, respectively.

THERMAL ABLATION:

Use of thermal energy for surgical removal of selected tissue has been reported bymedical practitioners as early as Hippocrates (460–370 bc), who used hot iron rods for cauterization of wounds⁹. In modern medicine, thermal ablation generally refers to tissue removal due to high temperature induced by various energy sources. Percutaneous thermal ablation for tumor targeting is well established but does not use devices with micron-sized operating dimensions and is discussed elsewhere¹⁰. More recently, devices with micro-scale ablation elements have been developed for controlled removal of stratum corneum and thus thermally microporate the skin for enhanced transdermal drug delivery.

It suggest that temperatures well above the boiling point of water are needed and that other processes, such as tissue combustion, may be at play¹¹

Ability of thermal ablation to deliver a number of different compounds, such as human growth hormone and interferonα-2b^12,13. Skin heating has been achieved using ohmic microheaters and radio-frequency ablation. The microscopic length scales of localized skin disruption caused by thermal ablation have resulted in the procedure being well tolerated.

2. Design Parameters:

The temperature, duration, and localization of thermal energy applied to the skin are all critical design parameters. Skin should be heated well above 100 C and possibly up to many hundreds of degrees Celsius. Because skin heating is done for a very short time and extreme temperature gradients exist within skin (e.g. >10,000 C/mm), it has been difficult to make precise measurements of skin temperature. To localize heating within the stratum corneum, thermal pulses are applied typically on the millisecond time scale or shorter. Longer pulses lead to heating of deeper skin tissue, which can cause undesirable damage to living tissues. Heating should also be localized to specific areas on the skin surface. Since it would generally be undesirable to ablate large areas on the skin surface for safety reasons, heating elements measuring just microns in size have been used. By employing an array of these micro-heaters, large area of skin can be treated for drug delivery, but only small spots of stratum corneum area are ablated within the treated area. One approach to achieving controlled heating in this way involves a two-dimensional grid of wires having micron-scale resistors between each of the nodes. Using such a device, a brief surge of electric current through the network causes the resistors to suddenly heat up due to ohmic resistance. The electrodes cool down as soon as the current is turned off. This transiently heats the skin surface and ablates stratum corneum. PassPort system fabricated by Altea Therapeutics Corp. (Atlanta, GA, USA) ¹⁴is based on this concept. A prototype of this device used an array of 80m diameter tungsten wires (72–75 wires/cm²) as resistive elements for producing focused short bursts of thermal energy for ablation of stratum corneum.³¹ Another approach involves an array of electrodes that are activated one by one or through a feedback mechanism to briefly pass radiofrequency (RF) current into the skin. The resulting heat generated within the stratum corneum selectively heats this tissue for localized ablation. One such handheld device based on RF energy is ViaDerm which has been developed by TransPharma Ltd. (Israel).¹⁵ the device employs a disposable array of stainless steel micro-electrodes (100m length and 40m diameter; 200 electrodes/cm²)mounted on a polycarbonate body. The activation of device is governed by pressure as the device is pressed on skin at the site of application. Repeated applications of up to 250 and 380V for in vivo and in vitro, respectively, were used at a frequency of 100 kHz for duration of 1ms each.

Figure-2 (a) micro-electrodes are pressed against the skin; (b) skin is ablated via heating due to RF energy or resistive heating in the electrodes, (c) After removing the ablation device, (d) micropores formed are covered with drug patch for delivery

THERMAL ABLATION TYPES

There are two types of thermal ablation:

1. Microwave Thermal ablation

2. Radiofrequency (RF) Thermal ablation

MICROWAVE ABLATION BY ARC-DISCHARGE JET EJECTION:¹⁶

Design and Fabrication:

Figure-3 Microjet Device

The microjet device utilizes the concept of generating heat rapidly within the device by passing a current through the ejectate formulation. This current generation is most effectively accomplished by generating an arc applying a high voltage pulse across closely spaced electrodes. This discharge of high currents through the ejectate formulation drives the ejectate in the form of a jet through a constriction at high velocity. This high velocity jet is then used to create micro pores in the exposed skin surface. In fabricating these microjet ejectors, micromachining approaches were considered with primary emphasis placed on utilizing the simplest fabrication schemes available. Also, as these microjet ejectors are one-time-use devices, fabrication techniques that enable easy batch fabrication (and concomitant ease of high volume manufacturing) were considered. Laser micromachining techniques and lamination of low-cost polymers and metals were used for fabricating different components of the microjet ejector. Fig. 3 shows a schematic of a single arc discharge jet ejector fabricated by laser micromachining. The microjet ejector assembly has four basic components: a micro-chamber, two electrodes and a nozzle. The chamber houses fluid to be ejected, typically an aqueous solution containing a drug or a drug model, salt, gelling agent and optional gold particles, while the electrodes were used to create an arc discharge within the chamber. The chamber and the substrate layers are patterned in a mylar layer, which is a low cost polymer, using a CO₂ laser that has a spatial micromachining resolution of 100 μm. The thickness of the chamber layer is 250 μm. The electrodes were made by patterning an inexpensive thin metal film such as brass or nickel using an IR laser. Feature sizes as small as 60 μm can be machined by the IR laser. The thickness of the metal used is approximately 25-50 μm. Conical or cylindrical nozzles are fabricated either by integrating these along the chamber in the same layer or are fabricated as a separate layer. These layers are then adhered together and laminated to the substrate layer in a hydraulic press between aluminum molds.

WIRELESS THERMAL MICRO-ABLATION OF SKIN:¹⁷

Here present a wireless induction heating system for generating micron-scale pores in the skin by thermal micro-ablation that seeks to combine the efficacy of previous wired approaches with the improved convenience and likely higher patient compliance of wireless power delivery. The separation between the power source and the heating elements provides the potential for design flexibility, such as easier integration of ablation heating components with the drug patches and removal of the inconvenience of being ‘plugged in’ to an energy source, while maintaining the advantages of thermal micro-ablation.

Figure 4 shows a schematic diagram of the inductive heating system, including an AC power source, an excitation (induction) coil, and micro-heating elements. The induction heating is based on eddy current and hysteresis loss induced in the heating elements by the alternating magnetic field of the excitation coil. In most metals, eddy current loss is the dominant source of induction heating. When a conductive material experiences alternating magnetic flux inside it, an electromotive force is induced in the material that causes a circulating current or eddy current, in accordance with Faraday’s law of induction. This eddy current is converted into heat due to the Joule effect (i.e., resistive loss) in the heating material.

Design and Fabrication:

Figure-4 Wireless inductive heating system for micro-ablation of stratum corneum

PASSPORT PATCH SYSTEM BY ALTEA THERAPEUTICS CORP:¹⁸

Figure-5 PassPort patch

1. Application of transdermal drug reservoir patches containing metallic filament array to the skin.

2 and 3. Placing the applicator above the patch.

4. and 5. Release of electrical energy from applicator which is converted to thermal energy.

6. Formation of micro channels due to thermal energy from which drug is delivered.

7.1 Design and Use:

The PassPort System is comprised of a single-use disposable PassPort Patch and a re-useable handheld Applicator. The rapid conduction of this thermal energy into the surface of the skin painlessly ablates the stratum corneum under each filament to create microchannels. When the Applicator is removed, a simple fold-over design aligns the transdermal patch with the newly formed microchannels.

Benefits:

The PassPort System enables fast, controlled drug delivery without the pain of an injection, the complications associated with inhaled medications, and the first-pass gastrointestinal and liver metabolism that occurs often after oral administration.

Delivery of a wide variety of drugs and vaccines via the skin:

Proteins, peptides, carbohydrates, water-soluble and lipid-soluble small molecules, genes, and vaccines all can be delivered using the PassPort System.

Painless non-invasive approach:

The PassPort System works by painlessly and almost instantaneously forming multiple tiny aqueous channels ('microchannels') through the stratum corneum, the outer dead surface layer of skin.

Sustained therapeutic levels in clinical trials:

Novel formulations result in rapid and sustained transdermal delivery at high utilization

Provides dose information and prevents abuse:

The Applicator can be programmed to provide dosing control, monitoring, and lock-out features.

PassPort Patch vs. Conventional Transdermal Systems:

Conventional transdermal system is typically limited to lipid-soluble drugs with a molecular weight of less than 500 daltons. The PassPort System enables continuous delivery of hundreds of milligrams of water-soluble drugs and up to 10 mg of peptides.

RF-MICRO CHANNEL THERMAL ABLATION:

Formation of Rf-Microchannels and Working:

RF ablation is a well-known medical technology used to eliminate living cells. It is widely used for various medical procedures such as performing incisions in minimally invasive operations or destroying small tumours. RF ablation is performed by conducting an alternating electrical current at a frequency higher than 100 KHz (radio frequency) through a particular tissue. The alternating current induces ionic vibrations in the vicinity of the electrode, resulting in heat. This, in turn, leads to water evaporation and cell ablation. RF MicroChannels are created by placing against the skin an array of closely spaced, tiny electrodes of very precise dimensions Figure-6^19,20. The alternating electrical current passing through the microelectrodes ablates the cells underneath each electrode, forming microscopic passages in the epidermis and outer dermis. These RF MicroChannels span only the outer layers of the skin, where there are no blood vessels or nerve endings, thus minimising skin trauma and unpleasant sensations. The whole process is completed within seconds. Immediately after formation, the microchannels fill with interstitial fluid, which is responsible for their hydrophilic nature. As a result, RF MicroChannels serve as aquatic channels into the inner layers of the skin that are embedded in the hydrophobic surroundings of the SC. The microchannels may last up to 24 hours, enabling prolonged drug delivery. After 36 hours, the drug delivery rate drops back to values characteristic of intact skin. The unique microelectrode-array is also designed to overcome differences in skin texture and elasticity between different people and different areas of the body.

A major difficulty in penetrating the skin for drug delivery is that the texture and softness of the skin change from site to site and from person to person. To address these variations, a unique microelectrode-array design was used. The microelectrode array design adapts to differences in skin type within and between treatment sites. This design is essential for forming RF MicroChannels with consistent, well-controlled depths, enabling the drug to reach the capillary bed without unnecessary trauma to the inner layers of the skin.

Figure-6 RF MicroChannels and skin

RF-MicroChannel Technology offers more therapeutic opportunities than existing technologies under development due to the following²¹

· RF-MicroChannels are created within milliseconds, with no resulting skin trauma or pain.

· Uniformity of RF-MicroChannels through all skin types is fully controlled by a unique feedback mechanism, offering precise and reproducible drug delivery

· The size and density of RF-MicroChannels enable delivery of relatively high doses of drugs, which could not previously be delivered transdermally.

· RF-MicroChannels can be used to deliver a wide variety of molecules through the skin. Other active technologies impose limitations as to molecule size, formulation or dose.

· RF-MicroChannels formed in the skin remain open for a relatively long time, up to and exceeding 24 hours. This enables sustained-release drug delivery to maintain constant drug blood levels and improved compliance

THE VIADERM DELIVERY SYSTEM BY TRANSPHARMA:²²

At TransPharma Medical, we have developed a system (ViaDerm^TM) consisting of a device used to pretreat the skin and form the RF MicroChannels in the outer layers, and a patch containing the drug, which is placed on top of the pretreated skin (see Figure 7). The device consists of a handheld electronic control unit and a microelectrode array. The control unit (see Figure 7a) is battery-operated, rechargeable and reusable for at least array 1,000 applications. This particular device is available in three sizes (treatment area of 1, 2.5 or 5cm2), depending on the desired dose of drug to be delivered. The microelectrode (see Figure 7b) contains hundreds of microelectrodes, is disposable and low-cost. 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 a matrix of RF Micro Channels, thereby preparing the treatment site for the patch containing the drug. After application of the patch (see Figure 7c) on the pretreated area, the drug passively diffuses from the patch through the RF MicroChannels into the inner layers of the skin and into the systemic circulation.

Design and Fabrication:

Figure-7 (a) The device (b) The microelectrode array (c) The patch

Figure-8 The handset system and the microelectrodes array

Figure-9 ViaDerm Device

The ViaDerm device is available in three sizes, depending on the desired dose of drug to be delivered. All three units are designed to enable easy application by the patient with minimal initial training

A ViaDerm System Working

1. 2.

3. 4.

Figure-10 ViaDerm system use

1. The 1 cm² microelectrode array is snapped onto the control unit.

2. The proprietary one-handed patch is then coupled with the control unit.

3. The ViaDerm assembly is then gently placed on the skin. Applying light pressure on the treatment site creates the RF-MicroChannels within one second. Upon completion, a green LED and beeping tone indicate that the RF MicroChannels have been successfully created.

4. After removing the ViaDerm from the treatment site, the patch is folded gently over the frame. At this time, the microelectrode array is disposed of using a quick release button which ejects the used array. The drug patch is now securely affixed to the treatment site, and the medication can now easily travel into the viable skin layers via the RF-MicroChannels that have been formed²³.

THE FUTURE

The market for transdermal devices has been estimated at U.S. $2 billion²⁴ and this figure represents 10% of the overall U.S. $28 billion drug delivery market. Such figures are surprising when we consider that the first transdermal patch was granted a license by the FDA in 1981, and only an additional 9 drugs have been approved since that time. This short list of “deliverables” highlights the physicochemical restrictions imposed on skin delivery. Transdermal drug delivery has experienced a healthy annual growth rate of 25%, which outpaces oral drug delivery (2%) and the inhalation market (20%). This figure certainly will rise in the future as novel devices emerge and the list of marketed transdermal drugs increases. The emergence of such devices will increase the use of the skin as a route of administration for the treatment of a variety of conditions.

However, subjective and objective analysis of these devices is required to make sure scientific, regulatory, and consumer needs are met. The devices in development are more costly and complicated compared with conventional transdermal patch therapies. As such they may contain electrical and mechanical components that could increase the potential safety risks to patients due to poor operator technique or device malfunction. Thus, for any of these novel drug delivery technologies to succeed and compete with those already on the market, their safety, efficacy, portability, user-friendliness, cost-effectiveness, and potential market have to be addressed.

APPLICATION OF DEVICES:

ViaDerm has been extensively tested in vitro for delivery across porcine skin and in vivo on pigs and Sprague-Dawley rats for delivery of testosterone, grainsetron hydrochloride, diclofenac sodium and plasmid DNA²³. the research consisted of either topical application of model drug or application of transdermal drug patch post ablation. Following in vivo testing, a number of human clinical studies have been reported for ViaDerm^TM TransPharma Medical (2008). A steady increase in plasma grainsetron levels for up to 12 h after patch administration followed by maintenance of a constant level till patch removal at 24 h was reported. Phase I human clinical trials were conducted for delivery of hPTH [1–34], a peptide fragment of human parathyroid hormone, as an anabolic treatment for osteoporosis. ViaDerm^TM system is currently in Phase I/II clinical trials for hGH delivery. A human clinical study has also been performed for delivery of insulin TransPharma Medical (2008).

Thermal ablation by PassPort^TM system device has also been tested for delivery of influenza antigens, tetanus antigen, erythropoietin. Also for Pain Management, Acute and Chronic Opioid analgesics for rapid control of pain (Hydromorphone HCl, Fentanyl citrate, and Apomorphine HCl), Diabetes, Type 1 and 2 (Insulin), Disease Prevention (vaccination)

Thermal Transdermal Drug Delivery systems approved for medical use:

RF energy	Via Derm^TM	Trans Pharma	Insulin, diclofenac, Testesterone
Thermal energy	PassPort Patch^TM	Altea Therpeutics	Insulin, Hydromorphone HCl, Fentanyl citrate, and Apomorphine (Clinical)

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18. Altea Therapeutics, 2008. Altea Therapeutics (Atlanta, GA) is manufacturer of PassPortTM thermal ablation system for transdermal drug delivery

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Received on 22.03.2010 Modified on 30.03.2010

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1004-1010