Business Briefings – PharmaTech, June 2004

Transdermal Drug Delivery – A Growing Market

The development of biotechnology drugs based on macromolecules, particularly polypeptide drugs such as interferons and erythropoietin, are a key factor in the growth of the drug-delivery market. Approximately 40 macromolecule drugs are currently being marketed, generating estimated worldwide sales of $20 billion. It is estimated that 400 additional macromolecule drugs are in clinical development. These macromolecules are notoriously difficult to formulate and administer due to their large size, relative instability and short circulatory half life. Conventional oral administration is typically impossible, as these drugs break down quickly and are poorly absorbed into the bloodstream, which means that they must almost always be administered via injection.

Non-invasive delivery systems that can replace injections will be important for these products, particularly for drugs that require repeated or chronic dosing. TransPharma Medical Ltd. believes that its new and comprehensive transdermal drug-delivery system can meet this challenge.

TransPharma's Innovative Technological Breakthrough – RF MicroChannels

TransPharma is an emerging biomedical company, located in Israel, engaged in the development of unique transdermal drug-delivery systems designed to better deliver peptides, proteins, hormones, vaccines and other macromolecules currently delivered via sub-optimal administration routes.

Unlike any of the techniques for transdermal drug delivery on the market today, RF-MicroChannel Technology uses radio-frequency (RF) electrical current to create passages through the skin. This novel and unique approach provides the following advantages:

• The dimensions and density of the RF-MicroChannels created can be predicted and carefully controlled, depending on the requirements of the drug. This enables the required dosage of the drug to be controlled very precisely.



• The drug-delivery rate is determined by the size and number of RF-MicroChannels created. The diameter of a typical channel is less than 50 microns, which is wide enough for even the largest drug molecules. This means that a wide range of different sized molecules, both small and large, can be delivered with this method.



• The RF-MicroChannels remain open in the skin up to 24 hours or more. This prolonged channel recovery time provides high flux rates and constant drug blood-level profiles.



• The creation of hundreds of precisely controlled RF MicroChannels covering less than 1% of the treated skin causes minimal skin trauma and discomfort, and cuts long-term side effects to an absolute minimum.



• RF-MicroChannels are formed rapidly (within a second), adding to the user's comfort. The application is painless, providing an alternate administration route to injections, without the associated discomfort.



• Uniformity of RF-MicroChannels through all skin types is fully controlled by a unique feedback mechanism not offered by any other active technology.



• The ease and comfort in which the RF-MicroChannels can be created can greatly increase chronically ill patients' compliance by providing a low-cost, painless, home-use solution.

How RF-MicroChannels Work

RF-MicroChannels are created by placing a closely spaced array of tiny electrodes against the skin. An alternating current at a particular radio frequency is then transferred through each of the microelectrodes, which forms microscopic passages in the stratum corneum and outer epidermis via a process called cell ablation. As shown below, these microchannels penetrate only the outermost layer of skin, where there are no blood vessels or nerve endings, minimizing skin trauma and unpleasant sensations. The passages created can be used for either drug delivery or analyte extraction. The whole process is performed rapidly, taking approximately a second to complete.

The formation and control of RF-MicroChannels are based on the integration of well-known technologies with new innovations:

• Micro-ablation of the skin via RF: TransPharma has applied a proven RF Technology, commonly used in minimally invasive surgeries such as laparoscopy, to create RF MicroChannels in the skin. RF ablation is safe and painless, as it is typically performed at frequencies above 100 kHz that do not stimulate the muscles and nerves. The electrodes that transmit the RF energy are simple, low cost, and ideal for disposable use.



• Electrode feedback and control systems: RF-MicroChannel Technology integrates a built-in closed-loop feedback mechanism to control and normalize RF-MicroChannel depth, regardless of skin type. The feedback mechanism monitors and controls the RF current being applied, making it possible to determine exactly when the RF-MicroChannels have been formed. After RF MicroChannel formation has been confirmed, the process ceases automatically, thus avoiding any further penetration into deeper layers of the skin and preventing skin irritation and trauma.



• Proprietary microelectrode array design: One of the primary difficulties in penetrating the skin for drug delivery is the fact that the texture and softness of the skin itself changes from site to site and person to person. To address these variations, TransPharma has developed a proprietary microelectrode design that adapts to these variations both within and between treatment sites, and requires only minimal skin contact. This design is essential to formation of RF MicroChannels with consistent, well-controlled depths, enabling the drug to reach the subcutaneous capillary bed without unnecessary trauma to the inner skin layers.

A Comprehensive Drug-Delivery System

TransPharma has created a complete, non-invasive transdermal drug delivery system that integrates an innovative, user-friendly device based on RF MicroChannel Technology and a drug-carrying patch. This comprehensive, patent-protected platform consists of:

• The ViaDerm(RF-MicroChannel) Device: The ViaDerm is a light, battery operated, handheld, reusable device containing an extremely accurate, disposable proprietary microelectrode array that adapts to variations both within and between skin treatment sites, and requires only minimal skin contact. This easy-to-use device is painless, very low-cost and can be operated by almost anyone.



• Innovative New Patch Technologies and Formulations: For macromolecules, a new technology of specially formulated, highly stable dry form printed patches has been developed. The patch remains in its dry form until the time it is administered, improving stability and prolonging shelf life. This approach is significantly superior to existing patch technologies, and provides a revolutionary and complete solution to the challenge of transdermal delivery of proteins and other macromolecules.

Pre-clinical and Clinical Data

A large number of pre-clinical and clinical studies have been done to test the efficacy of TransPharma's RF MicroChannel Technology. The examples presented below show that this technique can be used with molecules of different sizes and physicochemical characteristics, and that the administration of drugs delivered via the RF MicroChannels created is comparable to or better than other non-transdermal methods.

Human Growth Hormone (hGH)

A number of studies were carried out with hGH, a large (22 kDa) protein macromolecule. In one of the studies, hypophysectomized rats were divided into four groups: two groups with transdermal delivery of hGH, either with or without treatment with ViaDerm, one group of subcutaneous injection and one control group (no treatment). TransPharma used its unique, stable printed patch for transdermal delivery of proteins, which complements its ViaDerm delivery technology.

To determine bioactivity, serum hGH and IGF-I levels were measured over 24 hours post application. ViaDerm-treated rats had significant hGH plasma levels, with the maximum level occurring approximately four hours after application. Elevation of hGH levels was followed by an increase in IGF-I, demonstrating that the hGH delivered was in an active state. The areas under the curve of the hGH and IGF-I in the transdermal delivery route were comparable to that of the SC injection, indicating that the bioactivity of hGH delivered with RF-MicroChannel Technology was just as high as that of hGH delivered subcutaneously.

The study also clearly showed that TransPharma's transdermal drug delivery technology is able to open channels through the stratum corneum large enough for even very large molecules to pass through. This greatly increases the range of drugs that can be administered using this technique.

A study comparing the efficacy of subcutaneous and transdermal hGH delivery with ViaDerm treatment was carried out on pigs. The results of this study suggest a relative bioavailability rate of 17% for the hGH patch group compared to the subcutaneous injection group.

hGH Blood Plasma Levels in Pigs

Granisetron-HCl

This human clinical study measured the sustained transdermal delivery of Granisetron (a charged, hydrophilic molecule) over a period of 24 hours, administered via a small patch (5.6 cm2) using the ViaDerm system. The patch contained the Granisetron in a gel formulation, prepared with no penetration enhancers, and was removed after 24 hours. This was then compared to other delivery methods, including passive transdermal (without the use of ViaDerm), oral (one tablet every 12 hours) and intravenous (IV). Granisetron is a particularly appropriate candidate for transdermal delivery, as the effectiveness of oral delivery of this antiemetic drug may be severely compromised by the very nausea it is intended to prevent.

The study also evaluated the tolerability of transdermal Granisetron delivery using ViaDerm, by examining any erythema and edema that arose during the trial. The study was conducted on six healthy adult volunteers in each test group.

Granisetron Blood Plasma Levels in Humans

The experimental results show the advantages of RF MicroChannel delivery of Granisetron:

• Granisetron was delivered at constant therapeutic levels over the entire experiment period, as shown by the line marked ViaDerm treated in the figure. This indicates the RF MicroChannels' ability to remain open and enabled for prolonged periods of time.



• The results revealed differences in the plasma drug levels and profiles between the treatments. The oral delivery displayed a peak and-valley profile corresponding to the administration regimen; the IV delivery had a sharp increase and then a gradual decline. In contrast, the ViaDerm delivery resulted in a concentration increase up to 12 hours, and then a constant level up to 24 hours. This extended and gradual profile is much more suitable for Granisetron delivery than other profiles, as it enables longer-term nausea control. The control group (marked ViaDerm Untreated in the figure) showed very low plasma levels across the entire time period.



• Test subjects reported no pain during or after the ViaDerm treatment; similarly, no irritation was detected while the Granisetron patch was applied or afterwards.

Testosterone

To determine the efficacy of its ViaDerm system in delivering a hydrophilic formulation of a hydrophobic molecule, TransPharma compared its own special testosterone patch formulation (without alcohol, which is associated with skin irritation), to a commercially available patch. Using pigs, the results from this study clearly indicate that TransPharma's system was able to deliver testosterone at a rate three times higher than that of an existing commercial patch.

Transdermal Delivery of Testosterone in Pigs

Potential Applications and Partnerships

TransPharma's unique approach to transdermal drug-delivery surpasses all others available today. RF MicroChannels, with its proven efficacy, suitability for an extremely large variety of drug molecules, well-known technology and low production costs, make them the ideal solution for pharmaceutical companies looking to find a viable and successful transdermal drug-delivery system. TransPharma's unique patches are compatible with its delivery system, and offer potential pharmaceutical partners a comprehensive solution for transdermal drug development.

TransPharma's comprehensive system can also be used for local, regional and topical applications, for example, enhancing penetration of anti-inflammatory agents, local anesthetics and analgesics, as well as for a much more efficient penetration of a number of topical drugs to their target sites in various layers of the skin.

With pre-clinical and clinical trials demonstrating high therapeutic drug delivery levels, excellent bioavailabity and clear advantages compared to existing delivery methods, TransPharma believes that its comprehensive RF MicroChannel device and patch system is likely to become the delivery device of choice for biotech drugs.

 

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