Changing Healthcare Worldwide

IN VITRO DATA CONFIRMS DELIVERY OF MORPHINE

Release issued 12/20/2000

TransDermal Technologies, Inc. announced today the release of pre-clinical in vitro data which the company believes is supportive of its claims for its patent-pending, patchless transdermal delivery system, TDS(tm), in the delivery of Morphine Sulphate.

The study, conducted by a pharmaceutical company and employing a Franz DIffusion Cell, measured how much of a barrier dead skin presents to the ability of the TDS technology to deliver Morphine HCL.

In their introduction, the investigators noted that many previous attempts to transdermally deliver sufficient amounts of morphine to accomplish therapeutic outcomes had been completely unsuccessful, so the TDS, if proven able to do so, would represent a significant breakthrough. The study investigators also noted that the permeation flux, i.e. the amount of Morphine Sulphate transmigrating the skin barrier over time, was markedly enhanced with the TDS as compared with a control of Morphine Sulphate in water and the TDS also performed better than data developed from attempts to deliver Morphine with a patch.

The study investigators concluded that, although the flux of TDS Morphine across the dead skin barrier of the Franz Cell was significant and much higher than expected, the permeability of the skin is assumed to be a fixed given and further, is the limiting factor in the transdermal flux of drugs across the skin. Since the TDS Lag Time before Morphine was detected in the receptor vessel was faster than passive transdermal delivery vehicles, the TDS, while interesting, seemingly offered no competitive or clinical advantage.

TransDermal Technologies spokesperson Kenneth Kirby comments that despite the researchers' conclusions, this data is, in fact, supportive of the Company's claims, particularly in light of subsequent In Vivo data developed at The Department of Experimental Pathology of the William Harvey Institute of St. Bartholomew's and the Royal London School of Medicine and Dentistry. This data demonstrated morphine and the morphine 3 glucoronide metabolite were detectable at one hour after delivery at high therapeutic levels.

The logic for the invalidity of the Franz Diffusion Cell as a valid and reliable model for measuring flux generated by the TDS is as follows: while the data on lag time for the passive soaking of the TDS Morphine through the dead skin barrier of the Franz Diffusion Cell apparatus was painstakingly arrived at, and most certainly accurate and most likely reproduceable, the assumptions held by the literature and quoted in the report which underlie its use are problematical. That the permeability of the skin is always the controlling factor limiting drug flux cannot be denied, however the assumption that the physical barrier characteristics of the skin are static and immutable and further that these are equivalent to permeability cannot be supported from the literature. For example, it has been long known that lowering the melting point of a drug by adding menthol will enhance flux In Vivo. A model which neither controls for nor attempts to mimic physiological parameters which are manipulated by the TDS to enhance flux cannot be a valid predictor of the success of a system like TDS which employs physiology to achieve its ends. Such a model can only be a valid predictor of of the efficacy of the primary solvents included in the system at overcoming the physical barrier of the skin and this present data indicates the TDS' ability so to do.

The Company claims that the TDS not only makes transient modifications to the inanimate physical barrier properties of the skin, (which alone are the targets of patch carrier solvents) but also and most significantly to the skin's several biochemical responses to the challenge of the drug and carrier converting them to actively transport the TDS and drug complex. This represents a new approach to drug delivery which is patent-pending.

Furthermore, the company has been able to identify why the receptor cell of the Franz model might have encountered difficulty detecting morphine ions before some time had elapsed and why the research did encounter differing rates of detection for the two forms of the TDS Morphine provided, namely a formula designed to deliver morphine systemically and anothe designed to keep perfusion localized. The science of Combinational chemistry and the computer-aided modelling which it has spawned has been advancing rapidly in the last few years although it is still relatively unused in pharmacology laboratories. Models of the TDS complex for morphine show that the morphine complexed with TDS when exposed to a bath of physiological water as is the case in the Franz Diffusion Cell, remains in its dimer form with the sulphate ion oriented along side with the carbons rather than adjacent to the nitrogen atom as is normally the case in the absence of the TDS and furthermore, the sulphate ion is not readily cleved off. This un-dissassociated form presents a much different charge surface profile than morphine sulphate alone or the morphine ion in physiological water and it would be expected that the remaining presence of the sulphate ion delays the emergence of the Franz-detectable ion form. The Morphine may have been present in the receptor vessel but not in the detectable ionic form. Eventually the cycling of water the apparatus would result in dissassociation of the sulphate and the morphine would become detectable. In the case of the two forms, the researchers reported that the systemic formula was detectable much sooner than the localized form as the company had predicted. The company attributes this to the fact that the systemic form is less tightly complexed, being designed to more rapidly disassociate the sulphate ion and therefore rendering it more readily detectable by the Franz Cell apparatus. This theory was validated during the In Vivo trials when the localized from again proved harder to detect by HPLC than the systemic form.

Since the Franz Cell makes no provision for measuring the presence of the alternative charge surface interactions let alone metabolites which would point to other bio-active forms being available in the cell at earlier time points, the company believes that any conclusion of lack of commercial or clinical viability is premature if based on Franz Cell Diffusion Cell data alone.

The Company is grateful for this painstaking preliminary work done for it by experts at the company and are gratified that the subsequent In Vivo work referenced above better reflects the system's ability to create rapid flux of Morphine Sulphate supporting the Company's interpretation of this data. Other studies completed in 1998 and earlier this year in the U.S. and Britain have established the system's ability to enable flux of therapeutic, bioavailable doses of other large and difficult-todeliver drugs and the Company is expectant that the full scale studies will also support TDS Morphine as a viable development opportunity.

Morphine, while the most effective drug for management of chronic high-level pain, has been virtually impossible to deliver other than by IV infusion, suppository or by oral, sustained release form. Once validated in human clinical trials, other benefits may emerge for the delivery of Morphine by TDS.

TransDermal Technologies is actively seeking a licensing partner interested in exploiting this technology.

TransDermal Technologies' TDS is a platform system that is designed to be modified for each application and is believed to enable the rapid, safe and effective delivery of many medicaments across intact skin by means of its sprayed-on lotions. The Company is also currently testing Ibuprofen in In Vivo pre-clinical trials at The William Harvey Institute in London.

Company Contact: Kenneth B. Kirby - K.Kirby@transdermaltechnologies.com / 800-282-5511 / 561-848-9100