Medical Device Link.

DESIGN

The project

An international project consortium of 15 companies and institutions with pharmaceutical, clinical and technological backgrounds is focused on two major innovations in the field of portable drug delivery systems. One is investigating a new drug delivery route through the buccal mucosa. The second is the technological realisation of an integrated device that comprises a drug reservoir, sensors, pressure pump, microvalve and control electronics, all contained in a housing that takes the volume of two molar teeth. The main target application of the development is the treatment of drug addiction with naltrexone and of chronic diseases. The project is supported by a European grant under the Sixth Framework Programme (IST FP6 Contract No 002243). Details of the consortium can be found on the project’s website: www.intellidrug.org

Buccal drug delivery

Poor absorption or even destruction in the gastrointestinal tract or when entering the liver means many drugs show poor efficacy. A typical example is naltrexone, a drug used to treat drug and alcohol addictions. Only 5–40% of an orally administered dose reaches the systemic circulation. Poor adherence of dosage regimes by users is another reason for limited therapeutic effect and in this case a return to drug abuse. Established implantable drug delivery systems apply drugs subcutaneously to the adipose tissue, the vascular system or via catheter directly to the spinal cord. These delivery methods entail significant cost and risk.

Figure 1: Illustration of drug delivery from a tooth-like appliance to the buccal tissue as new route of drug delivery.

Aiming at an increased bioavailability of the delivered drug and automation of drug administration to reduce patient compliance problems, the target of the research is the development of an advanced drug delivery system that will deliver drugs via new pathways into the body. The IntelliDrug system allows the administration of drugs in a precise and programmable manner without the need for surgery by delivering directly to the buccal mucosa (Figure 1).

Based on results of in vitro experiments at the University of Palermo, Italy, HSG-IMIT in cooperation with Assuta Medical Center, performed a series of in vivo experiments on the penetration of naltrexone HCl through the buccal mucosa of pigs, which is similar to that of humans. Figure 2 shows the measured blood plasma levels over a period of six hours following 10 minutes of transbuccal administration of 10 mg naltrexone compared with intravenous delivery.

Figure 2: Measured blood plasma levels of naltrexone over a period of 6 hours for transbuccal administration compared with intravenous delivery. (click image to enlarge)

Transmucosal delivery is much better suited to maintaining constant levels of naltrexone within the therapeutic window than intravenous administration. The results of these experiments have encouraged in vivo experiments in humans with appropriate drug doses. These take place with the actual integrated drug delivery device in April 2007.

Technological challenges

The main benefit conferred by this delivery system is that the device can be inserted into the mouth and be refilled and exchanged without surgery. The device must be small enough to fit the space requirement while maintaining its level of integration, which poses several technological challenges. To achieve reasonable times of usage before replacement or maintenance is needed, the device must not require more energy during the period of two weeks than can be stored in two button cells.

Figure 3: Exploded view of the system setup. From the left to right: outlet cover, housing including drug reservoir and electronics, and front side cover on the buccal side of the device.

Other challenges are the harsh environment with regard to chemical resistance, mechanical loads up to 250 N and temperature changes in the range of 0–60°C.

Technological realisation

The system concept is depicted in Figure 3. The housing, including an electronic compartment and a drug reservoir, is closed by a front side cover that contains the semipermeable osmotic membrane that allows water from the saliva to enter the drug reservoir, dissolve the drug pill and thus build up the working pressure of the device. A printed circuit board (developed by Valtronic, Les Charbonnières, Switzerland) equipped with control electronics and batteries (Fraunhofer IBMT, St. Ingbert, Germany) is partly inserted into, and partly attached to, the housing of the device. The regulation unit includes a microvalve, a flow sensor and a fill-level sensor for built in redundancy for the detection of drug delivery. A fluidic resistance and electrodes that also support the drug administration to the buccal tissue by means of iontophoresis are implemented in the outlet cover. Iontophoresis may be required to enhance the tissue penetration of certain drugs because of physicochemical restrictions inherent in the mucosal barrier.

Figure 4: The prototype. On the left: from the lingual side. On the right: from the bottom side.

The device is reversibly fixed on the jaw and can easily be replaced. The system is able to operate for 1–2 weeks before it has to be opened for refilling, cleaning and exchanging the batteries. Figure 4 shows a prototype of the device from the lingual side. When removing the lingual cover, the drug pill and the batteries are accessible for exchange. The housing into which the individual system components are integrated is fabricated from biocompatible stainless steel (Sandvik Bioline 316LVM, Neuss, Germany) by wire discharge erosion.

Jörg Kohnle (Technological part) is Head of the Microdosage Systems Group at HSG-IMIT, Wilhelm Schickard Strasse 10, D-780252 Villingen Schwenningen, Germany, tel. +49 7721 943 263, e-mail: joerg.kohnle@hsg-imit.de, www.hsg-imit.de

Dr Andy Wolff (Project management) is Senior Researcher, Assuta Medical Centers, Tel Aviv, Israel, contact: Saliwell Ltd., Harutzim, 60917, Israel, tel. +972 9 746 1630, e-mail: awolff@zahav.net.il