Medical Device Link.

DESIGN

Optimum requirements

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To ensure optimum efficiency of therapy, chronotherapeutic drug delivery should occur with the correct amount of the required drug, delivered at any point in time and at the correct target.¹ These are the basic requirements for this type of drug delivery system. They can be fulfilled by using noninteractive, mobile and “technical” drug delivery devices (complete administration systems in addition to the drug) that have permanent access to the vascular system.² This type of system must be a wearable device and therefore size and comfort must be taken into consideration. A disposable or a refillable drug reservoir, including a suitable procedure for refilling, must be integrated within the device. The usability of the system must be addressed carefully because in an optimum solution the user should be able to use the device on its own, without any additional connections or mechanisms.

Pathways to the vascular system

For time dependent drug delivery, a fast and reliable pathway to the vascular system is the essential issue when developing novel, effective therapeutics for drug delivery on demand, or responsive drug delivery.³ Thus, a reliable interface with the human body is required, which can be utilised on demand.

In general, there are two ways to deliver drugs into the vascular system. The first is a direct approach using injection needles or catheters for fluid delivery into the blood vessel. This pathway is well known and is the fastest way for a drug to enter the vascular system of the human body. It is capable of meeting the demands of a chronotherapeutic drug delivery system. However, this method requires a mechanical connection between the vascular system and the device, which implies a significant risk of infection, especially in mobile applications. Furthermore, this method of drug administration often has to be performed by qualified personnel.

A second approach is to overcome different barriers of the human body by using drug molecules that are able to transit a selected barrier by diffusion or by additional chemical or technical assistance. The most common self-administrable pathway is the gastrointestinal tract where drugs can be absorbed within the stomach, the small intestine or the colon. Unfortunately, the transit time through the gastrointestinal tract depends on multiple factors such as activity or food consumption and it is, therefore, rarely reproducible in a single individual. The need to control the location of drug release within the gastrointestinal tract has led to the development of so-called smart pills. However, the position of the pill as a function of time still depends on the transit through the gastrointestinal tract. This approach, therefore, does not sufficiently meet the requirements of a chronotherapeutic drug delivery. Other pathways such as oral, anal, nasal and vaginal delivery address different mucous membranes and are suitable interfaces to the vascular system. All of them are available at anytime for drug delivery and fulfil the basic requirements for chronotherapy.

Transdermal drug administration

Transdermal delivery systems allow drug delivery from an extracorporeal device without using intravenous pathways and offer possibilities for self-administrated drug delivery. The skin is essentially a multilayer configuration with an outer protective layer, the stratum corneum, followed by the epidermis, basal membrane, dermis and fatty tissue. The drug has to be transported to the dermis, where the subpapillary network is located and drugs can diffuse into the vascular system and apply therapy. There are a number of ways in which the main barrier, the stratum corneum, can be penetrated to deliver the therapy, as follows.^4,5

• A variety of drugs are capable of penetrating through the stratum corneum.
• Current research is focusing on so-called penetration enhancers such as molecules attached to the drug, which open up the transdermal pathway.
• Electric fields can be used to support the transport of ionic drugs into the epidermis, a process known as iontophoresis.
• Hollow microneedle arrays penetrating the upper layer of the skin (epidermis and basal membrane if necessary) can access the subpapillary network with liquid drugs in a pain free manner. In contrast to enhancer technology and iontophoresis, the use of this microinvasive method is independent of the properties of the drug, thus obviating the need for an additional modification of the drug molecule. This is, therefore, considered to be a universal and suitable interface for chronotherapeutic drug delivery systems.

Novel drug delivery device

Figure 1: Replicated microneedle array for penetration of the stratum corneum made from polycarbonate.

A transdermal, time dependent drug delivery device is currently under development in which all the required components are located within a patch like configuration. With this device a defined volume of liquid drug will be delivered at a predefined time to the vascular system. For example, a patch for hypertension or rheumatism treatment can be attached in the evening and will deliver the drugs in the early morning when the therapeutic effect is highly efficient. The device consists of a transdermal interface, a drug reservoir, a time delay unit (patent pending) and a passive pumping mechanism. Because there will be no electrical powered component within the device, it can be considered to be “smart” packaging of a drug. It is expected to be low cost, completely made of plastic and suitable for single use.

Figure 2: Replicated single hollow microneedle for transdermal drug delivery made from polycarbonate.

Current work is focused on producing hollow plastic microneedle arrays made by injection moulding or hot embossing. Replications of sharp microneedle arrays have been produced without channels (Figure 1); and hollow needle structures (Figure 2) ranging from 400 µm down to 100 µm outer diameter and inner diameter down to 50 µm, fabricated with a customised hot embossing process in polycarbonate and medical grade polyetherimide. The manufacturing process is suitable for rapid prototyping different needle shapes, sizes and array densities. Transfer to a mass producible process and integration into the patch like system is being investigated. Furthermore, the technology is suitable for other applications such as microinfusion or cosmetic applications.

Work on designing the fluidic system requires far more knowledge of the mechanical and fluidic behaviour of the interface. Thus, an infrastructure to evaluate basic fluidic and mechanical properties of different microneedle arrays has been designed. A universal, spring powered applicator station has been set up to study the insertion behaviour of the microneedle arrays. This procedure is suitable for transfer into a simple, manual applicator system that will be used to attach the patch to the skin. With this system, an adequate and reproducible application procedure for various microneedles can be developed by modifying insertion speed and force and recording the penetration depth. To study the flow characteristics of the interface, a fluidic evaluation kit has been designed, which consists of a fluidic switchboard and sensors for pressure and flow. It enables a convenient reconfiguration of the microinfusion experiments to focus on the study of the pressure–flow relationship. Furthermore, the evaluation kit is suitable for testing new candidates for transdermal delivery within the drug development process.

It is hoped that this drug delivery device will make chronotherapeutic transdermal drug delivery reliable and available and increase the efficiency of the therapy accompanied by a reduction of adverse effects.