Medical Device Link.

DESIGN

Market drivers

Most of the market and technology drivers in the drug delivery industry remain the same as they were two years ago. Pharmaceutical companies are facing the dual challenges of cheap generic drugs entering the market as patents expire and the failure of the drug development pipeline to deliver new “blockbuster drugs.” In addition, drug counterfeiting is a growing problem, but one that can be combated using micro- and nanotechnology to create sophisticated delivery devices or nanoparticle labelling in the drug formulation process.²

Pills and liquid formulations are still the preferred drug delivery method because the formulation and administration of the drug can be easier than for other delivery methods. However, there are certain situations where a more sophisticated delivery system is needed. One example is where newer drugs are large molecules that are poorly absorbed by the gut wall or suffer substantial degradation by digestive enzymes. In addition, a limitation of oral delivery is that the dosage is systemic rather than directed to a particular organ and the drug concentration is only at the optimal level in the body for a limited time (Figure 1). Some form of controlled release method is therefore required to keep the drug dosage at the optimal level.

Figure 1. (click to enlarge) Variation of drug concen-tration over time.

Although it is typically the doctor who decides on the most appropriate therapeutic solution, patient preferences also play an important role. This will affect compliance with the intended optimal dosage. For a drug that has to be administered many times per day, missed doses are likely, which reduces its effectiveness. Poor compliance can also be the result of forgetfulness, or an unpleasant or painful administration procedure or one that cannot be performed discreetly such as needle injection.

These factors ensure that there is continuing pressure to develop new delivery mechanisms that are easy to use, maintain the optimum therapeutic level and target the drug directly at the location of the area of the body requiring treatment.

Transdermal drug delivery

Transdermal delivery methods that use gels, creams or patches are easy to apply and are rapidly growing in popularity. The challenge is how to deliver large proteins through the skin. Many techniques have been tried such as the application of electric fields, ultrasonic energy, laser energy and mechanical pressure from a gas jet, of which, only gas jet seems to have delivered adequate results in a cost-effective manner. Chemical penetration enhancers are the most common way to improve the transport of drugs through the skin, although these may cause irritation. Acrux (www.acrux.com.au) and 3M (www.3m.com/dds) are two of the leading developers of patch systems in a market that has now reached US$1.4 billion.

The list of requirements that new technologies have to meet includes low risk of skin irritation, attractive cosmetic appearance, dosage flexibility, ease of manufacture in a cost-sensitive market and suitability for a range of applications. Competing with adhesive patch technology are the newer techniques of gels and liquid or aerosol sprays that form a nonocclusive reservoir of drug and enhancer with the skin: the so-called Patchless Patch delivery method. However, it should be recognised that formulation for transdermal delivery is sometimes problematical, because of the need for the drug to be compatible with the gel, adhesive or chemical penetration enhancer.

Figure 2. Gel patch.

All of these techniques have the benefit of ease of application and reduced pain and discomfort compared with needle-based injections. In addition, multilayer drug-in-adhesive systems can achieve controlled release rates over prolonged periods. Some patch systems have drug reservoirs and a rate-controlling membrane that can suit the delivery of drug compounds with high molecular weight and lower permeability through the skin. Patches can provide constant drug levels in the body (within 610%) over periods in excess of 24 hours. The only other technology that can get close to this performance is an intravascular drip, but this restricts patient mobility and is not suitable for self-administration in the way that patches are. Figure 2 shows a modern
patch system developed by 3M Drug Delivery Systems (www.3M.com/DDS).

The range of conditions that can be treated with patches now includes

• hormone delivery
• prevention of osteoporosis
• analgesia prior to dermatological surgery
• Parkinson’s disease
• hypertension
• vitamin delivery and
• delivery of anti-inflammatory drugs.

Research and development

The level of patenting activity is an indication of how much research and development activity is taking place in this area.³ In 2004 more than 150 patent applications were published in the first half of the year compared with approximately 100 for the whole of 2003 and only 35 in 2002.
Some of the more novel techniques under development include the use of nozzles similar to those used in ink-jet printers.⁴ As yet, elaborate micromachined needles do not seem to have reached the market although the manufacturing technology has been transferred from the KTH research laboratory to the Silex production factory (www.silexmicrosystems.com) in Stockholm, Sweden, which will facilitate high-volume trials. 3M has a microneedle patch technology available for development with partners. This is a microstructured polymer using solid microneedles rather than hollow structures.

Needle-free injection systems

Liquid drug-delivery systems using needle-free jet injectors and automatic needle-based systems can be designed to work with existing drug formulations, which speeds up the development cycle and reduces development cost. The challenges that have been addressed by the systems now being introduced into the market include:

• overcoming a patient’s aversion to needles by being needle-free or at least hiding the needle from sight before, during and after injection
• eliminating the risk of infection from contact with used needles
• reducing the pain/discomfort level
• new formulations are being designed to gradually release the injected drug, thereby reducing the frequency of injections.

Figure 3. The pen needle-free injection system.

Both single-use disposable systems and refillable systems have been developed. In all cases, ease of use is an important design requirement in a market that is cost sensitive. Figure 3 shows a needle-free injector system that is powered by a spring system developed by The Medical House in Sheffield, UK (www.tmh-drugdelivery.com).

Other manufacturers have incorporated high-pressure gas reservoirs to act as the pumping mechanism. One of the main contributing technologies is precision microinjection moulding of the plastic components. Figure 4 shows a nozzle assembly that is fabricated to tight dimensional tolerances of the order of 10 µm.

Many of the advantages of needle-free systems can also be achieved with autoinjectors, which still use a needle to break through the skin, but keep the needle hidden and are simple to use. The liquid dose that can be delivered by needle-free systems is in the range of 0.02 to 0.50 mL, whereas the auto injector can deliver a much higher dose from 10 to 30 mL with ease.

Figure 4. Micromoulded injection nozzle.

Automatic mechanisms can deliver a consistent outcome because the volume of drug delivered, the depth of penetration and the rate of delivery can all be tightly controlled. This makes this delivery method suitable for use by children or older patients with limited manual dexterity. Auto retraction of the needle from the tissue back into the body of the unit helps with disposal and eliminates the risk of needle-stick injury.

Other technologies

This article has focussed on developments in patches and needle or needle-free injection systems. However, new technology is also proving important in both oral and inhaled drug delivery. Recent developments include micro-encapsulation of drugs in coatings that can mask unpleasant tastes for oral delivery or control the release rate as the drug passes through the gut. Dry-powder and liquid-delivery inhalers are now able to deliver an increasing range of drugs into the lungs. It is now accepted that insulin can be delivered into the blood via the lungs.

All in all, as can be expected in such a large market, there seems to be a niche for each of the different drug delivery technologies. However, it is clear that for many years to come, the proportion of drugs delivered by oral means will remain high because of the outstanding simplicity and ease of use of this method.

Dr J. Malcolm Wilkinson is Director of Technology for Industry Ltd, E-Space North, 181 Wisbech Road, Littleport, Ely CB6 1RA, UK, tel. +44 1353 865 400, e-mail: jmw@tfi-ltd.co.uk, www.tfi-ltd.co.uk.