Products based on the nasal delivery of low-molecular-weight compounds have been available for many years (for example oxytocin). Now, the nasal absorption of larger peptides is being investigated, so far with limited success. The nasal delivery of vaccines is, however, showing promise.

Similarly, inhalers of various types have of a long time been used to deliver drugs such as corticosteroids and beta2-agonists directly to the lungs. Now, though, researchers are testing a long list of drugs with a desi-rable systemic action as to their suitability for pulmonary administration.

The uptake of drugs delivered by the pulmonary route is rapid, and the absorption surface is huge. Sophisticated modern inhalation technologies are resulting in much higher lung deposition fractions (more than 50 percent of the inhaled dose) than those achieved in the past. These technologies often use an electronically regulated inhalation device (controlling the inhalation flow rate, inhaled volume and breathing interval) and produce only a narrow range of aerosol particle sizes (typically 2-5 microns) to optimize lung deposition.

Large molecules, such as the new generation of biotech-derived pharmaceutical proteins, tend to be rapidly degraded in the GI tract upon oral administration. In addition, these proteins are poorly absorbed from the GI lumen, because of their size and their poor membrane permeability. As a general rule, therefore, these proteins are administered parenterally, via a needle. Protein delivery via the pulmonary route is, though, a very active area of current research. In animals, the bioavailability of inhaled proteins has been shown to depend on the nature of the protein, and interestingly molecular size is not necessarily a critical parameter. The protein that has drawn most interest so far is human insulin. The pulmonary route is seen as a convenient way for patients with diabetes to administer their insulin, and clinical trials of inhaled formulations are already well underway.

Protein delivery strategies

What can we do if repeated administration of a therapeutic protein is necessary over a long period of time, for example one month or more? Is there an alternative to the immediate-release systems using a needle? Two approaches are being developed. The first is based on needle-free injection, in which micrometer-size drug-coated carrier particles are accelerated to high velocity within a brief burst of helium gas, and delivered into the skin. There, the compound is released into the surrounding tissue in the desired release pattern.

The second approach is to use biodegradable microspheres loaded with the biotech product, that slowly release their contents. Microspheres relating LHRH antagonist over three to six months have been available for a number of years, as have microsphere products containing the somatostatin analog ocreotide. But only very recently has the first commercial microsphere product for release over one month of a high-molecular-weight protein (human growth hormone) been launched. Various different microsphere technologies, some for example based on dextran hydrogels, are cur-rently in development.

Looking further ahead

Where will the scientific finding and technological strides discussed above take us? The increasing importance of effective drug delivery systems is shown by market size predictions. The proportion of US pharmaceutical sales accoun-ted for by ''drug delivery products'' (a definition that incorporates oral sustained/ controlled release systems, transdermal and pulmonary systems, implants and microspheres) is estimated to reach 20 percent by 2005, up from only 12 percent in 1996. This increase is being driven by the competitive advantages offered by drug delivery technologies - in particular the ability to extend pro-duct lines and product lifetimes, and prolong patent protection.

How will we be delivering drugs to our patients 10 years from now? It is likely that the relatively cheap and patient-friendly tablet will persist as the main dosage form for standard, ''mainstream'' pharmacotherapeutics. But we will have a wealth of alternative routes of administration and more sophisticated delivery strategies to hand.

As well as the advanced methods of transdermal, nasal and pulmonary administration, and new parenteral systems for controlled and targeted delivery of drugs, discussed above, we could be using self-regulating release (biofeedback) systems within the next decade. These involve encapsulating secretary cells in a semi-permeable membrane that is implanted into the host tissue. Insulin is again one of the first subjects for study - islets of Langerhans are being encapsulated and the resulting system put into direct contact with body fluids, such as in the peritoneal cavity. The semi-permeable membrane has a molecular weight ''cut-off'' point, stopping large molecules such as antibodies and immunolo-gically active cells from passing through. Endogenous glucose and other low-mole-cular-weight endogenous molecules do, however, have free access to the encapsulated cells, which will release insulin at a rate dependent on the glucose concentration. This is a highly promising method of delivery, but much work still has to be done to ensure it is safe and reliable.

The expected proliferation of modern biotech-derived drugs, based on high-molecular-weight proteins and DNA, will require highly effective drug delivery systems. Many biotech products will need special transport systems, not only for entering the body and finding the target tissue, but also for entering target cells and being transported to the proper target site (intracellular trafficking). It seems likely that drug deli-very issues will soon be considered at an even earlier stage of the drug development process than at present.

(Concluded)

About the authors:

The authors are scientific director and business development director, respectively, of OctoPlus, a company in Leiden, the Netherlands

- Pathways, The Novartis Journal