The Pharmaceutical Journal Vol 267 No 7168 p470-481
6 October 2001

BPC 2001 summary

How optimising particle size can lead to more effective inhaled drug therapy

Research into optimising particle size could lead to practical and convenient methods of delivering inhaled drugs, Dr Igor Gonda, chief scientific officer, Aradigm Corporation, California, told the Conference.

Giving the 2001 AstraZeneca Industrial Achievement Award lecture, Dr Gonda said that he had initially been interested in the effect of particle size on the distribution of inhaled medicines throughout the lung.

Particles with a large diameter tended to be deposited higher up in the respiratory tract than small ones. He had found that the humidity of the environment in the lung and the tonicity of the particles also affected diameter. High humidity increased particle size and, consequently, less drug was distributed in the lungs — in some cases, five-fold less. In healthy patients, the diameter of droplets in a hypotonic aerosol solution tended to shrink as they travelled through the lungs, whereas hypertonic droplets grew. Thus, hypotonic solutions were more likely to be distributed into the alveoli — hypertonic solutions were deposited in the upper respiratory tract and were swallowed. In addition, in patients with respiratory disease, hypertonic solutions caused bronchoconstriction and drug delivery was low.

Dr Gonda then moved on to discuss his work on targeting DNA therapy to specific sites in the lungs of people with cystic fibrosis. Initially, this had been done by delivering a precise dose of DNA to a given area of the respiratory tract using a bronchoscope. This method had been safe, there was no replication of the adenovirus that was used to deliver the DNA and no antibodies to the adenovirus developed. However, the genes delivered had stopped being expressed with repeated dosing, so they had limited efficacy.

His first breakthrough to be licensed was dornase alfa (Pulmozyme) in 1993. However, it was a nebulised therapy, which was inconvenient for patients, so compliance was low, and he was now involved in research into a dry powder formulation.

Dr Gonda said that one of the problems with developing inhaled formulations of drugs was that there was variability in the amount of drug deposition achieved per dose both in and between subjects. This did not matter with asthma drugs that had a wide therapeutic index but was more important with drugs, such as insulin, that required precise dosing. He demonstrated a possible delivery system for inhaled drugs — the AERx. Use of radioactively labelled drugs had shown that the AERx gave better drug delivery to the lungs than standard inhalers because the particles were smaller and were distributed more evenly throughout the lungs.

The AERx had been used to deliver DNAase to patients with cystic fibrosis and had produced results similar to those achieved with nebulised formulations. It was more convenient than a nebuliser, because it was hand-held, and had a similar side effect profile. The AERx had also been used to administer insulin to people with diabetes and seemed to provide tight control of the disease. It could allow earlier conversion of patients with type II diabetes to insulin, could replace mealtime injections and could improve compliance. When used to deliver insulin, the AERx had to be administered using controlled breathing. Inhaling insulin using shallow breaths gave a blood level similar to that achieved with subcutaneous insulin. Deep breaths gave a sharper, higher peak level that was useful for mealtime dosing.

The AERx had also been tested as a device for administering fentanyl to patients with cancer requiring pain relief. Of those tested, half had rated the pain relief achieved as excellent, 35 per cent as very good and 10 per cent as good. Fentanyl given this way had a rapid onset of action and could be useful for breakthrough pain.

Dr Gonda concluded by saying that he was now working on developing smaller, cheaper models of the AERx.

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