Intelligent inhalers for pulmonary delivery

The biotechnological revolution is leading to a growing range of drugs that are difficult to deliver other than by injection. Sarah Houlton talks to Profile Therapeutics about its Adaptive Aerosol Delivery system, which may simplify the delivery of such drugs through the lungs

In an ideal world, drugs would all be orally available. Tablets and capsules are easy to take, and give better dose regimen compliance than some of the alternatives. But many drugs are not orally available, notably most protein and peptide drugs that result from modern biotechnological research techniques, and these generally have to be administered by injection or infusion. A new system under development at Profile Therapeutics, based in Bognor Regis in the UK, may provide a solution to the problem of effective delivery of these drug products, by allowing their absorption through the lungs.

Profile's patented technology, the Adaptive Aerosol Delivery (AAD) intelligent inhalation system, is already in use for most currently-licensed nebuliser solutions. The principle is simple: the device monitors the patient's breathing pattern and then delivers the active at the right time in the breathing cycle for successful delivery to the lungs.

The precise moment in the breath a drug is delivered is crucial for effective delivery, as systemically-acting drugs have very different requirements to locally-acting bronchodilators. A traditional nebuliser, however, delivers a constant stream of drugs, so as much as 90% is wasted, escaping to the atmosphere rather than being absorbed by the lungs. Quite apart from the waste, this is potentially dangerous with toxic compounds, as they can be breathed in by others in the vicinity.

Breathing patterns differ from person to person. A healthy adult may have a peak inhalation flow of 35l/m, very different from the average figure seen for asthmatic patients of 54l/min. The range of flow rates mean a one-method-suits-all solution for inhaled therapies is difficult to achieve, and Profile's AAD technology is designed to overcome this.

coordinating breathing

The successful operation of a traditional MDI or DPI relies on the patient breathing correctly to suit the device. Young children and the elderly, in particular, can struggle to coordinate breathing with a delivery device, so inhaled treatments for asthma or chronic obstructive pulmonary disease (COPD) are not as effective as they should be. To an extent, this can be remedied by the use of spacer devices, where the drug is delivered from the aerosol into a holding chamber prior to inhalation, but the result is still far from ideal. Profile's HaloLite device is different, as it adapts the delivery of the drug to the breathing pattern of the patient.

The drug is introduced into the top of the HaloLite from a standard unit dose package. The patient then inserts the mouthpiece into their mouth, and breathes naturally. The device monitors breathing patterns for three breaths, and then generates an aerosol of the drug product using compressed air. This is released in pulses over the next few breaths, at precisely the right point during inspiration for optimal absorption, until the whole dose has been delivered. The HaloLite continues to monitor breathing throughout the delivery period, and the patient can even take a break, during which it simply waits for them.

concentrated formulation

The drug is delivered over maybe 10 to 50 or even 100 breaths, over a period of up to five minutes. The precise number of breaths will depend on the dose required and the strength of the formulation. If a sufficiently concentrated formulation is not possible, which is likely to be the case with products like proteins, then more breaths will be needed for efficient delivery. But even if it were possible to manufacture a sufficiently concentrated formulation to allow the whole dose to be taken in one breath, this would not be ideal as it puts too much pressure on the patient to get it right in one go.

'The patient can hear the pulses of drug being released,' explains Profile's chief technical officer John Denyer, 'and once the entire dose has been delivered, the device gives an audible signal that treatment is complete. This greatly aids patient compliance, as they can hear that the whole dose has been delivered. It is particularly useful for small children, who are likely to have their medicine administered by a parent.' Trials have shown that 90% of patients take their medication correctly using the device, with very high repeatability. This figure is significantly higher than for a traditional MDI or DPI where compliance is typically 50%. A recent long-term study in asthmatic children aged from 7 months to 7 years, using a very low dose of 25µg of the corticosteroid budesonide, showed compliance rates of 83.5%. It also gave an extremely good improvement in asthma scores (a measure of quality of life), twice the improvement seen with a traditional nebuliser.

adaptable system

The HaloLite is designed for use with steroids and bronchodilators, being programmed for two different types of drug with a button to press for each. Profile is now working on a new device, the AAD ProDose system, which is much more adaptable to different drug products. It has a 'disc', about an inch in diameter, with an integrated circuit and an aerial, which operates using a radiofrequency system. The disc is inserted into the device, which then reads the data programmed onto it. Operating by radiofrequency transmission means there no contact between disc and device is necessary, which makes it simpler to use: correct orientation is not essential, there is no barcode to scan, and accidentally getting dirt or liquid into the device does not break the contact. The disc can be used to collect compliance information for the doctor, or in conjunction with a modem and direct prescription systems for the automatic delivery of new supplies.

'The disc contains dose information and expiry dates, and would be packaged with supplies of the active,' explains Denyer. 'We may place the device with the patient for nothing, and charge royalty on the drugs. We provide the system and support, and half the calls we get are for advice rather than sales. Therapy is much more likely to be successful if it is properly supported.'

programming for patients

The flexibility of the AAD ProDose System means doctors can programme the device specifically for specific patients. It also has advantages for the manufacturers of the dosage vials. Currently, they have to produce a range of different dosage strengths and vial sizes, of which maybe only a couple have any great sales volume, but the others are necessary for some patients. With this system, fewer vial sizes are needed as variations in dose can be made with the device.

'The key aim is to make a device which is both easy to use and flexible,' says Denyer. Profile's intelligent inhalers use existing liquid formulations, meaning there is no need for costly reformulation into MDI or DPI form. For an MDI, these costs can easily run into the millions.

Another use for AAD technology is the creation of super-generic products that add benefits for patients, while delivering extended patentability and increased revenues to the drug company. PT Pharma, a division of Profile, is undertaking a number of clinical studies on generic compounds. Among these is a project with Forum Bioscience, which is investigating an inhaled antibiotic in cystic fibrosis patients, to be used principally as a prophylactic therapy against lung infections, notably Pseudomonas aeruginosa. Phase III trials were begun in late 1999, and initial data are expected to be available in the last quarter of this year. Profile hopes to be in a position to apply for UK marketing authorisation in the first half of next year.

A third device under development at Profile is an intelligent MDI/DPI system that uses AAD technology to improve effectiveness, notably in children. Some drugs cannot be formulated in a sufficiently concentrated liquid form, and so are limited to an MDI or DPI system. The basic AAD concept is the same, but the product is delivered in a different format. The aerosol is released into a spacer device, and then metered out into the child when the correct dose has been released. It is being developed in conjunction with the University of Leicester, with some funding from the NHS.

validation procedures

The company expects the AAD ProDose System to be available for initial clinical work early in 2002. It is now almost fully developed, and is being put through the validation procedures. Profile aims to work with drug development companies from the early stages of clinical trials, which will reduce the time-to-market for successful drugs. 'Phase I trials can establish where the dose should be targeted, and all that needs to be done before beginning Phase II trials is programming the disc,' says Denyer. 'If an MDI or DPI must be formulated, this is a very slow process.'