Breath test

Asthmatics and those with other pulmonary disorders could soon benefit from a new generation of inhalers that instead of using a liquid aerosol spray, deliver the active ingredients as a fine powder.

A new version of the dry powder inhaler concept, developed by Italian pharmaceutical company Chiesi Farmaceutici and UK design firm Cambridge Consultants, has made its debut at a major pharmaceuticals conference in the US.

Dry powder inhalers (DPIs) were first developed during the 1990s, partly due to the need to replace conventional aerosol inhalers because of the phase-out of ozone-depleting propellants. However, they have other advantages — they tend to be easier to use than aerosol inhalers, because the dose is triggered by the patient breathing in rather than having to co-ordinate taking a deep breath with pressing down the aerosol canister.

There are several types of inhaler, some of which store individual doses of medicine, others keeping a 'reservoir' of the drug formulation which is measured out inside the device. The Chiesi/ Cambridge Consultants' NEXT DPI is a bulk reservoir inhaler, storing up to 120 doses of its respiratory agent, which is intended to be used to treat asthma and chronic obstructive pulmonary disease (COPD), ranked as the fourth largest cause of death worldwide by the World Health Organisation. The two companies presented it to the Respiratory Drug Delivery Conference in Florida last month.

'The inhaler's design incorporates two major improvements,' explained David Ellis, commercial director of Cambridge Consultants' healthcare business. 'It has a very simple mode of operation, with only three steps — open, inhale, and close — and incorporates an automatic dose counter, so the patient always knows how much of the drug is left. And it is very effective at getting the active ingredient into the lungs.'

The design of the inhaler went back to first principles. Ellis's team had several problems to solve, including how to ensure that the powdered drug formulation was measured out into accurate doses every time the inhaler was used, and how to protect the drug formulation from moisture.

The inhaler also had to be easy to use, to ensure that patients didn't skip doses and received the full benefit from the drug with every dose.

The team decided that both dosage and counter should both be breath-actuated, as 'this would give the user greater confidence in the device and reassurance about how many doses were remaining.'

The device harnesses the force of gravity, working like a miniature version of a bulk powder silo. The drug is stored in a reservoir chamber whose floor falls away in an angled ramp, down which the powdered medicine falls into a shallow cup-shaped dosing chamber.

The cup sits on a shuttle section, connected to the cover of the inhaler. When the patient opens the cover to take a dose of the drug, the shuttle pulls the dose into the base of a cylindrical cyclone chamber. As the cup is pulled out from the base of the reservoir, it passes a chamfered edge. 'This shaves the top of the powder in the cup, making sure that it's full and the same amount of the formulation is in the cup every time it's used,' explained Ellis. 'Dose repeatability is very important for devices like this.'

Once in position, the powder is pulled by the partial vacuum created by the patient's breath into a 'swirl chamber', or cyclone, which deaggregates it into the fine particles needed for optimum absorption inside the lungs.

'The active ingredient is mixed with lactose powder in the formulation,' Ellis said. 'What the cyclone does is separate the drug from the lactose, which ensures there are no larger particles in the airstream, and makes sure that the largest fraction possible of the formulation is in the form of fine particles, because that's what you need for inhalation into the deep lung, where these drugs work.' The fine powder fraction of the NEXT inhaler is around 60 per cent, said Ellis, compared with 20-50 percent for the majority of DPIs on the market.

Design of all the parts of the inhaler required a high degree of modelling, said Ellis. The team used statistical methods to determine the best shape for the reservoir, tweaking attributes such as the aspect ratio of the width to the breadth of the chamber; the slope of the ramp; the radius of any curves in the shape; and the position in which the device would be used before arriving at the short, squat shape of the final inhaler. This ensured both the best metering of the drug into the dosing cup and the easiest shape for people to use.

For the desiccant, other factors came into play. Moisture control is vital when handling bulk powders at any scale, said Ellis. 'we've got a design where a powder falls down a slope into a cup, and you need a free-flowing powder. Chiesi has high-performance formulation technologies, which plays a major part in ensuring the powder's properties, and we developed the device in parallel with Chiesi developing the formulation. But we knew that if the moisture in the reservoir built up, it would reduce powder flowability, and could damage the effectiveness of the active ingredient.'

The membrane separating drug from desiccant controls the rate at which the desiccant material absorbs water from the desiccant. The design process involved calculating the relative humidities of both drug and desiccant chambers over the lifetime of the desiccant, and optimising both desiccant and membrane to ensure that the conditions in the reservoir chamber would be correct for the range of drugs Chiesi specified.

The shape and size of the cyclone chamber required computational fluid dynamics to model, as it needed to ensure that there were no points inside the chamber where deaggregated powder could build up. The team modelled chambers with diameters varying from 6-10mm, and with different shapes, finally choosing an 8mm diameter design with the central chamber bracketed by two offset arcs.

'The offset eliminated any dead spots that could have attracted deposition and affected drug delivery within the airflow,' explained Ellis. It's this geometry that sets up the spinning motion of the powder which separates active ingredient from lactose, and fine particles from larger ones.

The final part of the mechanism, the breath actuator, ensures that the drug is always delivered over the same pressure drop of 1.5kPa. 'There's a sprung flap protecting the drug,' said technical programme manager Simon Smith.

'When the breath pressure reaches the right level, the flap releases. As it only happens at a certain pressure, the powder is entrained into the airflow straight away, which is a very efficient way of ensuring the dose is delivered.' As the protective cover pulls away, it also primes the dose counter. After inhaling, the patient closes the inhaler cover, which advances the counter and resets the breath actuation mechanism.

'The counter can only move on if it's been primed by the protective cover,' said Smith. 'This means that the counter registers the number of times the inhaler has been used successfully.'

The device has been tested in focus groups and as part of a clinical trial, which tested how the drug is absorbed by the body.

'The design team is delighted with the results,' said Ellis. 'This device should have a positive impact on the lives of millions of asthma and COPD sufferers.'