Drug Delivery Report

By David Harris
Cambridge  Consultants Ltd, Science  Park, Milton Road, Cambridge  CB4 0DW, UK

Introduction

The Dry Powder Inhaler (DPI) is becoming  increasingly important within the respiratory field. There are numerous reasons for this, including the ease of creating novel formulations  in powder  form, the need to deliver efficacious and consistent  doses to the patient,  and the opportunity to formulate  a new compound with a new device, which provides additional patent protection and increased value. The alternative route  of developing a Metered  Dose Inhaler (MDI) is fraught  with complications. In particular, the change  from CFC to HFA propellants
was more difficult than  many envisaged and required substantial  early investment  in an HFA propellant  filling plant. These factors and others have led many in the healthcare industry to investigate the opportunities provided by DPIs.

DPI Design

The greatest issue facing developers is that  a 'passive' DPI relies solely upon the patient's ability to inhale through the device in order to create  a respirable drug aerosol. As all of us are different in some way, the very nature  of a DPI raises important questions  such as, 'how much energy is available from the patient?'  and 'how does it vary between users?'
To answer these  questions,  Cambridge  Consultants modified a technique used to evaluate the airflow power response  of in-line centrifugal fan motors to measure  the power  of healthy human  lungs. Our goal was to gain an understanding into the nature  of the available energy, and the resulting implication upon optimal DPI design.
Sixteen healthy volunteers were invited to participate  in the study. They were asked to 'breathe  out gently, as far
as is comfortable',  then  inhale 'as quickly, hard and deeply as possible'. Each maximum exertion test was performed
in duplicate for various airflow resistances,  thus allowing a power/airflow  profile to be calculated.
An interesting  finding is that  many factors contribute to the overall performance of a passive DPI, which are often in conflict with one another. For example, it may be advantageous to have an extended inhalation event
duration,  yet this would limit the maximum airflow power available. Similarly, an inhaler with excellent perceived user
comfort may have insufficient airflow velocity to produce the required aerosol performance. The most important conclusion we reached  was that  a thorough understanding of the energy available in the target  therapeutic market is essential for the successful development of a passive DPI.
Consequently, we identified a number  of principles that provide guidance  for future DPI development:
•  Conduct  a representative study using volunteers from the target  therapeutic area;
•  Prioritise the performance characteristics  of the device; for example, absolute  aerosol performance, flow rate (or input power) independence, user comfort,  etc.;
•  Use these  as ranking criteria in conjunction  with the lung power  data to outline a technical operating window for the device;
•  Design aerosolisation  concepts  based upon the expected input power  available;
•  Evaluate performance across the measured range of input power,  to select the most promising concepts.

Results

Method

A miniature  version of the British Standard  'airwatts box' with a range of airflow resistances was used to measure the pressure / flow temporal  profiles of 16 healthy, adult volunteers.

Key Findings

A mean mouth  pressure of almost 8 kPa, resulting in a flow rate of 90 LPM (litres per minute), was achieved with a restriction equivalent to a 'medium' resistance inhaler,1 producing  approximately 12 airwatts of power  (Figure 2). However, an inhaler with a significantly lower resistance2 could run at almost 200 LPM, receiving 17 airwatts of power.  This lower resistance would also improve perceived user comfort,  although at the expense  of peak velocity (which is important to aerosolise the drug formulation within the inhaler) and consistency between users.

1  A 'medium' resistance inhaler requires a pressure drop of 4 kPa to draw a flow rate of
60 LPM through it. The resistance is therefore 0.105  ÷cm H2O / LPM.
2  An inhaler which requires a pressure drop of 0.6 kPa to draw 60 LPM through it would actually run at almost 200 LPM, at a pressure drop of just over 5 kPa - i.e. consuming
~17 airwatts.   This is a very low resistance inhaler, with R = 0.04 ÷cm H2O / LPM.

The detailed results from the study were presented as a poster at RDD in Florida in April 2006.
Should you wish to discuss the study in more detail please contact  the author  of this article at: David.Harris@CambridgeConsultants.com