1. Loss of Dose Patient Simulation Dan Clarke 3M Drug Delivery Systems Loughborough Leicestershire LE11 1EP Testing was performed using two suspension formulations and the 3M Face Seal Valve. The aerosols were cold filled at laboratory scale. A HFA 134a, salbutamol sulphate and ethanol formulation and a challenging HFA 134a, salbutamol sulphate formulation were prepared and metered into cans. 3M Face Seal Valves were crimped on and the units were stored at 40°C/75% RH for a month. All analysis was performed by actuating into specialist Dose Collection Apparatus (DCA) at 28.3 L/min. “Ex-actuator” salbutamol sulphate was then recovered from the DCA using appropriate solvents and quantitatively determined using HPLC analysis. Through Life Uniformity of Delivered Dose UoDD testing was performed with dose weight measurements taken at the start, middle and end of the aerosol life. The units were first primed four times (to enable assessment against retention valve controls) and then shots # 5 to # 7 were collected in the DCA to be tested as Start of Life (SoL). Patient Compliance is a term used by healthcare professionals to indicate that a patient correctly follows the medical advice given them. It is estimated [1] that around 50% of asthma patients do not comply with their physician-prescribed regimens. There are a wide variety of reasons why patients do not comply, ranging from forgetfulness to improper education to a perceived lack of effect. Because of this it can be beneficial to design regimen assisting features into a new drug delivery device. This way patient compliance can be better assured by the nature of the device and is less reliant on the patient. FFFE valves provide a step towards improved patient compliance by making pMDI regimens easier. The 3M Face Seal Valve is a FFFE valve developed in response to industry research into the desirable attributes of a next generation valve. This valve differs from the standard dose retention valve by utilising a metering chamber that is open to the bulk formulation. In a dose retention valve, the metering chamber is filled through a narrow filling port. As the patient releases the valve after the expulsion of one dose, the next is immediately sampled from the bulk formulation. This can lead to a dose being stored in the metering chamber for some time, especially if the patient does not follow their daily regimen. Over time part of the stored dose can also seep back into the bulk formulation leading to problems known as Loss of Dose and Loss of Prime (LoP). This results in the patient needing to actuate a dose to “waste” if they are to get a proper dose when they next use their inhaler. As a FFFE valve samples a dose immediately before actuation these issues are not experienced. 3M Drug Delivery Systems Excellent data was obtained for both the formulations. A selection of the data is presented in this section. The Benefits of Fast Fill Fast Empty Valves to Patient Compliance John Moore, 3M Drug Delivery Systems, Upbrooks, Clitheroe, Lancs. BB7 1NX. UK. Georgina Fradley, Dave Hodson, Karen Hunt, David Greenleaf and Scott Parker 3M Drug Delivery Systems, Morley St, Loughborough, Leics. LE11 1EP. UK. [1] Cochrane MG, Bala MV, Downs KE, Mauskopf J, Ben-Joseph RH. Inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique. Chest 2000; 117: 542–550. [2] Fradley G., Hodson D. “Optimisation of Fluid Flow in pMDI Valves” In Dalby R.N, Byron P.R. Eds: Proc. Respiratory Drug Delivery 2008, Davis Healthcare International Publishing, River Grove IL, Pp 329-332. FFFE valves are a beneficial new technology that reduces issues commonly seen with the more traditional dose retention valves. Compared to dose retention valves, the patient doesn’t need to prime the valve or fire waste shots, even after a long period of inhaler inactivity, as shown by both Patient Simulation and LoD testing. FFFE valves thus increase patient compliance by reducing the dependence on firing regimens to ensure correct valve dosing. The 3M Face Seal Valve in particular shows low variation in dose delivery under both laboratory and patient representative test regimens, even with challenging suspension formulations. Consistent and reproducible valves potentially allow products to use single shot regimens. This will improve compliance by again presenting the patient with a simpler and quicker dosing procedure. Materials and Methods Conclusion Introduction Figure 2 – TLUoDD data with HFA 134a, salbutamol sulphate and ethanol formulation Figure 2 shows good TLUoDD with a HFA 134a, Salbutamol sulphate, and ethanol formulation. All individual values fall within ± 20% of the calculated mean. Figure 3 shows patient simulation with the challenging HFA 134a salbutamol sulphate formulation. During a patient style actuation regimen the 3M Face Seal Valve is shown to be robust and consistent. Figure 3 – Patient Simulation data with challenging HFA 134a, salbutamol sulphate formulation Figure 4 – 28 day LoD data with 134a, salbutamol sulphate and ethanol formulation Figure 4 shows data from five units. There was a time delay of 28 days between shots # 42 and # 43. The data clearly confirm that even when stored upright for such periods, the 3M Face Seal Valve experiences no depletion of dose. Results and Discussion Through Life Uniformity of Delivered Dose References Acknowledgements Actuations # 8 to # 54 were fired to waste, # 55 to # 58 were priming actuations and # 59 to # 62 were collected as Middle of Life (MoL). Similarly actuations # 63 to # 113 were fired to waste, # 114 to # 117 were priming actuations and # 118 to # 120 were collected as End of Life (EoL). Patient Simulation The formulations were tested according to a regimen used to replicate patient conditions. The pMDIs were primed four times prior to start of the study and then actuated in the morning and late afternoon. Every other day, morning and afternoon actuations were collected and analysed. Loss of Dose LoD testing was performed using a number of delay periods. 24 hours, 48 hours, 7 days, 14 days and 28 day periods were all tested. The units were primed four times prior to start of the study, then two individual 1-shot actuations were collected in the DCA and analysed. The units were then left for the specified period of time, and a further three individual 1-shot actuations were collected. Figure 1 – The 3M TM Face Seal Valve The philosophy behind this new technology was two-fold. The first factor was the drive from industry for improved Dose Content Uniformity (DCU)/Uniformity of Delivered Dose (UoDD). Currently, most products require a two shot regimen to ensure a full dose has reached the patient’s lungs. Single shot dosing would potentially offer significant benefits by simplifying the process. The second impetus is that pharmaceutical companies desire a valve that works more effectively in the patient’s hands, therefore giving better performance when used by a patient. One way of increasing patient compliance is to eliminate LoD/LoP, issues. A valve with superior UoDD/DCU and no LoD/LoP reduces the “patient effect” and consequently improves patient compliance. The 3M Face Seal Valve has been designed using the FFFE principle, with a design based upon consideration of Raleigh-Taylor instability theory [2]. The chosen dimensions ensure the free flow of formulation into the metering chamber with even the slowest inversion. This ensures that the metering chamber fills properly every time, giving increased dose consistency even with “difficult” suspension formulations.