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Download Paper Drug Delivery to the Lungs (DDL2017), 2017 – Myrna Dolovich Looking Back and Looking Ahead: Developments in Aerosol Medicine over the last 50 Years – Devices, Drug and Detection of Disease Myrna B Dolovich, B.Eng., P.Eng Faculty of Health Sciences, McMaster University/St Joseph`s Healthcare Hamilton, 50 Charlton Ave E, Hamilton, Ontario/ L8N 4A6, Canada Introduction Over the years, advances in technology, coupled with discovery in physiology, physics and pharmaceutics have been applied extensively to the delivery of aerosol therapy and respiratory medicine. Innovations in the design of all categories of aerosol drug delivery devices (ADDD) and also pharmaceutical formulations have resulted in highly efficient delivery systems as well as tailored aerosols. Dual and triple combination therapies are now widely prescribed in portable inhalers for patients with asthma and COPD. By manipulating particle size and inhalation variables, the possibilities of providing targeted treatments to specific regions of the lung may also be feasible, enhancing treatment for patients with various respiratory and non-respiratory diseases. Devices, Drugs and Detection of Disease Changes in delivery device design and performance over the years have been extensive for all categories of devices1,2. A major change in pMDIs occurred with the acceptance of the 1987 Montreal Protocol mandating transitioning propellant-based formulations from CFCs to HFAs. Reformulation was not a simple process for many drugs and some pMDIs could not be converted as an HFA propellant formulation. The addition of ethanol to co- solve corticosteroids in HFA134a produced one of the most significant developments, namely, the production of HFA solution steroids. These extra-fine 1µm steroid aerosols resulted in lower prescribed ICS doses for patients and, in addition, due to their aerodynamic size, were expected to target the distal lung. Recently, treatment protocols combining inhalation of coarse and extra-fine corticosteroid aerosols from different inhalers have met with some success in providing better outcomes in patients with hard-to-treat asthma. The introduction of spacers and holding chambers to be used with pMDIs was a major advance in helping adult and pediatric asthmatic patients inhale their pressurized aerosols;. ensuring that the dose was delivered through the chamber contributed to controlling their symptoms3. Chambers with mouthpiece and also facemasks were designed not only for ambulatory patients but also to interface with ventilator circuits in the ICU. In the last 20 years, advances in nebulizer design resulted in the portable Soft Mist Inhaler (SMI)™ and the battery-operated Vibrating Mesh (VM) nebulizer4. These ADDDs are high efficiency delivery devices, used to dispense multiple therapies and in various clinical settings. VM nebulizers have also been used in diagnostic challenge inhalation tests to assess airway hyper-reactivity (AHR) in asthma and Sputum Cytology in asthma and COPD5,6. Developments in DPI design have produced several capsule – based inhalers, medium resistance devices and single use/disposable, inexpensive DPIs for administering unit doses of, for example, vaccine powders7.8. Another design improvement was the incorporation of a dose counter in all reservoir and multi-unit dose DPIs and pMDIs, making it easier for patients to know that they had taken their dose and also when to refill their prescriptions. The correct use of inhalers by patients and their adherence to therapy have become areas of active research as misuse and non-use continue to be major causes of treatment failures. Human Factors (HF) studies demonstrating how patients actually use their inhalers, with or without benefit of instruction, should help the industry design `patient-friendly` inhalers9. These types of studies are now required by regulatory agencies in North America and Europe. Specific Guidances from the FDA and EMA are available to guide the various pharma and device companies in designing and implementing HF trials. Imaging the Lungs to Assess Lung Dose and Regional Deposition Research studies to determine where aerosols deposit in the lung have provided data on total and regional deposition for a number of inhaled pharmaceutics and delivery devices. These studies if coupled with routine clinical response measurements, for example, spirometry and PK, can provide a correlation between where the drug is deposited in the lung and clinical efficacy. Methods for indirect and direct radiolabelling of drugs have been used with success9. Imaging technology and data analysis are extremely sophisticated today compared to early studies where single scintillation counters were positioned behind the subject at specific geometric locations10. Data from each counter were then analyzed individually. With SPECT/CT or PET/CT hybrid scanners, the lung is viewed in 3D and combined with protocols to segment the airways, these tomographic modalities provide regional deposition data from many lung slices and defined regions within the lung. The quantity of data grows exponentially with increased resolution of these scanners and also the number of outcome measures that can be determined from the datasets. MRI with inhalation of HHe3, and now 129Xe, to locate ventilation defects in the lung is also being used to study patients with lung disease and may be used to monitor changes in the lung over time11. Drug Delivery to the Lungs (DDL2017), 2017 - Looking Back and Looking Ahead: Developments in Aerosol Medicine over the last 50 Years - Devices, Drug and Detection of Disease Methods to alter API particle size, the use of different excipients in formulations, modifying particle density and other innovative measures, have produced pharmaceutics that can target distal airways in the lung12. Ultra-fine particles of Technegas, a gas-like aerosol consisting of solid nanoparticles of carbon, <1µm in size and labelled with 99mTc, are used daily in Nuclear Medicine departments worldwide to assess ventilation, a clinical test that requires inhaling a gas-like aerosol. The technique that produces these particles, essentially a burning or vaporizing of a solid at high temperature, is food for thought as to whether this concept can be adapted to reliably produce viable therapeutic particles that could target and treat the distal lung. Possibilities for new devices used to administer therapeutic aerosols are evident at this meeting. Using the lung and nasal surfaces as part of the aerosol delivery system to reach the systemic circulation has created opportunities, not pursued in the past, for treating non-pulmonary diseases such as diabetes and Parkinson`s among others. Drugs, drug delivery systems and methods to detect and measure responses have played major roles and continue to do so, in these areas of research. It is also recognized that barriers to absorption of drug through the airway epithelium may have to be overcome for effective treatment to occur. And the possibility of side effects must always be considered when new treatment avenues are explored. 1 Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. The Lancet 2011 Mar 19;377(9770):1032-45. 2 Pirozynski M, Sosnowski TR. Inhalation devices: from basic science to practical use, innovative vs generic products. Expert Opin Drug Deliv 2016;13(11):1559-71 3 Nikander K, Nicholls C, Denyer J, Pritchard J. The Evolution of Spacers and Valved Holding Chambers. J Aerosol Med 2014; 27(S1):S-4. 4 Dhand R. Nebulizers that use a vibrating mesh or plate with multiple apertures to generate aerosol. Respir Care 2002 Dec;47(12):1406-16. 5 Nair P, Martin JG, Cockcroft DC, Dolovich M, Lemiere C, Boulet LP, et al. Airway Hyperresponsiveness in Asthma: Measurement and Clinical Relevance. J Allergy Clin Immunol Pract 2017 May;5(3):649-59. 6 Nair P, Dasgupta A, Brightling CE, Chung KF. How to Diagnose and Phenotype Asthma. Clinics in Chest Medicine 2012 Sep;33(3):445-57. 7 Islam N, Gladki E. Dry powder inhalers (DPIs)--A review of device reliability and innovation. Int`l J Pharmaceutics 2008 ;360(1-2):1-11. 8 Roche N, Scheuch G, Pritchard JN, Nopitsch-Mai C, Lakhani DA, Saluja B, et al. Patient Focus and Regulatory Considerations for Inhalation Device Design: Report from the 2015 IPAC-RS/ISAM Workshop. J Aerosol Med 2016; 30(1):1-13. 9 Dolovich MB. 18F-Fluorodeoxyglucose Positron Emission Tomographic Imaging of Pulmonary Functions, Pathology, and Drug Delivery. Proc Am Thorac Soc 2009 Aug 15;6(5):477-85 10 Milic-Emili, J., J. A. M. Henderson, M. B. Dolovich, D. Trop and K. Kaneko. Regional distribution of inspired gas in the lung. J. Appl. Physiol. 2 I (3) : 749-759. 1966. 11 Svenningsen S, Kirby M, Starr D, Coxson HO, Paterson NA, McCormack DG, et al. What are ventilation defects in asthma? Thorax 2014 Jan;69(1):63-71. 12 Hoppentocht M, Hagedoorn P, Frijlink HW, de Boer AH. Technological and practical challenges of dry powder inhalers and formulations. Adv Drug Deliv Rev 2014;75:18-31 .
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