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30 OctOber 2022 Inhalation References 1. Chambers TK. On the inhalation of nitrate of silver and other mechanical agents. London Medi- cal Gazette 1849; 43 (8): 639-640. https://archive. org/details/londonmedicalgaz43londuoft/page/639 (accessed April 16, 2019). 2. Cornell WM. Observations on the inhalation of various vapors and powders in diseases of the air tubes and lungs. Boston Med Surg J 1850 (17); 43: 329-336, 355-357, 375-378, 395-401. https://archive.org/ details/bostonmedicalsur4318mass/page/328 (accessed April 16, 2019). 3. Warren I. roat diseases. Boston Med Surg J 1851; 45 (17): 344-350. https://archive.org/details/boston medicalsu4518mass_0/page/344 (accessed April 16, 2019). 4. Solis Cohen J. Inhalation in the treatment of dis- ease: its therapeutics and practice. A treatise on the inhalation of gases, vapors, fumes, compressed and rarefied air, nebulized fluids, and powders. 2nd Edi- tion. Lindsay & Blakiston, Philadelphia, US, 1876. 412pp. https://archive.org/stream/inhalationintrea 00cohe/inhalationintrea00cohe#page/n7/mode/1up (accessed April 16, 2019). 5. Jones J. Improved apparatus for facilitating the inhalation of medicinal substances. UK Patent No. 1,161. Filed May 7, 1864, granted September 30, 1864. 6. Carbolic Smoke Ball Company, advertising. e Illustrated London News, February 25, 1893: 24. 7. Carlill v Carbolic Smoke Ball Co. Wikipedia, the free encyclopedia. https://en.wikipedia.org/wiki/ Carlill_v_Carbolic_Smoke_Ball_Co (accessed April 15, 2019). 8. Fields MR. Inhalator. US Patent Number 2,470,296: May 17, 1949. 9. Sanders MJ. Upjohn penicillin dust inhaler. Inha- latorium. A collection of inhalers and asthma ther- apies. http://www.inhalatorium.com/wpcproduct/ upjohn-penicillin-dust-inhaler/ (accessed April 16, 2019). 10. Cox JSG, Bell JH, Hartley PS. Administra- tion of disodium cromoglycate. Br Med J 1969; 2 (5657): 634. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1983591/pdf/brmedj02035-0078c.pdf (accessed April 16, 2019). 11. Pilcer G, Wauthoz N, Amighi K. Lactose charac- teristics and the generation of the aerosol. Adv Drug Del Rev 2012; 64 (3): 233-256. With the development of less environmentally- damaging propellants, the choice between DPI and pMDI devices may be driven by other factors, such as user technique and preference. e choice of plastics for DPI manufacture will drive towards recyclable alternatives with use of recycled materials becoming more of a consideration. Generic substitution will raise its profile as highly successful formulations and devices emerge from patent protection. 31 e extent to which similar devices can be said to match originator devices is currently contested and will continue to be so. Pay- ors and regulators will seek economic and scientific rationales to permit the use of bioequivalent work- alike, feel-alike devices. Formulation technologies will permit the delivery of higher payloads and more efficient lung delivery, tar- geting lung deposition 32 while conferring properties that will enhance flow and storage. Manufacturing efficiencies will also be a key driver. is review has concentrated on approved, patient-available devices: currently these are all pas- sive technologies. e grail of the more complex, active DPI—one that uses an internal power source as opposed to the "external" patient breath, removes the requirement of high flow rate dependency and raises the possibility of delivery of a large powder payload—has been more of a poisoned chalice to developers. e potential to aerosolize a greater drug mass sparked a surge of interest in systemic delivery of inhaled macromolecules (proteins [insulin], anti- biotics, RNAs, vaccines) that, in active devices, has not been successful. 33 e Spiros™ (battery, Dura), Oriel™ (piezoelectric, Sandoz), and Aspirair (com- pressed air, Vectura) devices, for example, failed to reach the market, while Exubera (compressed air) was withdrawn. 19 Research with more potential for success has focused on new passive DPIs that are capable of delivering the larger payloads: Orbital ® (Pharmaxis) and Twincer ® (Groningen Centre for Drug Research), for example. 34 ese are invariably single unit-dose devices that have benefitted from the parallel progress in formulation technology. e deciding factors in any continuing enthusiasm for active DPIs may be regulatory complexity and higher unit cost; plus, their mechanism of action poten- tially re- introduces the actuation/inhalation coordi- nation issues of pMDIs. ese significant challenges for active DPIs are likely to ensure the continued use and further development of passive devices.