The History of Therapeutic Aerosols: A Chronological Review.

In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical aerosol industry. The MDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers, and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry, particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol delivery systems produced by people completely disconnected from contact with the patient. This trend continued and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a look to the future. We hope that you will find this chronological summary intriguing and informative.

The Evolution of Pressurized Metered-Dose Inhalers from Early to Modern Devices.

Pressurized metered-dose inhalers (pMDIs) are sometimes viewed as old-fashioned and as having been superseded by dry powder inhalers (DPIs). Here, we review the technological advances that characterize modern pMDIs, and consider how they can influence the effectiveness of drug delivery for patients with asthma and chronic obstructive pulmonary disease. Compared with old chlorofluorocarbon (CFC)-based inhalers, many hydrofluoroalkane (HFA)-driven pMDIs have more favorable plume characteristics such as a reduced velocity and a higher fine particle fraction; together, these advances have resulted in the development of pMDIs with reduced oropharyngeal deposition and increased lung deposition. In addition, the plume from many HFA-pMDIs is warmer, which may facilitate their use by patients; moreover, devices are equipped with dose counters, which improves their reliability. As well as reviewing the technological advances of pMDIs, we also discuss the importance of individualizing inhaler therapies to each patient by accounting for their personal preferences and natural breathing patterns. Because pMDIs and DPIs differ considerably in their handling characteristics, matching the right inhaler to the right patient is key to ensuring effective therapy and good compliance. Finally, the majority of patients can be trained successfully in the correct use of their pMDI; training and regular monitoring of inhalation technique are essential prerequisites for effective therapy. While the 'ideal inhaler' may not exist, pMDIs are an effective device option suitable for many patients. pMDIs, together with other types of devices, offer opportunities for the effective individualization of treatments.

The evolution of spacers and valved holding chambers.

Spacers and valved holding chambers (VHCs) are pressurized metered dose inhaler (pMDI) accessory devices, designed to overcome problems that patients commonly experience when administering aerosol via a pMDI. Spacers were developed in direct response to patient-related issues with pMDI technique, particularly, poor coordination between actuation and inhalation, and local side-effects arising from oropharyngeal deposition. Current clinical guidelines indicate the need for widespread prescription and use of spacers, but, despite their apparent ubiquity, the devices themselves are, unfortunately, all too commonly "disused" by patients. An understanding of the background from which spacers developed, and the key factors influencing the optimization of the spacer and the later VHC, is crucial to developing an appreciation of the potential of these devices, both contemporary and future, for improving the delivery of pressurized aerosols to patients. This review, informed by a full patent search and an extensive scientific literature review, takes into account the clinical and laboratory evidence, commercial developments, and the sometimes serendipitous details of scientific anecdotes to form a comprehensive perspective on the evolution of spacers, from their origins, in the early days of the pMDI, up to the present day.

Twenty years of HFA pMDI patents: facts and perspectives.

OBJECTIVES: Over the past 20 years, the inhalation drug delivery industry has undergone a quiet revolution after the phasing out of the chlorofluorocarbon propellants used to formulate pressure-metered dose inhalers (pMDIs). This review looks back to the creative landscape of those 20 years through a study of patent application trends. To this end, an analysis of the hydrofluoroalkane pMDIs patent landscape was undertaken. METHODS: A statistical analysis demonstrates that 20 years after the introduction of hydrofluoroalkanes in the inhalation delivery field, the original patent applications are coming to the end of their legal life. KEY FINDINGS: Detailed analysis revealed that, from a total of 971 of the patents identified, up to 2.3% will expire within the next 5 years, rising to up to 7.3% in the next 10 years. The UK and USA were the main patent destinations and locations of inventive activity, as measured by patent filing location. Interestingly, the UK was the first destination and location of inventive activity in Europe, largely due to the activity of GlaxoSmithKline, followed by Italy, thanks to the work of Trinity-Chiesi. The analysis also showed that patent assignees are not always major pharmaceutical companies, with suppliers of propellants, as well as companies without major inhalation activity (such as Novadel), making substantial contributions to the landscape. CONCLUSIONS: These developments may have a significant impact on innovation trends and key company activity around novel pMDI formulations, in particular for generics manufacturers.

Espaçador artesanal: uma forma simples, eficiente e barata de ajudar os pacientes a usarem seus inaladores dosimetrados em spray (bombinhas) corretamente / Homemade spacers: a simple, efficient and cheap way of helping the patients to use their metered dose inhaler correctly / Espaciador hecho a mano: una manera sencilla, eficientes y de bajo costo de ayudar los pacientes a utilizar los inhaladores de dosis spray (bombinhas) correctamente

Objetivo: rever os conceitos básicos da inaloterapia e sua estreita relação com o tratamento da asma, bem como o uso dos inaladores dosimetrados acoplados a espaçadores artesanais com alternativa para minimizar erros na técnica inalatória. Metodologia: foi realizada revisão de literatura em revistas nacionais e internacionais, nas bases de dados PubMed/Medline e Cochrane. Foram selecionados ensaios clínicos randomizados, metanálises e revisões sistemáticas utilizando-se os descritores asma, inaladores dosimetrados e espaçadores. Resultados: os inaladores dosimetrados apresentam vantagens como custo e facilidade de transporte, porém a necessidade de sincronização entre o movimento de disparo do dispositivo e a inspiração pelo paciente representa a principal desvantagem deste tipo de inalador. A utilização de um espaçador valvulado acoplado ao IDs minimiza em muito essa necessidade de sincronização mão inspiração,mas acrescenta custos ao tratamento, o que tem estimulado a utilização de espaçadores artesanais em comunidades mais pobres. Conclusão: os inaladores dosimetrados em spray ocupam lugar de destaque na prática clínica sendo a sua eficácia comparável ou até melhor do que àquela do nebulizador sobretudo quando utilizado acoplado a um espaçador, seja ele convencional ou artesanal. Entretanto, muitos pacientes que se beneficiariam do uso dessa associação, não o fazem porque não são ensinados a utilizá-los corretamente.(AU)

Objective: to review the inhalation therapy basic concepts and their straight relation with asthma treatment and the metered dose inhalers attached to homemade spacers as an alternative of decreasing mistakes made at the inhalation practice. Methodology: a literature review has been made integrating the national and international publication searched at Scielo, PubMed/Medline, Cochrane. Randomized clinical trials have been selected, metanalysis and systematic reviews by using describers asthma, metered dose inhalers and spacers. Results: the metered dose inhalers show advantages like cost and ease of transportation, however the synchronization required between device´s shot movement and the patient´s inhalation appear as the main disadvantage in that kind of inhaler. The utilization of a valved spacer attached to metered dose inhalers decreases strongly the synchronization hand-lung needed, but increases costs to the treatment, which have stimulated the use of homemade spacers in poorer countries. Conclusion: the metered dose inhalers take a remarkable place in the clinical practice being their efficacy similar to the nebulizer treatment above all when attached to a spacer, being it a conventional or a homemade one. However, many patient who would take benefits of that association, don´t do that because they aren´t taught the device´s correct manageme.(AU)

Objetivo: revisar los conceptos básicos de la terapia de inhalación y por su estrecha relación con el tratamiento del asma y el uso de espaciadores medido inhalador de dosis, junto con la alternativa a mano para minimizar los errores en la técnica de inhalación. Metodología: se realizó una revisión bibliográfica de la información publicada en revistas nacionales y internacionales en el PubMed/Medline y Cochrane. Se seleccionaron los ensayos controlados aleatorios, metaanálisis y revisiones sistemáticas con el asma palabras clave, dosificadores, los inhaladores y espaciadores. Resultados: los inhaladores de dosis tienen ventajas tales como el costo y la facilidad de transporte, pero la necesidad de sincronización entre el movimiento del dispositivo de disparo y la inspiración a través de la paciente representa la principal desventaja de este tipo de inhalador. El uso de un espaciador junto a los identificadores que minimiza en gran medida la necesidad de la inspiración de sincronización de ocasión, sino que agrega los costos de tratamiento, lo que ha fomentado el uso de espaciadores de fabricación casera en las comunidades más pobres. Conclusión: el aerosol inhalador de dosis medidas un lugar destacado en la práctica clínica y su eficacia comparable o mejor que la de nebulizador usa especialmente cuando se combina con un espaciador, ya sea convencional o la artesanía. Sin embargo, muchos pacientes que se beneficiarían del uso de esta asociación, no porque no se les enseña a usarlos correctamente.(AU)

The rejuvenated pressurised metered dose inhaler.

The pressurised metered-dose inhaler (pMDI) has now been available for 50 years. Once regarded as an inefficient and difficult-to-use device, the technology has evolved significantly over the last few years, particularly since the introduction of novel formulations containing hydrofluoroalkane (HFA) propellants. Many modern HFA pMDIs deposit drug more efficiently in the lungs, impact less forcefully on the back of the throat and feel less cold than their chlorofluorocarbon pMDI counterparts. An improved understanding of technical factors makes it possible to design HFA pMDIs to have specific spray properties, particularly in terms of fine particle dose and spray velocity. Device technology has also progressed with the introduction of compact and convenient breath-actuated, breath-coordinated and velocity-modifying devices, which help patients to achieve a reliable lung dose. Although it faces competition from dry powder inhalers and possibly from novel soft-mist inhalers containing liquid formulations, the rejuvenated HFA pMDI is a device with a significant future for asthma, chronic obstructive pulmonary disease and wider treatment indications.

Metered-dose inhalers: actuators old and new.

The actuator has been the patient interface of the metered-dose inhaler for the past 50 years. The original 1956 design remains a significant influence upon today's actuators and, moreover, its distinct geometry is still recognisable on the market. The actuator has contributed to the metered-dose inhaler's success as a clinically effective and cost-effective device. This review focuses upon developments since the actuator's introduction as an integral part of the metered-dose inhaler and discusses key aspects of its design that influence lung deposition potential. The ability of the actuator to reduce unwanted oropharyngeal drug deposition, facilitate correct patient use and provide valuable patient feedback is highlighted.

History of aerosol therapy: liquid nebulization to MDIs to DPIs.

Inhaled therapies have been used since ancient times and may have had their origins with the smoking of datura preparations in India 4,000 years ago. In the late 18th and in the 19th century, earthenware inhalers were popular for the inhalation of air drawn through infusions of plants and other ingredients. Atomizers and nebulizers were developed in the mid-1800s in France and were thought to be an outgrowth of the perfume industry as well as a response to the fashion of inhaling thermal waters at spas. Around the turn of the 20th century, combustible powders and cigarettes containing stramonium were popular for asthma and other lung complaints. Following the discovery of the utility of epinephrine for treating asthma, hand-bulb nebulizers were developed, as well as early compressor nebulizers. The marketing of the first pressurized metered-dose inhaler for epinephrine and isoproterenol, by Riker Laboratories in 1956, was a milestone in the development of inhaled drugs. There have been remarkable advances in the technology of devices and formulations for inhaled drugs in the past 50 years. These have been influenced greatly by scientific developments in several areas: theoretical modeling and indirect measures of lung deposition, particle sizing techniques and in vitro deposition studies, scintigraphic deposition studies, pharmacokinetics and pharmacodynamics, and the 1987 Montreal Protocol, which banned chlorofluorocarbon propellants. We are now in an era of rapid technologic progress in inhaled drug delivery and applications of aerosol science, with the use of the aerosolized route for drugs for systemic therapy and for gene replacement therapy, use of aerosolized antimicrobials and immunosuppressants, and interest in specific targeting of inhaled drugs.