Metered-dose inhaler aerosol delivery device

Several portable inhalation devices have been developed and are being tested to determine whether they improve protein and peptide delivery via the airways. Aerosolized DNase has been shown in patients with cystic flbrosis to significantly reduce the buildup of mucus in the lung and the incidence of infections. Devices for delivery of therapeutic proteins to deep-lung alveoli to achieve systemic effects are also in development. These products are formulated so that the device aerosolizes the protein in a defined particle size range that cannot be easily achieved by means of conventional metered dose inhalers. 

Wilkes W, Fink J, Dhand R. Selecting an accessory device with a metered-dose inhaler variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler. J Aerosol Med 2001 14(3)251-360. 

Pulmonary deposition efficiency depends on physicochemical characteristics, such as density of the aerosol or dry powder particles [33-35], Generally, particle diameters less than than 5 pm are required for efficient pulmonary delivery [36, 37], Pulmonary deposition also depends on the nature of the delivery device and differs between metered dose inhalers (MDIs). For example, pulmonary deposition expressed as the ratio of pulmonary versus total (pulmonary + oral) absorbed drug, ranged from 15-55% for a number of salbutamol devices and from 66-85% for drugs with lower oral bioavailabilities such as budesonide. 

Metered dose inhaler has been the most popular aerosol delivery device for the treatment of respiratory diseases, which is attributable to its portability and simple operation. Although seemingly easy to use, the MDI is a sophisticated device in design. The drug(s) are suspended or dissolved in a liquefied propellant system, which may also contain excipients such as cosolvents or surfactants. The formulation is kept pressurized in a small canister, sealed with a metering valve. Upon actuation through an actuator, the valve opens and the metered dose is dispensed as an aerosol spray from the expansion and vaporization of the propellant under ambient pressure. The inhalers may be used alone or with spacer devices, the electrostatic issues of which are considered in a later section. The present discussion focuses on the inherent charging of particles produced from MDIs. 

Peart, J. Magyar, C. Byron, P.R. Aerosol electrostatics— metered dose inhalers (MDIs) reformulation and device design issues. In Respiratory Drug Delivery VT, Dalby, R.N., Byron, P.R., Farr, S.J., Eds. Interpharm Press Buffalo Grove, IL, 1998 227-233. 

Pulmonary delivery of drugs is the administration route of choice in respiratory diseases such as chronic obstructive pulmonary disease and asthma. Different devices are available, including metered-dose inhalers, dry powder inhalers, and nebulizers, and nearly 80% of asthmatic patients worldwide use metered dose inhalers (1). Chlorofluorocarbons have been used as an aerosol propellant in metered-dose inhalers however, they deplete the ozone layer and are being replaced by more environment-friendly propellants, even though the contribution of aerosols of this type to the total global burden of chlorofluorocarbons is less than 0.5%. The first chloro-fluorocarbon-free metered-dose inhaler for asthma treatment was approved by the FDA in 1996 (2) and the European Union has set 2005 as a target date for the withdrawal of all chlorofluorocarbon-based inhalers (1). In the USA, prescriptions for chlorofluorocarbon-free medications rose from 16.4 million in 1996 to 33.8 million in 2000 (2). Most of the chlorofluorocarbon-free medications were steroids for nasal use (27.2 million). However, chlorofluorocarbon-containing medications stiU represented two-thirds of all prescriptions and increased from 63.0 to 67.6 million dispensed (2). 

Derksen F, Olszewski M, Robinson N 1996 Use of a handheld, metered-dose aerosol delivery device to administer pirbuterol acetate to horses with heaves. Equine Veterinary Journal 28 306-310 Derksen F, Olszewski M, Robinson N 1999 Aerosolized albuterol sulfate used as a bronchodilator in horses with recurrent ainway obstruction. American Journal of Veterinary Research 60 689-693 Duvivier D, Votion D, Vandenput S et al 1997 Technical validation of a facemask adapted for dry powder inhalation in the equine species. Equine Veterinary Journal 29 471-476... 

In particular, the propellant-driven metered-dose inhalers release the aerosol cloud at the very high velocity caused by the pressure of the propellant. The open-mouth technique of inhalation [79] helps to slow down the droplets (and to evaporate the volatile excipients). An even more effective solution is to use spacer devices [4,79-87], in which the aerosol cloud can slowed down, the volatile constituents can evaporate, and any large particles will sediment out. Moreover, the patient can then inhale the remaining aerosol under optimal conditions for pulmonary delivery [4,8,56,79], that is, with a slow inspiratory flow rate. 

Despite their availability, neither dry powder nor metered-dose inhalers have been used to deliver aerosolized pentamidine. The use of metered-dose inhalers may be problematic because these devices are better suited for frequent delivery of small doses rather than intermittent delivery of the large doses that have been therapeutically successful in prophylaxis of PCP. Dry powder devices may produce an increased incidence of cough due to airway deposition. 

Unlike most other drug delivery systems, those in the respiratory area can have a major influence on physician/patient acceptance. A wide range of devices are available in the three main categories of dry powder inhalers (DPIs) and metered dose inhalers (MDIs), i.e., pressurised aerosols and nebulisers. The preferred type of inhaler varies considerably between countries (e.g., DPIs in Scandinavia and MDIs in the United States), and between patient groups (e.g., nebulisers for paediatrics). 

In the United States, federal regulation of aerosol doses varies with devices. The metered-dose inhaler (MDI) utilizes a metering valve that is highly regulated and functionally precise. Nebulizers as drug delivery systems are essentially unregulated. 

Ashurt IC, Ambrose CV, Russel DJ. Pharmaceutical evaluation of a new spacer device for delivery of metered-dose inhalers to infants and yonng children. J Aerosol Sci 1992 23 S499-S502. 

The metered-dose aerosol inhaler is not only a most convenient system for the delivery of therapeutically active drugs but it has proven to be a life-saving device for many asthmatics. This system has made it possible for millions of asthma sufferers to lead normal lives. The convenience of self-administering a dose of drug accurately and quickly has made the metered-dose aerosol the dosage form of choice for the delivery of drugs to the respiratory system. From epinephrine to albuterol, from triamcinolone to flunisolide, from proteins and peptides to hormones, this dosage form has proven its value. 

Powder inhalation devices are currently proving very popular, in spite of the fact that patients generally prefer metered dose aerosols. However, this preference is counterbalanced by the fact that compliance is much more difficult to achieve with aerosols. There is also a third category where the pack and the device are totally independent, e.g. a unit dose of nebuliser solution which is subsequently transferred to a pressurised or an ultrasonic nebuliser unit for delivery to the patient. 

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