Metered-dose inhalant devices

The combination of albuterol sulfate and ipratropium bromide is available commercially in a metered-dose inhaler device for humans. In human patients with chronic obstructive pulmonary disease, this anticholinergic p2 agonist combination provides more complete bronchodilatation than... 

The most common adverse effects from inhaled corticosteroids include oropharyngeal candidiasis and hoarse voice. These can be minimized by rinsing the mouth after use and by using a spacer device with metered-dose inhalers. Increased bruising and decreased bone density have also been reported the clinical importance of these effects remains uncertain.1,2,19... 

Other delivery systems are transdermal patches, metered dose inhalers, nasal sprays, implantable devices, and needle-free injections. A description of needleless injection is given in Exhibit 5.16. 

Newman, S.P., Clark, A.R., Talaee, N., and Clarke, S.W., Pressurized aerosol deposition in the human lung with and without an open spacer device. Thorax, 44 706-710 (1989). Newman, S.P., Clark, A.R., Talaee, N., and Clarke, S.W., Lung deposition of 5 mg Intal from a pressurized metered dose inhaler assessed by radiotracer technique, Int. J. Pharm., 74 203-208 (1991). 

As described in Section 3.3 in more detah, particles in the aerosol cloud should preferably have an aerodynamic diameter between 0.5 and 7.5 pm. Currently three different types of devices are used to generate aerosol clouds for inhalation nebulizers (jet or ultrasonic), (pressurized) metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). The basic function of these three completely different devices is to generate a drug-containing aerosol cloud that contains the highest possible fraction of particles in the desired size range. 

DPIs do not utilize Freon propellants, but use either with or without lactose as vehiculum. These devices have a clinical efficacy similar to standard metered-dose inhalers, but may be easier to use in selected patients, since a minimal inspiratory flow rate is necessary to inhale from a DPI. Therefore, the DPI may be difficult for patients with an insufficient inspiratory flow rate, which occurs in children, the elderly, people with severe COPD shared with diaphragm dysfunction, and during an exacerbation. The inspiratory flow rate is associated with the internal resistance of the device used. For instance the turbuhalor has a significant internal resistance and its delivered dose is dependent from the inspiratory flow rate. 

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. 

Ram FS, Brocklebank DM, Muers M, et al. Pressurised metered-dose inhalers versus all other handheld inhalers devices to deliver bronchodilators for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2002 CD002170. 

The Easyhaler (by Orion Pharma, Finland) and the Clickhaler (by Innovata pic, United Kingdom) are available at present in some European markets. Unlike the DPIs described earlier, these two reservoir-type inhalers meter the dose when the patient presses the top of the device similar to actuation of a pressurized metered-dose inhaler. Both devices contain a dose indicator, which is standard for reservoir multidose DPIs. Recently, Innovata presented the Twinhaler for asthma combination therapy, a new development based on the Clickhaler. This device does not require the combined drugs to be formulated in one powder blend but delivers two powder formulations from two reservoirs into one airflow path. 

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. 

S. P. Newman, J. Brown, K. P. Steed, S. J. Reader, and H. Kladders, Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines Comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices, Chest 113 951 (1998). 

Delivery devices play a major role in the efficiency of pulmonary delivery, and major advances have been made in the development of new devices in recent years. The most commonly used devices for pulmonary drug delivery include nebulizers, metered-dose inhalers (MDIs) and dry-powder inhalers (DPIs). These de-... 

Aerosol devices can be difficult to use for example, it has been estimated that approximately 50% or more adult patients have difficulty using conventional metered-dose inhalers efficiently, even after careful training. Dexterity is also required, which may be lacking in the very young and elderly populations. 

Patients who have difficulty in coordination with inhalers can use a spacer device. These remove the need for coordination between actuation of a pressurised metered dose inhaler and inhalation. The spacer device reduces the velocity of the aerosol and subsequent impaction on the oropharynx. In addition, the device allows more time for evaporation of the propellant so that a larger proportion of the particles can be inhaled and deposited in the lungs. The size of the spacer is important, the larger spacers with a one-way valve (Nebuhaler, Volumatic) being most effective. Spacer devices are particularly useful for patients with poor inhalation technique, for children, for patients requiring higher doses, for nocturnal asthma, and for patients who have poor coordination. 

Since the introduction of metered-dose inhalers, nasal solutions have increasingly been formulated as nasal sprays. Initially, aerosol-based systems containing chloro-fluorocarbons were employed however, the Montreal Protocol put an end to this. Thereafter, mechanical pumps or actuators were employed to deliver nasal formulations as sprays. These devices, using actuators, can precisely deliver as little as 25 pL and as much as 200 pL of a formulation. However, various factors must be considered in formulating the spray these include viscosity, particle size, and surface tension, all of which may affect the accuracy of the dose administered. 

Terzano, C. (2001), Pressurized metered dose inhalers and add-on devices, Pulm. Pharmacol. Ther., 14, 351-366. 

Asmus, M. J., Liang, J., Coowanitwong, I., and Hochhaus, G. (2004), In vitro performance characteristics of valved holding chamber and spacer devices with a fluticasone metered-dose inhaler, Pharmacotherapy, 24,159-166. 

Hindle, M., and Chrystyn, H. (1994), Relative bioavailability of salbutamol to the lung following inhalation using metered dose inhalation methods and spacer devices, Thorax, 49,549-553. 

Smyth, H. D., Beck, V. P, Williams, D., and Hickey, A. J. (2004),The influence of formulation and spacer device on the in vitro performance of solution chlorofluorocarbon-free propellant-driven metered dose inhalers, AAPS PharmSciTech, 5, E7. 

Administration errors can also occur with devices used to administer and monitor medications. Metered-dose inhalers, nebulizers, infusion pumps. 

Most inhalation devices deliver approximately 10% of the administered dose to the lower respiratory tract. A number of devices have been developed to increase lung delivery, and delivery of up to 21% has been reported with a pressurized metered-dose inhaler. Despite these advances, drug delivery via the lung is still inefficient. 

---