Metered-dose inhaler actuators

Lewis D (2007) Metered-dose inhalers actuators old and new. Expert Opin Drug Deliv 4(3) 235-245... 

Following delivery of 1,200 mg of HFC-134a by inhalation from metered-dose inhalers to four healthy adult male volunteers (16 actuations of 75 mg per inhalation each inhalation within 30 s of the previous inhalation), the only fluorinated urinary component was trifluoroacetic acid. Urinary trifluoroacetic acid accounted for less than 0.0005% of the administered dose, indicating minimal metabolism (Monte et al. 1994). 

Metered-dose inhalation aerosols Delivered dose per actuation, number of metered doses, color, particle-size distribution, loss of propellant, pressure, valve corrosion, spray pattern, and absence of pathogenic microorganisms... 

The metered dose inhalers consist of four basic functional elements, container, metering valve, actuator and mouthpiece. 

Aerosolized medications are available as pressurized or breath-actuated metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulized or wet aerosols. Most inhaled medications currently used are available as metered-dose inhalers (Table 3). For the patient who has difficulty to coordinate activation of a MDI, a spacer improves delivery. Spacers reduce deposition of the drug in the... 

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. 

A change in the primary packaging components for any product when the primary packaging components control the dose delivered to the patient (e.g., the valve or actuator of a metered-dose inhaler). 

Figure 4 Schematic production sequence for the manufacture of metered-dose inhalers by pressure filling (1) suspension mixing vessel (2) can cleaner (3) can crimper and filler (4) check weigher (5) can coder and heat tester (6) priming and spray testing (7) labeler (8) feeds for tested cans and actuators. (Courtesy of Ellis Horwood Publishers, Ref. 10.)...

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. 

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. 

Breath-actuated metered dose inhalers - evohalers... 

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. 

Berry, J., Heimbecher, S., Hart, J. L., and Sequeira, J. (2003), Influence of the metering chamber volume and actuator design on the aerodynamic particle size of a metered dose inhaler, Drug. Dev. Ind. Pharm., 29, 865-876. 

Smyth, H., Brace, G, Barbour, T., Gallion, J., Grove, J., and Hickey, A. J. (2006), Spray pattern analysis for metered dose inhalers Effect of actuator design, Pharm. Res., 23, 1591-1596. 

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. 

Larsen, J.S. Hahn, M. Kochevar, J.W. Morris, R.J. Kasier, H.B. Weisberg, S.C. Halverson, P.C. Quessey, S.N. Administration errors with a conventional metered dose inhaler versus a novel breath actuated device. Ann. All. 1993, 71, 103-106. 

Metered dose inhalers (MDIs) are pharmaceutical delivery systems designed for oral or nasal use, which deliver discrete doses of aerosolized medicament to the respiratory tract. The MDI contains the active substance, dissolved or suspended in a liquefied propellant system held in a pressurized container that is sealed with a metering valve. Actuation of the valve discharges a metered dose of medicament as an aerosol spray through an actuator during oral or nasal inhalation. 

Actuator body Fig. 1 Sectional view of a metered dose inhaler. 

There have been three randomized, double-blind studies in adult asthmatics of the efficacy and safety of a beclomethasone dipropionate-hydrofluoroalkane 134a formulation, equivalent in dose per actuation to the currently marketed beclomethasone dipropionate chlorofluorocarbon products (19-21). Daily doses of beclomethasone dipropionate hydrofluoroalkane 134a 1000 pg over 12 weeks given by metered-dose inhaler (19) or a spacer jet device (20) were equivalent in terms of safety and efficacy compared with beclomethasone dipropionate chlorofluorocarbon 1000 pg. The same was true for doses of 400 pg (21). 

Timing of the aerosol entry at a particular point in the breathing cycle can have a profound effect on deposition. With the metered-dose inhaler without a spacer, poor synchronization of inspiration with the firing of the valve can result in a substantial loss of the aerosol bolus. For this reason, breath-actuated valves have been developed [91-93]. 

Most aerosol delivery systems have surfaces that are designed to collect or disperse particles. Jet nebulizers have spheres, as shown in Fig. 4, or plates placed immediately in front of the jet to collector break up large droplets. Metered-dose inhalers do not traditionally have baffles however, the surface of the actuator collects aerosol particles as they pass through the mouthpiece. Dry powder... 

Metered-dose inhaler (MDI) Canister held inverted Formulation (CFC, HFA, solution, suspension) Actuator cleanliness Addition of a spacer device Inspiratory flow (slow, deep) Breath-holding Coordinating actuation with inhalation Priming and shaking the device... 

Riker Laboratories, now 3M Healthcare, invented the pressurised metered dose inhaler (MDI) in 1955 when they combined the atomising power of CFCs and a metering valve design. The great majority of valves still use this basic retention valve principle, and hence pressurised MDIs (pMDIs) are all similar in appearance and operation when used with a standard actuator in the normal press and breathe manner. 

Metered-dose inhalations and nasal aerosols should be evaluated for appearance (including content, container, and the valve and its components), color, taste, assay, degradation products, assay for cosolvent (if applicable), dose content uniformity, labeled number of medication actuations per container meeting dose content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial limits, valve delivery (shot weight), and extractables and leachables from plastic and elastomeric components. Samples should be stored in upright and inverted/on-the-side orientations. 

Everard ML, Devidason S, Le Souef PN. Effect of multiple actuations on total and respirable dose delivered by metered dose inhalers. Thorax 1995 50 746-749. 

Newnham DM, McDevitt DG, Lipworth BJ. Comparison of the extrapuhnonary P -adrenorecptor responses and pharmacokinetics of salbutamol given by standard metered dose inhaler and modified actuator device. Br J Clin Pharmacol 1993 36 445 50. 

Many drugs have been formnlated for use with pressurized metered-dose inhalers (pMDIs) (Table 1). The main market for these devices is in the treatment of asthma, allergic diseases, and chronic obstructive pulmonary disease (COPD), for which approximately 500 million pMDIs are produced each year. Their major selling points are that they are cheap and portable. Despite their huge sales, there is increasing concern that the dose of drug patients with asthma receive will vary considerably due to their inhalational technique and to a lesser extent to the variabihty of dose delivery from the pMDI. It is likely, however, that the popularity of pMDIs will continue due to various modifications and additions that are aimed to help with inhalational technique and improve drug delivery. Examples of these include breath-actuated devices, discussed in this chapter, and spacer devices discussed in a subsequent chapter. 

Key pMDI, pressurized metered-dose inhaler VC, vital capacity BHT, breath holding tune BA, breath-actuated measured by scintigraphy. 

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