Metered-dose inhaler metering valves

Clarke JR, Aston H, Silverman M. Dehvery of salbutamol by metered dose inhaler and valved spacer to wheezy infants effect on bronchial responsiveness. Arch Dis Child 1993 69 125-129. 

Pharmaceutical powder aerosols have more stringent requirements placed upon the formulation regarding moisture, particle size, and the valve. For metered-dose inhalers, the dispensed product must be deflvered as a spray having a relatively small (3—6 -lm) particle size so that the particles can be deposited at the proper site in the respiratory system. On the other hand, topical powders must be formulated to minimize the number of particles in the 3—6-p.m range because of the adverse effects on the body if these materials are accidently inhaled. 

Fig. 4 (A) Propellant-driven metered dose inhaler. (B) Metering valve.

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... 

Pressurized metered dose inhalers are still the most frequently used systems and they have proven their value in therapy. However, their application in early phases of biopharmaceuti-cal research and further development of dosage forms seems less convenient, since they require special components including propellants, special containers, metering valves, and controlled filling conditions (pressure-filling or cold-filling). 

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

Metered-Dose Inhalers and Nasal Aerosols Content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial bioburden, valve delivery, extractables, leachables from plastic and elastomeric components. 

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). 

Introduced in the 1950s, pMDIs have remained the most popular means for achieving domiciliary inhalation therapy. The pMDI provides for multiple dosing by utilizing a metering valve in conjunction with a propellant. A typical unit (Figure 10.7) comprises ... 

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. 

Metered-Dose Inhalation Aerosols Quantity of delivered dose, total number of acceptable doses delivered, color, solvate formation with propellant, particle size distribution, weight loss of canister (i.e., loss of propellant), pressure, valve corrosion, and storage in both upright and inverted positions. 

TABLE 3 Summary of Components and Materials Used In Metered Dose Inhaler Valves... 

Berry, J., Kline, L., Naini, V., Chaudhry, S., Hart, J., and Sequeira, J. (2004), Influence of the valve lubricant on the aerodynamic particle size of a metered dose inhaler, Drug. Dev. Ind. Pharm., 30, 267-275. 

Tiwari, D., Goldman, D., Dixit, S., Malick, W. A., and Madan, P L. (1998), Compatibility evaluation of metered-dose inhaler valve elastomers with tetrafluoroethane (P134a), a non-CFC propellant, Drug Dev. Ind. Pharm., 24,345-352. 

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. 

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. 

The modern pressurized metered dose inhaler (pMDI) was developed between 1955 and 1956. However, the pMDI had its roots in research carried out many years before.During the 1930s and 1940s, the discovery of liquefied propellants (chlorinated-fluorocarbons or freon propellants) such as CFC12, CFC114, CFCll, and CFC22 was a major step in the realization of a portable inhaler. However, the first pMDI was not invented until 1956, when the metering valve used in the device was developed and patented. ... 

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. 

Tiwari D, Goldman D, Dixit S, et al. Compatibility evaluation of metered-dose inhaler valve elastomers with tetrafluoroethane... 

Different types of spacer device are available for use with metered dose inhalers but all work in basically the same manner. The spacer usually consists of two parts that slot together with a mouthpiece at one end and an opening for an inhaler at the other. There is a one-way valve which ensures that when a dose of the inhaler is expressed into the spacer the drug is stored in what is basically a holding device. This makes it easier to use a metered dose inhaler successfully as the two actions (pressing down on the metered dose inhaler and inhaling the medication) can be separated into two separate events. 

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]. 

The metering valve is the key to measuring and presenting a consistent and accurate dose to the patient it is made up of a number of precision-made plastic or metal components. The valve is crimped onto a canister, which is ordinarily made of aluminum. Finally, there is the actuator, which holds the canister and through which the patient inhales the dose. 

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. 

Cummings, R. H. 1999. Pressurized metered dose inhalers Chlorofluorocarbon to hydrofluoroalkane transition—Valve performance. /. Allergy Clin. Immunol. 104 (6) S230. 

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. 

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