The Metered-Dose Inhaler

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. 

The initial part of this review focuses on the traditional chlorinated fiuoro-carbon (CFC) pMDIs that are still by far the most common formulations available at present. Developments in pMDI technology relating to the ongoing switch to non-CFC pMDIs (hydrofluoroalkanes, or HFAs) are highlighted toward the end of this chapter. 

Marcel Dekker, Inc. 270 Madison Avenue, New York, New York 10016 

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Ipratropium is the most commonly used anticholinergic for treating bronchoconstriction in asthma. It is available as an MDI and solution for nebulization. Ipratropium has an onset of action of approximately 30 minutes and a duration of action of 4 to 8 hours. Care should be taken not to spray the metered-dose inhaler into or allow the nebulized solution to get in the patient s eyes, as it can cause mydriasis and blurred vision. 

Kohler, D., Fleischer, W., and Matthys, H., New method for easy labeling of beta-2-agonists in the metered dose inhaler with technetium-99m, Respiration, 53 65-73 (1988). 

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

Inhalation aerosols have been used for the delivery of drugs to the respiratory system since the mid-1950s. The most common dosage form for inhalation is the metered-dose inhaler (MDI), by which the drug is delivered from a pressurized container using a liquefied gas propellant. Medication delivered via this dosage form has allowed for a quick therapeutic response to the symptoms of asthma, emphysema, and chronic obstructive pulmonary disease (COPD), and has resulted in an improvement in the quality of life for millions of asthma sufferers. 

R. Ahrens, C. Lux, T. Bahl, and S. H. Han, Choosing the metered-dose inhaler spacer or holding chamber that matches the patient s need evidence that the specific drug being delivered is an important consideration, J. Allergy Clin. Immunol. 96 288 (1995). 

Inhalation drug products, also referred to as orally inhaled and nasal drug products (OINDPs including inhalation aerosols and solutions, nasal aerosols and sprays), have a high likelihood of packaging component-dosage form interaction,and therefore have individual USFDA guidance documents. As an example, consider the metered dose inhaler (MDI), shown... 

Fig. 2 The metered dose inhaler. (A) Medihaler-Ept and (B) Medihaler-Iso. (Courtesy of Charles Thiel.)...

Additional multiple-unit containers are in widespread use such as collapsible tubes, metered-dose inhalers, and aerosol containers. The f/j / /AF provides standards for aerosols and containers used for aerosols in Aerosols, Metered-Dose Inhalers, and Dry Powder Inhalers (601) and Pharmaceutical Dosage Forms (1151). Commonly used for ointments and pastes, the collapsible tube container is often constructed of plastic, metal, or some lamination of plastic and metallic layers. Although such preparations can be packaged in jars or bottles, collapsible tubes can offer better protection from contamination and from environmental hazards. The metered-dose inhaler and aerosol container are other specific multiple-unit dosage form examples that are commonly fabricated from metal and are closely tied to the process of medication administration. " ... 

For the use of an inhaled medication (e.g., p2-agonists, corticosteroids, antivirals, cromolyn, etc.), it is crucial for the child and parents to understand the mechanism of the metered dose inhaler (MDI) or nebulizer, if used. The package insert should also be reviewed for information about the specific drug product. A decision may also need to be made as to whether a spacer may be needed for use with the medication canister. 

As a consequence of the suppression or reduced use of CFC propellants, a new kind of dosage form is under worldwide development drug powder inhalers (DPIs). The metered dose inhalers (MDIs) will probably be replaced by these. The MDIs were formulated several years ago. A drug in powder form (with a particle size close to 5 pm) was suspended in propellant 11 with a surfactant. Propellant 12 was added to the can after closure. 

Nine percent of the medication sprayed reaches the bronchioles. Using a spacer increases the delivery of medication to the bronchioles to 21%. The spacer is a funnel-like device that attaches to the mouthpiece of the meter dose inhaler. When administering medication using an inhaler ... 

When using the metered dose inhaler, the patient should be in semi-Fowler or high Fowler position. 

Figure 9.4 shows a metered dose inhaler attached to a spacer device. The metered dose inhaler is attached to one end of the spacer and the other end contains a mouthpiece which is... 

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]. 

As with the metered-dose inhalers, some old drugs have been repackaged in new devices. For dry powder inhalers these are not true generics but have a similar impact on the marketplace. Most notable of these in the Clickhaler (Innovata Biomed), which is marketed in Europe, for the delivery of albuterol (salbutamol) and beclomethasone. 

Dosage forms with different mechanisms may bypass the organ of absorption, such as the GI tract. These include, for example, the transdermal testosterone patch. Also capable of bypass is the metered dose inhaler for pulmonary delivery of biological products such as a peptide or protein, with a propellant for lung absorption. 

Although chronic theophylline administration has been used extensively in the past, this therapy is being employed with decreasing frequency in favor of aerosolized /32-receptor agonists. Albuterol is used most commonly, one to two puffs of the metered-dose inhaler three to four times daily. The role of aerosolized surfactant also has been assessed in patients with stable chronic bronchitis and has demonstrated encouraging results with respect to improvement in pulmonary function and sputum transport by cilia (i.e., clearance). The role of surfactant as a carrier vehicle for other aerosol medications also appears promising and most likely will continue to be evaluated. 

Inhalers are not a very efficient way of delivering medications to the lungs because only 9% of the medication reaches the lungs. The efficiency increases by using a spacer, which delivers 21% of the medication to the lungs. The spacer is a funnel-Kke device that attaches to the mouthpiece of the metered dose inhaler (MDI). The medication is released into the spacer and then the patient inhales slowly and deeply to get the drug into the airway. 

A spacer, a device that attaches directly to the metered-dose inhaler, should be used because a spacer increases the delivery of the drug to the lungs and decreases deposition of the drug on the oropharyngeal mucosa. 

The most important development in antiasthma drug delivery was the advent of the metered-dose inhaler in 1956, which resulted in a huge increase in the use of antiasthma therapy. Sales of pressurized metered-dose inhalers now run at approximately 500 million per year. However, the introduction of this device was not without problems. This section of the chapter covers the early use of propellants in atomization, the origin of the metered-dose inhaler, and the epidemic of asthma deaths. 

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. 

Newman and colleagues (78), found lung deposition was improved over the metered-dose inhaler alone at both slow (25 L/min) and fast (100 L/min) inhalation rates, with the slower inhalation rate achieving the highest total and peripheral lung delivery. Oropharyngeal deposition was halved. 

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