Metered-dose inhaler requirements

Meter-dose inhalers which can either be dry power inhaler or metered-dose inhalers require a greater amovmt of testing because the metered valve, oral adapter, and the formulation are collectively responsible for the delivery the API to the appropriate site in the respiratory passages. Similar to aerosols and nasal sprays, very specialized tests which include leakage rate, number of dose per container (i.e., emitted dose test), particle distribution, and value delivery tests have been devised to test the suitability of the metered-dose inhalers. 

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. 

FIGURE 80-2. Home management of acute asthma exacerbation. Patients at risk of asthma-related death should receive immediate clinical attention after initial treatment. Additional therapy may be required. (MDI, metered-dose inhaler PEF, peak expiratory flow.) (Adapted from NHLBI, National Asthma Education and Prevention Program, Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 97-4051. Bethesda, MD U.S. Department of Health and Human Services, 1997.)... 

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). 

Part IE Specific requirements for manufacture of metered-dose inhalers (MDIs)... 

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. 

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. 

He is started on salbutamol metered dose inhaler (MDI) two puffs when required and beclometasone (Qvar) 50 micrograms twice daily. 

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. 

A 62-year-old man requiring a metered-dose inhaler (for the first time) was told to spray the medicine to the throat. He was foimd to have been conscientiously aiming and firing the aerosol to his anterior neck around the thyroid cartilage, four times a day for two weeks (Chiang A A, Lee J C 1994 New England Journal of Medicine 330 1690). 

Raoult s law is important because it allows the calculation of vapour pressure from a knowledge of the composition of the solution. The requirement of the Montreal Protocol in 1989 for the replacement of chlorofluorocarbon (CFG) propellants in pressurised metered-dose inhalers with hydrofluoroalkanes (HFAs), because of the ozone-depleting... 

They are suitable for patients who have difficulty with metered dose inhalers as less coordination is required. 

The concentrations of the drug at the desired sites and at the sites of toxicity within the respiratory tract will depend on the balance of the drug supply and clearance rates at these sites [37]. We may speculate that this is one of the reasons for the higher doses required for the delivery of topical medications by nebulizers (typically over 10-25 min) vs. metered-dose inhalers or dry powder inhalers that deliver the medication in one or two breaths. There is little doubt that prolonged inhalation reduces the patient s enthusiasm for the therapy. It is therefore appropriate to evaluate nebulizers in terms of their useful output, that is, the dose of the therapeutic or diagnostic agent delivered in the desired aerodynamic size range per unit time [145]. 

Following the debate surrounding sampling by inertial impaction in the early 1990s, the apparatus required for propellant-driven metered-dose inhalers and dry powder inhalers has been specified by the USP [33] and EP [147]. In addition, the FDA has issued guidelines on the methods to be employed for both pulmonary and nasal delivery products [148]. 

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