Metered-dose inhaler products

The development pharmaceutics section should also include consideration of possible overdosing of the active ingredient that might arise from normal use of the dosage form—e.g., deposition of drug substance from a metered dose inhalation product in the mouth. 

Jinks, P., and Marsden, S. (1999),The development and performance of a fluoropolymer lined can for suspension metered dose inhaler product, in Fradley, G., Ed., Proceedings of Drug Delivery to the Lungsa X, The Aerosol Society, Portshead, United Kingdom, pp. 177-180. 

TABLE 1 Summary of HFA Metered Dose Inhaler Products Available in United States, June 2006... 

Committee for Proprietary Medicinal Products. Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products. 1993, MCA Eurodirect Publication No. 5378/93. 

Nasal spray Inhalation spray Inhalation solutions and suspensions Metered dose inhaler MDI Dry powder inhaler DPI, device metered Dry powder inhaler DPI, pre-metered Not included Non-pressurized metered dose nasal spray Nasal single use sprays Non-pressurized metered dose inhaler Product for nebuhzation (single and multiple use) Pressurized metered dose nasal sprays Pressurized metered dose inhaler Dry Powder Inhaler, device metered Nasal powders, device metered Dry Powder Inhaler, pre-metered Nasal drops (single and multiple use)... 

Stability test Nonpros surized metered dose nasal spray Nasal single use sprays Non-pressurized metered dose inhaler Product for nebulization (single and multiple use)... 

Ross DL, Schultz RK. Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler and metered dose inhaler products. J Aerosol Med 1996 9 215-226. 

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. 

In the United States, use of CEC propeUants, designated as PropeUants 11, 12, and 114, is strictly limited to specialized medicinal aerosol products such as metered-dose inhalers. The physical properties and chemical names of these propeUents are given in Table 2. 

Draft Guidance for Industry-Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation, Nov. 13, 1998. 

To measure lung deposition by imaging, the aerosol must be first labelled or tagged with a suitable radionuclide. Radiolabelling techniques have been developed for current inhalation products including nebulizers, propellant-driven metered dose inhalers, and dry powder inhalers. 

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. 

U.S. Food and Drug Administration (FDA) (1998, Oct.), Guidance for industry Metered dose inhaler and dry powder inhaler drug products, FDA Washington, DC. 

Stress Testing (drug product) — Studies undertaken to assess the effect of severe conditions on the drug product. Such studies include photostability testing (see ICH Q1B) and specific testing of certain products (e.g., metered dose inhalers, creams, emulsions, refrigerated aqueous liquid products). 

Inhalation drug products include inhalation aerosols (metered dose inhalers) inhalation solutions, suspensions, and sprays (administered via nebulizers) inhalation powders (dry powder inhalers) and nasal sprays. The CMC and preclinical considerations for inhalation drug products are unique in that these drug products are intended for respiratory tract-compromised patients. This is reflected in the level of concern given to the nature of the packaging components that may come in contact with the dosage form or the patient. 

FDA. Guidance for industry metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products. CDERGUID 2180dft.wpd, Nov 1998, http //www.fda.gov/cder/gui-dance/2180dft.pdf, 1998. 

Gupta A, Stein SW, Myrdal PB. Balancing ethanol cosolvent concentration with product performance in 134a-based pressurized metered dose inhalers. J Aerosol Med 2003 16(2) 167-174. 

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). 

Fewer than 12 different excipients in MDI products have been formulated into metered aerosols. The availability of established FDA-approved excipients limits the formulator to a select few such ingredients. Table 1 lists excipients and the approximate amounts of some of these excipients that are currently used in MDIs. Metered-dose inhalers formulated with CFCs contain propellant 12, propellant 12/11, propellant 12/114, or propellant 12/114/11. These propellant... 

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.)...

Complex dosage forms, such as modified-release products, transder-mal patches, metered-dose inhalers... 

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