Suspensions metered dose inhalers

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. 

Byron PR. Dosing reproducibility from experimental albuterol suspension metered-dose inhalers. Pliarm Res 1994 11 (4) 580—584. 

Zheng, J. Y., Fulu, M. Y., Lee, D. Y., Barber, T. E., and Adjei, A. L. (2001), Pulmonary peptide delivery Effect of taste-masking excipients on leuprolide suspension metered-dose inhalers, Pharm. Dev. Technol., 6,521-530. 

Berry, J., Kline, L. C., Hart, J. L., and Sequeira, J. (2003), Influence of the storage orientation on the aerodynamic particle size of a suspension metered dose inhaler containing propellant HFA-227, Drug Dev. Ind. Pharm., 29, 631-639. 

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)... 

Tablets Capsules Emulsions Oral solutions and suspensions Metered dose inhalers Topical ophthalmic and otic preparations Parenterals...

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. 

Warren SJ, Farr SJ. Formulation of solution metered dose inhalers and comparison with aerosols emitted from conventional suspension systems. Int J Pharma 1995 124 195-203. 

Williams RO III, Brown J, Liu J. Influence of micronization method on the performance of a suspension triamcinolone acetonide pressurized metered-dose inhaler formulation. Pharm Dev Technol 1999 4(2) 167-179. 

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.)...

Schultz, R. K., Miller, N. K., Christensen, J. D. Method for evaluation of suspension characteristics relevant to metered dose inhaler formulations. Pharm Res 7(9, suppl.) 5 - S (1990). 

Samples may be introduced directly into the laser beam, as is the case with aerosols and metered dose inhalers, passed through a sample cell whose windows are transparent to the laser beam, or suspended in a cuvette under agitation. Dry powders are either blown through the beam or allowed to fall through it under gravity whereas particles in suspension are recirculated through the beam via a pump. 

In a metered dose inhaler, where fine drug particles are suspended in a propellent, stability and aggregation of the suspension are crucial for the performance of the inhaler. In an investigation into the aerosol formulation stability. Span 80 was added to a suspension of lactose to study the effect on deaggregation under shear.f An increase in shear stress was found to decrease aggregate size and boundary fractal dimension (Fig. 9), which was interpreted as a more compact aggregate. 

Surfactants are found in both solution and suspension formulations of metered dose inhalers (MDIs). The most common surfactants found in pressurised aerosol preparations include sorbitan trioleate (Span 85),... 

Clarke, J.G. Wicks, S.R. Earr, S.J. Surfactant mediated 42. effects in pressurized metered dose inhalers formulated as suspensions. I. Drug/surfactant interactions in a model propellant systems. Int. J. Pharm. 1993, 93, 221-231. 

The adsorption or incorporation of molecules, such as surfactants and polymers, can create a steric repulsion that prevents aggregation [288-290]. This can also increase suspension stability, important for metered-dose inhaler formulations [291]. Lung surfactant coating on the surface of poly(lactic-co-glycolic) acid microparticles has been shown to dramatically improve dry powder aerosol performance by reducing particle-particle interactions [134,292],... 

This method could either be used as a one-step process for the preparation of protein or peptide suspension for pressurised metered dose inhaler or the suspension could be poured into a flask and rotated at room temperature until the propellant evaporates. The powder derived from this could be used for the preparation of a dry powder for inhalation, which makes this technique versatile. 

Co-solvents in metered dose inhalers were commonly used in CFG formulations to aid in drug solubilization. In HFA formulations, co-solvents continue this same function, but have additional benefits in the new systems, such as solubilization of other excipients. Vervaet and Byron discuss water solubility in the various propellants addressed here, where the addition of ethanol to the HFA system considerably increases the solubility of water (Vervaet and Byron, 1999). Likewise, ethanol was found to increase the solubility of several surfactants in HFA (Vervaet and Byron, 1999 Stein and Stefely, 2003). Suspension formulations using this technique (surfactant plus ethanol) must be made with caution however, as ethanol can also increase the solubility of the drug substance, potentially causing increased particle growth via Ostwald ripening. Nonetheless,... 

Phillips EM, Byron PR, Dalby RN. Axial ratio measurements for early detection of crystal growth in suspension-type metered dose inhalers. Pharm Res 1993 10 454-456. 

The pressurized metered dose inhalers in the use of environmentally friendly propellants means the choice of hydrofluoroalkanes, wherein the dosage form can be a suspension of the solution form. The problems of formulating suspensions, as discussed earlier, apply here as well, but particularly with respect to interactions with the formulation components specific to pressurized inhaler systems. 

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... 

Information about the true density of a powder can be used to predict whether a compound will cream or sediment in a metered dose inhaler (MDI) formulation. The densities of the hydrofluoroalkane (HFA) propellants, 227 and 134a, which are replacing chlorofluoro-carbons (CFCs) in MDI formulations, are 1.415 and 1.217 g/cm , respectively. Therefore, suspensions of compounds that have a true density less than these figures will cream (rise to the surface), and those that are denser will sediment. Those that match the density of the propellant will stay in suspension for a longer period (Williams III et al. 1998). It should be noted, however, that the physical stability of a suspension is not merely a function of the true density of the material. 

In pressurised metered dose inhaler (pMDI) technology, CFC propellants are being replaced with the ozone-friendly hydrofluoroalkanes (HFA)-134a and -227. In pMDI drug delivery systems, the drugs are formulated as a suspension or as a solution, depending on the solubility of... 

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