Pressurized metered dose inhaler formulations

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. 

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. 

Lofdahl CG, Andersson L, Bondesson E, Carlsson LG, Friberg K, Hedner J. Differences in bronchodUating potency of salbutamol in Turbuhaler as compared with a pressurized metered-dose inhaler formulation in patients with reversible airway obstruction. EurRespir J 1997 10 2474—2478. 

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. 

Hallworth, G.W. The formulation and evaluation of pressurized metered-dose inhalers. In Drug Delivery to the Respiratory Tract Jones, D.G.T., Ed. Ellis Horwood, Ltd. Chichester, England, 1987 87-118. 

Constantinou, M. Waters, S. Steel, C. Poole, K. Marino, P.P.I. Phodes, C. A birhio, F. Moore, A. Pike, V. Luthra, S. Flixotide -pressurized metered dose inhalers loaded with [ F] fluticasone propionate particles for drug deposition studies in humans with PET-formulation and analysis. J. Label. Comp. Radiopharm 2004, 47, 55-70. 

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. 

The pressurized metered-dose inhaler (pMDI) for the delivery of antiasthma drugs originated in the U.S. cosmetic industry. George Maison, the president of Riker Laboratories, and Irvin Porash, who worked in Riker s pharmaceutical development laboratory, are credited with the development of the first pMDI (32). Experiments were conducted to formulate pressurized aerosols of isoproterenol and epinephrine, which had been dissolved in alcohol, using the freon propellants 12 and 114. 

Sharma K, Somavarapu S, Colombani A, Govind N, Taylor KMG. CrossUnked chitosan nanoparticle formulations for delivery from pressurized metered dose inhalers. Eur J Pharm Biopharm. 2012 81(1) 74-81. 

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. 

Tetrafluoroethane is a hydrofluorocarbon (HFC) or hydro-fluoroalkane (HFA) aerosol propellant (contains hydrogen, fluorine, and carbon) as contrasted to a CFC (chlorine, fluorine, and carbon). The lack of chlorine in the molecule and the presence of hydrogen reduces the ozone depletion activity to practically zero. Hence tetrafluoroethane can be considered as an alternative to CFCs in the formulation of metered-dose inhalers (MDIs). It has replaced CFC-12 as a refrigerant since it has essentially the same vapor pressure. Its very low Kauri-butanol value and solubility parameter indicate that it is not a good solvent for the commonly used surfactants for MDIs. Sorbitan trioleate, sorbitan sesquioleate, oleic acid, and soya lecithin show limited solubility in tetrafluoroethane and the amount of surfactant that actually dissolves may not be sufficient to keep a drug readily dispersed. 

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