Metered dose inhalers formulation development

Liquid instillation and nebulised aerosols are the most common methods for pulmonary administration to experimental animals [22, 54, 109, 134], The use of pressurised metered dose inhaler (pMDIs) and dry powder inhaler (DPIs) in preclinical studies is limited by the need for formulation development, which often cannot be performed in early drug discovery due to short supply of test materials. A number of alternative techniques for intra-tracheal administration of coarse sprays and powder formulations have been described [9, 15, 21, 36, 71, 80, 99, 138],... 

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. 

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. 

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. 

The most significant developments in metered-dose inhaler technology to occur since the early 1990s have been the introduction of hydrofluoroalkane (HFA) systems as alternatives to chlorofluorocarbon (CFC) systems [174]. This has largely been caused by the link between the use of CFC systems and ozone depletion in the upper atmosphere [152,175]. Albuterol and beclomethasone have been reformulated in HFA products, but as yet the CFC products are still subject to an annually renewable medical exemption. The Food and Drug Administration has recently published its position on alternative propellant formulations, which should initiate the phase-out of CFCs [176]. In the meantime, a number of generic CFC products of albuterol have been manufactured. The opportunity for reformulation of products as they come of patent is likely to increase research and development in this area in the near future. New formulation opportunities will also arise from these developments, including solutions [177], micellar [178,179], and microemulsion [180]. 

For instance, fluticasone propionate is dosed topically to the lung via metered dose inhalers or dry-powder inhalers, and its high lipophilicity and low aqueous solubility are important for the drug s pharmacokinetic and pharmacodynamic profile [8, 9]. Models predicting solubility in specific formulations, or models predicting dissolution rate, may be useful in formulation development and drug delivery. 

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. 

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