Nebulizer Solution Formulations

Nebulizers are designed primarily for use with aqueous solutions or suspensions. Typically the drug suspensions use primary particules in the range of 2-5 microns. As a consequence, pharmaceutical solution technology, consistent with that used for parenteral products, may be applied to nebulizer solution or suspension formulation and processing.

Nebulizer solutions are usually formulated in water, although other cosolvents, for example, glycerin, propylene glycol, and ethanol, may be used. However, it is important to note that any excipients with possible airway toxicological implications might compromise a drug product; thus, such additional excipients should not be introduced unless essential and, if so, formulated at the lowest feasible concentration. The range of suspending agents in approved products is limited.

Nebulizer solution pH may be an important factor in determining compound physical or chemical stability. It has been recommended [31] that solution pH be greater than 5.0, because there is considerable evidence to show that bronchoconstriction is a function of hydrogen ion concentration.

Nevertheless, the formulation "buffer capacity" and "titratable acid content," in addition to the nature of the acid present, are perhaps the most important factors for nebulizer solutions of greater than pH 2.0.

With the advent of the potential of using the inhaled route to deliver macromolecules there has been considerable interest in the development of nebulized formulations of macromolecules [32]. Compound stability is a significant issue for these biotechnology products; as such, aqueous nebulizer solutions do not provide an inert vehicle. Moreover, the high shear experienced with an air-jet nebulizer may induce secondary or tertiary structural changes in peptide or proteins. In addition, reservoir temperature changes during nebulization may compound problems in physical or chemical stability with biotechnology products. Furthermore, macromolecules often produce viscous solutions, with modified interfacial and surface tension. A complete investigation of these factors is critical during early product development.

Nebulizer solutions are typically filled as unit dosages in plastic containers. The latter uses blow-fill-seal technology [33]. Thus drug formulation compatibility with plastics is an important factor. Characterization of any sorption processes of plasticizer, monomer, and "extractables" or "leachables" is critical during long-term product-evaluation studies. Such sterile unit-dose formulations, in essence, do not require chemical preservation.

In summary, although widely used, nebulizers are a highly variable, in general poorly understood means of achieving respiratory drug delivery despite their successful therapeutic use for many years.

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