November 2002 / Volume 47 / Number 11 / Page 1305
Formulations and Nebulizer Performance
IntroductionTo deliver a drug by nebulization, the drug must first be dispersed in a liquid (usually aqueous) medium. After application of a dispersing force (either a jet of gas or ultrasonic waves), the drug particles are contained within the aerosol droplets, which are then inhaled. Some drugs readily dissolve in water, whereas others need a cosolvent such as ethanol or propylene glycol. Some drugs are delivered as suspensions, and the efficiency of nebulizers can be different for solutions and suspensions. Solutions are delivered more efficiently with most devices. In general, conventional ultrasonic nebulizers should not be used to aerosolize suspensions, because of low efficiency. Newer strategies to improve the delivery of non-water-soluble drugs include the use of liposomes and the milling of the drug into very small "nanoparticles." In addition to the active therapeutic ingredient and solvents, drug formulations may include buffers (the solubility of some medications is influenced by pH), stabilizers, and, in the case of multi-dose preparations, antibacterial agents. Though formulations are designed to optimize drug solubility and stability, changes in formulation can also affect inhaled mass, particle size, and treatment time, though the differences between nebulizer brands probably have a greater impact than differences in formulation. Ultrasonic and jet nebulizers may damage protein and other complex agents through heat or shear stress. Additives to multi-dose formulations, especially antimicrobial and chelating agents, may cause adverse events, so there is a trend towards single-use, preservative-free vials.
Solubility in Water
Modification of Other Characteristics of Solutions
Nebulization of Suspensions
Preservatives and Antioxidants
Alterations to Formulations During Nebulization
Aerosolization of aqueous solutions and suspensions is an important therapeutic option in the management of respiratory disease. Even though the majority of patients with respiratory disorders use pressurized metered-dose inhalers and dry powder inhalers to administer inhaled |gb-agonists and inhaled corticosteroids, nebulization remains a popular choice for certain groups of patients: for example, corticosteroids are nebulized for young children, and beta2-agonists are nebulized for critically ill, emergency room patients. In those settings, nebulizers' simplicity of use and reliability are advantageous because patient cooperation may be limited.
Nebulizers are also an attractive option for drugs that need to be delivered in relatively large quantities (eg, hundreds of milligrams in the case of antibiotics for cystic fibrosis patients). In addition. because of the relatively simple design, nebulizers will probably remain an attractive option for early "proof of concept" studies with new chemical entities and the exploration of new indications for established medications. The latter objective has often been pursued by aerosolization of existing intravenous or even nasal formulations. However, the recent death of a research volunteer after inhalation of an investigator-prepared formulation of hexamethonium is expected to lead to closer scrutiny of proposals for inhalation of new chemical entities or formulations that are only approved for noninhalation modes of delivery.