Formulations for Nebulizers

Nebulizers and dry powder inhalers seem more appropriate systems to be used in the early stages of development of drug products for pulmonary drug delivery. However, it should not be concluded from this that the development of formulations for nebulizers or DPIs is easier and exhibits fewer theoretical and practical problems. 

Klyashchitsky, B. A., Owen, A. J., Nebulizer-compatible liquid formulations for aerosol pulmonary delivery of hydrophobic drugs glucocorticoids and cyclosporine,... 

For nebulizer and other aqueous aerosol products that use suspension systems, excipients are used to influence particle physical and chemical stability (e.g., microcrystalline cellulose for nasal sprays). The suitability of the physicochemical properties of these critical excipients should be thoroughly investigated and documented (12). Far more excipients have been included in formulations designed for nasal administration (Table 4). 

Although routine oral delivery of proteins has not been realized, some protein formulations have been developed for pulmonary delivery. Pulmonary delivery can result in either parenteral or local administration of the drug and, like oral delivery, is considered non-invasive. As with other routes of delivery, the size of the protein may limit its ability to be delivered systemi-cally via the pulmonary route of administration. Pulmozyme , a DNase-based formulation approved for the treatment of cystic fibrosis (CF), is delivered to the lungs by a nebulizer to clear blockage of the airways in the CF patient.Formulations for insulin to be administered by inhalation for systemic delivery of... 

Clark, AR. Shire, S.J. Formulation of Proteins for Pulmonary Delivery Protein and Formulation Delivery, McNahy, E.J., Ed. Marcel Dekker, Inc. New York, 2000 201-234. O Riordan, T.G. Formulations and nebulizer performance. Respir. Care 2002, 47 (11), 1305-1313. 

Chlorocresol is used primarily as a preservative in topical pharmaceutical formulations but has also been used in nebulized solutions and ophthalmic and parenteral preparations. It should not, however, be used in formulations for intrathecal, intracisternal, or peridural injection. 

This chapter presents an overview of formulation design, describes device function, and addresses product operation in relation to inhalation delivery system performance for nebulizers, MDIs, and DPIs. Methods of manufacture of... 

As a guide to formulation development, studies should be undertaken to evaluate the contribution of candidate excipients, including preservatives, antioxidants, chelating agents, cosolvents, and buffers on compound stability and solubility. This is particularly important in the development of suspensions for nebulization. Compatibility with packaging components also needs to be considered as a matter of priority. Peptides and proteins in particular are notorious in their ability to adsorb onto a variety of surfaces, particularly plastic. 

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. 

Nebulizer formulations are normally solutions, however, suspensions are also used, e.g., the insoluble steroid budesonide has been successfully formulated for delivery by nebulization (Dahlback 1994). Some important preformulation considerations for nebulizers are stability, solubility, viscosity and surface tension (McCallion et al. 1996 Nikander 1997). In terms of solubility, the common ion effect may be important where, e.g., a hydrochloride salt is to be dissolved in saline. In addition, the temperature dependence of the solubility of the drug may... 

Patients suffering from cystic fibrosis often use various aerosolized drugs. To reduce the viscosity of the mucus in the airways, recombinant human deoxyribonuclease is used. This enzyme is the first recombinant protein that has been developed for specific delivery to the lungs via the airways. It has a local action on the mucus in the airways and its absorption is minimal. Another drug that decreases the viscosity of the mucus is acetylcysteine. Aerosolized antibiotics are a further group of therapeutics that is widely used by cystic fibrosis patients. Solutions of antibiotics like tobramycin or colistin are used in nebulizers to prevent exacerbation of the disease. Pentamidine has been used for the prophylaxis of Pneumocystis pneumonia in patients infected with HIV virus, while chronic rejection of lung transplants provided a reason to develop an aerosol formulation of cyclosporine A. 

Pentamidine is an aromatic diamidine (Figure 52-3) formulated as an isethionate salt. Pentamidine is only administered parenterally. The drug leaves the circulation rapidly, with an initial half-life of about 6 hours, but it is bound avidly by tissues. Pentamidine thus accumulates and is eliminated very slowly, with a terminal elimination half-life of about 12 days. The drug can be detected in urine 6 or more weeks after treatment. Only trace amounts of pentamidine appear in the central nervous system, so it is not effective against central nervous system African trypanosomiasis. Pentamidine can also be inhaled as a nebulized powder for the prevention of pneumocystosis. Absorption into the systemic circulation after inhalation appears to be minimal. The mechanism of action of pentamidine is unknown. 

Inhalation solution and suspension drug products are typically aqueous-based formulations that contain therapeutically active ingredients and can also contain additional excipients. Aqueous-based oral inhalation solutions and suspension must be sterile (21 CFR 200.51). Inhalation solutions and suspensions are intended for delivery to the lungs by oral inhalation for local or systemic effects and are used with a specified nebulizer. Unit-dose presentation is recommended for these drug products to prevent microbial contamination during use. The container closure system for these drug products consists of the container and closure and can include protective packaging such as foil overwrap. 

Nebulizers are designed primarily for the atomization of aqueous formulations either as solutions or suspensions, and typically contain additional excipients. These systems are nonpressurized formulations and do not contain propellants. Traditionally, nebulizers operated using one of two basic mechanisms jet nebulization or ultrasonic nebulization. Jet nebulizers (Fig. 3) function using the Venturi effect to... 

Solution-based systems are common to both nebulizers and nasal formulations. In general, water will form the greatest fraction of the formulation, but, in some cases, cosolvents such as ethanol and propylene glycol may be added for increased stability. Acidifying and alkalizing excipients may also be added to optimize pH from the perspective of the drug stability as well as the physiological effect on the airways. Similarly, iso-osmotic and iso-tonic solutions are preferred. 

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