Nebulizers formulation

Nebulizer formulation conforms to sterile product preparation, which means that drug stability in solution in the presence of additives must be evaluated. Historically, it was sufficient to use antimicrobial agents in the formulation, notably benzalkonium chloride. Adding antimicrobials is not now considered an acceptable approach to the formulation of nebulizer solutions. The solubility of the drug is important since it may impact upon the performance of the solution in a selected nebulizer. Additives may form complexes with the drug. 

Smaldone GC, McKenzie J, Cruz-Rivera M, Hoag JE (2000) Budesonide inhalation suspension is chemically compatible with other nebulizing formulations. Chest 118(4) 98S... 

Nebulizer systems are universally aqueous in nature and can be either solution or suspension based. Excipients that have been used in nebulizer formulations relate to typical aqueous formulations and the formulation issues common to this type of preparation (i.e., stability and sterility issues). Table 3 provides several examples of nebulizer formulations that are commonly marketed along with the excipients... 

Solutions or suspensions are available as nebulizer formulations. Due to the relative simplicity in formulating a liquid nebulizer formulation and because of the relatively large range of doses available for delivery, the nebulization method is often chosen as the aerosol method for proof-of-concept investigational studies. 

Suspension nebulizer formulations exhibit a complex behavior in which the particle or aggregate size in suspension may influence the size of the droplet delivered from an air jet nebulizer, and as the size of the particles approaches and exceeds the droplet size produced, size selectivity in dispersion of the particles may occur.46 Ultrasonic nebulizers are also susceptible to particle size in dispersion.47... 

Nebulizer formulations are normally solutions, but suspensions (particle size of less than 2 (jim) are also used. Important preformulation considerations include stability, solubility, viscosity, and surface tension of the solution of suspension. 

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... 

Many firms tend to staff their technical service efforts with personnel that have experience solely in the particular business involved. It is often of value to consider individuals having experience in related industries, both to provide a different set of skills and to provide a different perspective than that of in-house experts. This is particularly important in the specialty chemicals arena, where formulations experience is generally of paramount importance. This variety of knowledge is often largely experiential, as much of the treatment and behaviors of formulations in the chemical industry are empirical or experience-based rather than quantitatively understood. It is therefore extremely difficult to train personnel ia dealing with the often nebulous aspects of formulations technology. 

Nebulized colistin using the IV formulation may be an option in patients with tobramycin-resistant strains or intolerance to inhaled tobramycin. Due to an increased risk of bronchoconstriction after colistin inhalation, patients should pre-treat with albuterol and administer the first doses under medical observation.1,5... 

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

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. 

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. 

Because the relationship between the physical characteristics and the nebulizer performance is less straightforward than expected, it should be stressed once again that laboratory evaluation of the specific drug formulation in combination with the intended nebulizers is required, before their use in vivo. 

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. 

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). 

Later, Lizio et al. [78] used a new aerosol delivery system (ASTA-ADS) to investigate the pulmonary absorption and tolerability of four different cetrorelix formulations delivered as nebulized aerosols to orotracheally cannulated rats. After only 5 min exposure to the cetrorelix aerosol, serum testosterone concentrations were reduced to subnormal levels over a 24-h period. After dose adjustment (dose delivered minus exhaled amount), the bioavailabilities for pulmonary delivery ranged from 48.4 27.0% to 77.4 44.0% compared to IV administration. In addition, the lung function parameters did not reveal any formulation-related changes. Overall, the results of cetrorelix aerosol administration compared well with those obtained with intratracheal instillation of cetrorelix solution [77]. 

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