AERx Pulmonary Delivery System for Morphine and Fentanyl

Another aerosol pulmonary delivery system with a built-in electro-mechanical liquid aerosol generator is shown in the following figure. The physical and mechanical details of the AERx® System is initated by an aerosol generated in about 1 s by means of mechanical extrusion of a piston of an aqueous formulation through an array of micron-sized laser micromachined holes. The extrusion causes the formation of aqueous jets that break up into droplets of sizes that relates to the sizes of the holes in the nozzle. The temperature controller warms up the dilution air to enhance stabilization of small, respirable droplets. The prototype system used for this study is a scaled-down version designed for inhalation delivery to dogs. For the majority of the studies described, the system was run at a flow rate of 15L/min.

AERx® consists of a single-use, disposable drug container (the AERx Strip™) and a device that aerosolizes the drug formulation into the patient's inhalation air stream through a nozzle in the strip. The AERx® system has electronic components in the device in order to operate features related to dose titration, breath actuation and coordination, inhaled air temperature control, and electronic storage of dosing information (Fig. IV-36).

The AERx®Pulmonary Delivery System has unique features that guide the patient to breathe in an optimal manner each time a dose is taken, which enhances repro-ducibility and efficiency of delivery. The AERx® System delivers aerosolized medication from a dosage form comprising of a blister containing 50 ^L of liquid drug formulation and a micromachined nozzle array. The aerosol is generated by extruding the formulation under pressure through an array of holes. The AERx® System also incorporates a temperature controller to minimize the effects of ambient air conditions and enhance the generation of aerosol droplets optimal for pulmonary targeting.

Nebulizers are relatively easy to use and no coordination is required, as the patient is instructed to breathe normally. However, a disadvantage of nebulizers is their low efficiency and poor reproducibility of delivery. The amount of aerosol reaching the lung from a jet or ultrasonic nebulizer has been estimated by several researchers at no more than about 10%, even when the nebulizer is operated to dryness. A significant contributor to this inefficiency is that nebulizers operate on the basis of continuous nebulization. Thus, a large proportion of the dose will never reach the patient. To improve delivery efficiency, it is important to deliver the aerosol only during the inhalation cycle. Aerosol delivered at the beginning of an inspiration can fill distal parts of the lung, while aerosol inhaled at the very end of the inspiration is likely to deposit predominantly in the oropharynx and central airways. The AERx® System is designed to sense the flow rate and volume and determine if it is optimum to deliver the targeted dose. The patient's inspiratory flow rate is measured and integrated. The actuation of the aerosol generation can occur only at the pre-programmed inspiratory flow rate and inspired volume to prevent delivery at suboptimal doses. Another critical issue for inhalation drug delivery is the potential for contamination with pathogenic microorganisms. Published reports on nebulizers show that contamination can be traced to multidose liquid packaging. Sterile unit-dose disposable systems such as the AERx® dosage form overcome this problem. The AERx® System thus has unique features that are highly desirable for delivering future therapies.

Figure IV-36. The AERx Essence® system offers a level of performance (efficiency and reproducibility) close to the existing AERx® system, but in a smaller and lower-cost package that does not have the dose titration, air temperature control, or dosing history features

The AERx® System has been previously used for the pulmonary delivery of both small molecules such as morphine [105, 106] and fentanyl [107]. It generally has been yielding emitted doses in the range of 60%-75%. The vast majority has been shown to deposit in the lung. Studies in normal fasting volunteers inhaling an aqueous solution of insulin from AERx® show that reduction in glucose levels is at least as reproducible as that achieved by subcutaneous injection, in both magnitude and time to maximum reduction in glucose levels. In a clinical study to evaluate pharmacokinetics of inhaled fentanyl delivered via the AERx® System, plasma concentration time courses for the AERx® System and intravenous route were comparable [107].

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