frequencies, we can see that the percentage of the droplets below 5.79 mm was higher and the median diameter lower for the 2.4-MHz frequency,although ventilation was higher.

    The increase in vibration frequency decreased the size of emitted droplets. This is difficult to observe with the 1.63-MHz frequency compared to 1.5MHz because ventilation was at its highest.

   Table 5 presents the influence of a coupling liquid on solution temperature after nebulization for 10 min. With nebulizers B and C, the increase in temperature was moderate because of the presence of a coupling liquid that prevented contact between the solution and the transducer. With nebulizer A,the temperature of the solution after nebulization for 10 min was higher than 40 .The coupling liquid absorbed the energy produced by ultrasonic vibrations and cancelled out any heating of the solution, which often occurs with ultrasonic nebulizers

(11–13). The rise in temperature might be responsible for drug degradation.For example,after ultrasonic nebulization,Ip et al. (13) reported denaturing of a protein (recombinant methionyl interferon consensus) that could be avoided by not

heating the solution. In the same way, Cipolla et al.(12) noted an aggregation of rH DNase because of heightened temperature.

   The use of ultrasonic nebulizers at high vibration intensity and low ventilation gives satisfactory nebulization of solutions as regards the size of emitted droplets, the quantity of drug nebulized, and the nebulization time. A low ventilation level is preferable,on the one hand, for the emission of the

smaller-size droplets required to administer the drug deep into the lungs and, on the other hand, for better compatibility with patient administration.High intensity is preferred because it increases the quantity of drug nebulized and therefore the quantity of drug likely to reach the lungs. The presence

of a coupling liquid is interesting because it prevents the increase in temperature that could degrade some drugs. High vibration frequency is better because it makes it possible to obtain smaller-size droplets.

    For a given ultrasonic nebulizer, the vibration frequency of the transducer is fixed. Only vibration intensity and ventilation level have to be defined to nebulize a given solution with an ultrasonic nebulizer.In contrast, with jet nebulization, a nebulizer with given geometric characteristics has to be chosen: liquid and air tube orifice diameters, size and shape of the reservoir, shape and position of the impaction system. All these have to be associated with defined airflow and pressure conditions.

CONCLUSION

An ultrasonic nebulizer is efficient, with high vibration frequency, for drug administration into the lungs. High vibration intensity associated with a low ventilation level is preferable for the delivery of drugs deep into the lungs. Using a coupling liquid that transmits ultrasonic vibrations to the solution and limits any increase in temperature is favorable. This is particularly interesting for thermosensitive substances that could be used with this type of nebulizer.

To maintain a constant quantity of drug for the patient at each administration, it is necessary to standardize operating conditions: vibration intensity and ventilation level therefore have to be defined.

It is indispensable that solutions for nebulization should be subjected to thorough pharmaceutical trials before use to define the best-adapted nebulizer(s) and the operating conditions for those retained. In the interest of public health, when a Marketing Authorization Application file is requested for a liquid preparation to be nebulized and its droplet size greatly influences drug therapeutic activity, it seems important to us not only to define the formulation, but also to associate with it the proper nebulizer(s) and administration conditions.This is the case for both specialties Pentacarinat* (Bellon, Neuilly/Seine, France) containing pentamidine and Pulmozyme* (Roche, Neuilly/Seine,France) containing dornase alpha, which obtained the Marketing Authorization Application file in 1989 and 1994.