Stg 4 Stg 5 Stg 6 Stg 7

Figure 3 Individual stage plates and inlet from the Anderson Cascade Impactor showing the pattern of radioactivity on the plates following sizing of a radiolabeled pMDI formulation. The plates and inlet were placed on the planar gamma camera face and imaged to measure the amount of deposited radioactivity. The plates were subsequently washed with solvent and assayed using UV spectroscopy to obtain the amount of drug deposited.

measured on the individual stage plates and then the drug can be dissolved off the plates and assayed chemically by UV spectroscopy or HPLC. The latter is particularly useful for single doses or small quantities of drug. Using these data allows the frequency distributions for particle diameter in terms of radioactivity and mass of drug to be plotted in parallel.

Fig. 4a and b give examples of graphs plotted from sizing data obtained for a radiolabeled formulation in comparison to the unlabeled or control formulation. The graphs plotted are the frequency and cumulative mass distributions for drug mass and radioactivity [86]. Fig. 4c gives the Line of Identity (LOI) between drug mass and radioactivity in this particular formulation. All the data from all the impactor stages from 19 sizing runs have been plotted. The deviation from the line of identity allows one to see the extent of the variability of the "match" within the aerosol. Statistically, the radiolabel was considered to be a match and reliable surrogate for the drug, and it was subsequently used in a deposition study in asthmatic subjects.

Measurement of Dose of Radioactivity and Drug to be Administered. As described earlier, unit doses of dispensed aerosol—pressurized, powder, or liquid—can be collected in the apparatus shown in Fig. 1 [84,91]. The single doses are dispensed into the tube, using a suction airflow matching that for the impactor sizings and the inspiratory flowrate to be used by the study subjects. The radioactivity in the tube can be counted and the drug content assayed chemically by UV spectroscopy or HPLC to provide the emitted dose. For pMDIs, mean actuator mouthpiece content of radioactivity and drug can be determined from the total of 10 doses by counting the actuator in the dose calibrator; the drug is measured by dropping the actuator into a fixed volume of solvent and assaying the drug content chemically.

Fig. 5 [86] shows an example of the mean unit spray content for drug and radioactivity for several study days using this labeled powder. Each bar of the graph represents a mean ± standard deviation of 10 unit doses. While the CV of the daily measurements for both drug and radioactivity must be within specified limits, it should be understood that the mean daily level of radioactivity in the formulation or nominal dose of radioactivity varies as a function of the level of the specific activity available from the generator on the day of the study. This variability in the amount of radioactivity affects only the absolute dose of radioactivity inhaled and not the measured deposition distribution. Deposition results should be normalized to account for these differences, even for the small, day-to-day variability in the supply of radioactivity.

Because radiolabeling techniques are not precise and specific activities of the isotopes can vary, validation and calibration should be done for each radiolabeled aerosol produced. In particular, the measurement of emitted doses

Figure 4 (a) Frequency distribution of drug mass and radioactivity for a radiolabeled powder and the drug in the original (control) powder versus aerodynamic particle diameter, obtained to validate the radiolabeled powder for deposition experiments. Measurements were obtained using the Anderson Cascade Impactor operated at 28 lpm. While the statistical comparisons showed significant differences between some of the amounts of drug and radioactivity on several of the stages, the differences were small and not sufficient to preclude the aerosol from being used in deposition studies. The drug was unchanged by the labeling process. (b) Cumulative distribution plotted from the sizing data for drug and radioactivity in the radiolabeled formulation and the drug in the original powder. A mean difference of approximately 3.0% was obtained between the radioactivity and drug on the lowest stage of the impactor. This resulted in a small but significant difference in the FPF (% < 5.8 mm) between the three distributions (p = 0.01, ANOVA). The FPF for the control powder and the drug in the labeled powder were the same. (c) Identity plot for the drug and radioactivity on all impactor plates from 19 sizings of a labeled powder formulation. The correlation is high, indicating that the radioactivity mirrors the drug. (From Ref. 86.)

Figure 4 Continued.

Figure 5 Graph demonstrating in vitro reproducibility of the emitted dose for a radiolabeled drug powder inhaled at two different inspiratory flowrates. Although the mean dose of drug and radioactivity varied between study days, the coefficient of variation for the emitted doses of drug or radioactivity on each study day was low. The amount of radioactivity used in the labeling of the powder varied with the specific activity of the 99mTcO42 supply on each labeling day [86].

Figure 5 Graph demonstrating in vitro reproducibility of the emitted dose for a radiolabeled drug powder inhaled at two different inspiratory flowrates. Although the mean dose of drug and radioactivity varied between study days, the coefficient of variation for the emitted doses of drug or radioactivity on each study day was low. The amount of radioactivity used in the labeling of the powder varied with the specific activity of the 99mTcO42 supply on each labeling day [86].

provides the mean value for the dose of radioactivity administered, which must be further corrected for decay between the time of production and the time of use. This value is critical if calculating absolute doses inhaled rather than percentages of radioactivity distributed within the respiratory tract.

Provided that the radiolabeling process does not alter the particle size distribution of the emitted drug and that the size distribution of the radiotracer is similar, the radiolabeled formulation may be used to measure total lung deposition and distribution of the inhaled drug. If clinical response measurements are performed following inhalation of the radiolabeled pMDI aerosol, the particle size characteristics and dose of drug per actuation in the radiolabeled formulation must match those of the drug in the unlabeled or original formulation. A successful match is indicated by an equivalent in vivo clinical response to the labeled and unlabeled formulations. Useful information from these studies will be obtained only if the label accurately follows the drug during inhalation.

Other Factors. Additional factors that should be standardized for the in vitro characterization of the aerosol size distribution are:

• The ambient temperature and humidity

• The inlet stage or entry port for the sizing system (Fig. 6 [92])

• The coupling of the inhaler to the inlet stage

• The number of priming doses to be "wasted" from the inhaler prior to sampling the aerosol

• The number of doses sampled

Figure 6 Different inlets used to couple a cascade impactor to an aerosol delivery system. The inlets range in volume from 66 to 1080 mL [92] and collect varying amounts of drug, depending on their volume. This in turn affects the amount of aerosol sampled by the impactor.

• The time between actuations

• Whether a pMDI is shaken between doses

• The type of pMDI actuator mouthpiece used

• The expression of the results

With a sensitive balance, it is possible to measure the actual weight of drug deposited on the various stages of the impactor. The weight, however, would include the weight of any excipients in the formulation as well as the drug. For any impactor sizing system used and where drug assays are required for analysis, reproducible standard curves must be produced for each drug tested. Standard curves for the drug on impactor plates, filters, impactor inlets, and the unit dose collection apparatus should be obtained to correct for the possibility of interference from extractibles.

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