Ibuprofen delivered by nanoaerosol
Aerosol lung administration is a convenient way to deliver water-insoluble or poorly soluble drugs. For ibuprofen, we found that for the outbred male mice, the pulmonary administration of ibuprofen nanoparticles requires a dose that is six orders of magnitude less (i.e 1000000 times) than that for the orally delivered particles at the same analgesic effect.
Scheme of the experimental setup for inhalation experiments is shown in Fig. 1.
The aerosol evaporation generator consists of a horizontal cylindrical quartz tube with an outer heater. Argon flow was supplied to the inlet, and aerosol was formed at the outlet. The particle mean diameter and number concentration varied from 10 to 100 nm and 103--107 cm-3, respectively. We investigated the analgesic action and side pulmonary effects caused by the inhalation of ibuprofen nanoparticles. First, we verified that the chemical composition of aerosol particles was identical to the maternal drug (by UV absorption, liquid chroma- tography and X-ray diffraction). Then, using the nose-only exposure chambers (see Fig. 2), the mice lung deposition efficiency was evaluated as a function of the particle diameter.
Indomethacin derlivered by nanoaerosol
Fig. 3  RAI as function of ibuprofen dose delivered as nanoaerosol or orally. Mean particle diameter of nanoparticles is indicated for each point.
CASE STUDIES:
Fig. 2  Nose-only exposure chamber.
Fig. 4 Typical diameter distribution for ibuprofen nanoparticles (as measured by the aerosol spectrometer).
A similar study was carried out for indomethacin. The anti-inflammatory action and side pulmonary effects caused by the inhalation of indomethacin nanoparticles were investigated. We found that the aerosol administration was much more effective than the peroral treatment. The aerosol route required a therapeutic dose six orders of magnitude less (i.e 1000000 times) than that for peroral administration. The data in Fig. 5 are obtained on about 210 animals. The typical-size spectrum is shown in Figure 6.
Fig. 5 Mean relative edema index (REI) versus the lung deposited dose.  The particle mean diameter is shown at every point. The fitted dose-response curve is shown as solid line. The per-oral treatment point is a mean value throughout six experimental trials (each trial included groups of 8 to 10 animals).
Fig. 6 Typical diameter distribution for indomethacin nanoparticles.
Fig. 9 Lung deposition efficiency versus mean diameter of nisoldipine nanoparticles. Line is an eye guide.
Nisoldipine derlivered by nanoaerosol
Ibuprofen
Indomethacin
Nisoldipine
A similar study was carried out for nisoldipine. Nisoldipine is a dihydropyridine subclass calcium channel blocker with low oral bioavailability. Therefore, novel drug delivery systems able to enhance nisoldipine bioavailability are urgently needed. We use the aerosol pulmonary administration of nisoldipine on WISTAR and ISIAH rats. The dose-dependent effect from aerosolized nisoldipine was compared with that from the intravenous and oral drug delivery. We found that nisoldipine aerosol administration is more effective than traditional oral treatment. The data show that the aerosol inhalation gives the same reduction of systolic blood pressure as oral treatment, with the body delivered dose for inhalation about 100 times smaller than that for oral treatment. Figure 7 compares the blood pressure reduction for WISTAR rats after the drug delivery in different ways versus.the body delivered dose. In Fig. 7, one can see that for aerosol delivery, the blood-pressure reduction is already observed at doses of 0.1 mg per kg. It is important to note that there is a good agreement for the blood-pressure reduction between aerosol delivery and intravenous delivery.
Fig. 7 Relative reduction of the arterial blood pressure (P - Pa) / P for WISTAR rats versus the dose delivered, where P and Pa are pressures before and after treatment, respectively, Circles - Whole-Body chamber; triangles - Nose-Only-Exposure chamber; diamonds - injections, and gray circles - oral delivery. Mean particle diameter is shown for each aerosol inhalation point. Dash and solid lines are eye guides.
Fig. 8 Relative reduction of the arterial blood pressure versus the lung delivered dose: circles - WISTAR rats in Whole-Body chamber; squares - ISIAH rats in Whole-Body chamber. Solid line is an eye guide.
It is of interest to see if any strain effect in the antihypertensive action can be observed. For this purpose, the relative blood pressure reduction was compared for WISTAR and ISIAH rats. The data are shown in Fig. 8. Within the experimental accuracy, there is no difference in the blood pressure reduction effect for the WISTAR and ISIAH rats.

The histologic analysis was performed to observe possible hemodynamic abnormalities. Both the control and aerosol-treated animals reveal the normal appearance of lungs without any destructive and /or hemodynamic pathologic changes.
The lung deposition efficiency of nisoldipine nanoaerosol particles as a function of mean diameter of the particles is shown in Fig. 9.
Fig. 1  Scheme of the experimental setup for inhalation experiments
The dose-dependent analgesic effect of aerosolized ibuprofen was studied in comparison with the oral treatment. We found that the dose for aerosol treatment is three to five orders of magnitude less than that required for oral treatment at the same analgesic effect. Accompanying effects were moderate venous hyperemia and some emphysematous signs. Figure 3 shows the Relative analgesic index (RAI) for the aerosolized animals as well as RAI for the orally treated animals versus the lung-deposited dose. Figure 4 shows typical diameter distribution for ibuprofen nanoparticles.
Other medicines successfully delivered by nanoaerosol
Other drugs
The following medicines were also tested and delivered by nanoaerosol:

NSAIDs - Voltaren (Diclofenac Sodium), Analgin, Cortisone acetate, Butadion (Phenylbutazone)

Stimulant - Caffeine

Sedative - Sodium barbital, Nozepam

TB - Isoniazid

Antihypertensive - Nifedipine
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