Pharmacokinetics of cisplatin administered by the pulmonary route were established in mice using dry powders inhaler (DPI) formulations showing immediate (F1) and controlled release (CR, solid lipid microparticles) in vitro, without (F2) or with PEGylated excipients (F3, F4). Formulation administration was realized using dry powder blends (correspondingly named thereafter F1B to F4B) able to reproducibly deliver particles in vivo using a DP-4M Dry Powder Insufflator™. Their platinum pharmacokinetics were established over 48h in lungs, total blood and non-target organs vs. IV and endotracheal nebulization (EN). EN and F1B were rapidly distributed from the lungs (t1/2i 2.6 and 5.0min). F2B was eliminated in ∼1h (t1/2i 9.0min). F3B lung retention was sustained for ∼7h (t1/2i 59.9min), increasing lung AUC 11-, 4- and 3-fold vs. IV, F1B and F2B. Total blood tmax were higher and AUC and Cmax lower using the pulmonary route vs. IV. Kidney Cmax was reduced 6-, 2- and 3-fold for F1B, F2B and F3B. AUC in kidneys were 2- to 3-fold lower for F1B and F2Bvs. IV but comparable for IV vs. F3B, probably because of kidney saturation. PEGylated solid lipid microparticles provided cisplatin particles with interesting lung retention and CR properties.
Keywords: Alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS, PubChem CID:71406); Cisplatin; Cisplatin (PubChem CID:441203); Controlled release; Distearoyl phosphoethanolamine polyethylene glycol 2000, sodium salt (DSPE-mPEG-2000, PubChem CID:86278270); Dry powder for inhalation; Lung cancer chemotherapy; Lung retention; Solid lipid microparticles; Stealth formulation; d-mannitol (PubChem CID: 6251), tristearin (TS, PubChem CID:11146); l-leucine (PubChem CID: 6106).
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