Development of a pulmonary peptide delivery system using porous nanoparticle-aggregate particles for systemic application

• The entrapment efficiency of peptide loaded nanostructured lipid carriers (NLCs) could reach to 95%.
• The porous nanoparticle-aggregate particles (PNAPs) powders could remain in lungs for a longer time than octreotide acetate (OA) solution and reach a sustained release.
• The bioavailability was markedly enhanced by pulmonary deliver PNAPs compared with pulmonary deliver OA solutions and subcutaneous inject OA solution.
• As far as we know, this is the first report on the anti-hepatic ischemia–reperfusion injury (HIRI) effects through intrapulmonary administration.

As a non-invasive administration route, pulmonary peptide delivery for systemic application has shown great promise. However, many barriers exist that prevent effective peptide delivery. The use of porous nanoparticle-aggregate particles (PNAPs) is an excellent option because of their proper aerodynamic size and maximal deposition. However, in most cases, the spray drying heating process for PNAPs has been challenging in regard to maintaining peptide stability and activity. To overcome these issues, we developed a spray freeze-drying method for PNAP preparation. To solve the low entrapment efficiency problem of nanostructured lipid carriers, we used hydrophobic ion pair complexes to increase the lipophilicity of the peptide, thus increasing entrapment efficiency and drug loading. Here, we used a model peptide, octreotide acetate, for PNAP preparation, which has a high entrapment efficiency (>95%) and proper aerodynamic size (~3 μm). In addition, after intrapulmonary administration, we evaluated the pharmacokinetics and pharmacodynamics in a rat preventive hepatic ischemia–reperfusion injury model. Our in vivo data showed significantly increased area under the curve and improved plasma aspartate aminotransferase levels for our PNAP intrapulmonary delivery system vs. the clinically used octreotide acetate delivery via subcutaneous injection. Together, PNAPs may have great potential for carrying peptide drugs for pulmonary delivery.

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