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The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer–surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0–24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer–surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug.

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The objective of this study was to develop a novel anhydrous reverse micelle nanoparticles (ARM-NPs) system to overcome the sedimentation instability of peptide-containing pressurized metered-dose inhalers (pMDIs). A bottom-up method was utilized to fabricate ARM-NPs. Tertiary butyl alcohol (TBA)/water system, freeze-drying and lipid inversion method were successively used to produce the ARM-NPs for pMDI. Various characteristics of ARM-NPs were investigated including particle size, morphology, secondary structure of the peptide drug, aerosolization properties and storage stability. As revealed by the results, ARM-NPs with spherical shape possessed 147.7 ± 2.0 nm of particle size with 0.152 ± 0.021 PdI. The ARM-NPs for pMDI had satisfactory fine particle fraction (FPF) value of 46.99 ± 1.33%, while the secondary structure of the peptide drug was unchanged. Stability tests showed no pronounced sedimentation instability for over 12 weeks at 4-6 °C. Furthermore, a hypothesis was raised to explain the formation mechanism of ARM-NPs, which was verified by the differential scanning calorimetry analysis. The lecithin employed in the reverse micelle vesicles could serve as a steric barrier between peptide drugs and bulk propellant, which prevented the instability of peptide drugs in hydrophobic environment. Homogenous particle size could avoid Ostwald ripening phenomenon of particles in pMDIs. It was concluded that the ARM-NPs for pMDI could successfully overcome sedimentation instability by the steric barrier effect and homogeneous particle size.

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An optimum carrier rugosity is essential to achieve a satisfying drug deposition efficiency for the carrier based dry powder inhalation (DPI). Therefore, a non-organic spray drying technique was firstly used to prepare nanoporous mannitol with small asperities to enhance the DPI aerosolization performance. Ammonium carbonate was used as a pore-forming agent since it decomposed with volatile during preparation. It was found that only the porous structure, and hence the specific surface area and carrier density were changed at different ammonium carbonate concentration. Furthermore, the carrier density was used as an indication of porosity to correlate with drug aerosolization. A good correlation between the carrier density and fine particle fraction (FPF) (r2 = 0.9579) was established, suggesting that the deposition efficiency increased with the decreased carrier density. Nanoporous mannitol with a mean pore size of about 6 nm exhibited 0.24-fold carrier density while 2.16-fold FPF value of the non-porous mannitol. The enhanced deposition efficiency was further confirmed from the pharmacokinetic studies since the nanoporous mannitol exhibited a significantly higher AUC0-8h value than the non-porous mannitol and commercial product Pulmicort. Therefore, surface modification by preparing nanoporous carrier through non-organic spray drying showed to be a facile approach to enhance the DPI aerosolization performance.

Netilmicin (NTM) is one of the first-line drugs for lower respiratory tract infections (LRTI) therapy, but its nephrotoxicity and ototoxicity caused by intravenous injection restrict its clinical application. Dry powder inhalation (DPI) is a popular local drug delivery system that is introduced as a solution. Due to the nature of NTM hygroscopicity that hinders its direct use through DPI, in this study, L-leucine (LL) was added into NTM dry powder to reduce its moisture absorption rate and improve its aerosolization performance. NTM DPIs were prepared using spray-drying with different LL proportions. The particle size, density, morphology, crystallinity, water content, hygroscopicity, antibacterial activity, in vitro aerosolization performance, and stability of each formulation were characterized. NTM DPIs were suitable for inhalation and amorphous with a corrugated surface. The analysis indicated that the water content and hygroscopicity were decreased with the addition of LL, whilst the antibacterial activity of NTM was maintained. The optimal formulation ND2 (NTM:LL = 30:1) showed high fine particle fraction values (85.14 ± 8.97%), which was 2.78-fold those of ND0 (100% NTM). It was stable after storage at 40 ± 2 °C, 75 ± 5% relative humidity (RH). The additional LL in NTM DPI successfully reduced the hygroscopicity and improved the aerosolization performance. NTM DPIs were proved to be a feasible and desirable approach for the treatment of LRTI.

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