Inhaled ciprofloxacin-loaded poly(2-ethyl-2-oxazoline) nanoparticles from dry powder inhaler formulation for the potential treatment of lower respiratory tract infections

Abstract

Lower respiratory tract infections (LRTIs) are one of the fatal diseases of the lungs that have severe impacts on public health and the global economy. The currently available antibiotics administered orally for the treatment of LRTIs need high doses with frequent administration and cause dose-related adverse effects. To overcome this problem, we investigated the development of ciprofloxacin (CIP) loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) for potential pulmonary delivery from dry powder inhaler (DPI) formulations against LRTIs. NPs were prepared using a straightforward co-assembly reaction carried out by the intermolecular hydrogen bonding among PEtOx, tannic acid (TA), and CIP. The prepared NPs were characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction analysis (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The CIP was determined by validated HPLC and UV spectrophotometry methods. The CIP loading into the PEtOx was between 21–67% and increased loading was observed with the increasing concentration of CIP. The NP sizes of PEtOx with or without drug loading were between 196–350 nm and increased with increasing drug loading. The in vitro CIP release showed the maximum cumulative release of about 78% in 168 h with a burst release of 50% in the first 12 h. The kinetics of CIP release from NPs followed non-Fickian or anomalous transport thus suggesting the drug release was regulated by both diffusion and polymer degradation. The in vitro aerosolization study carried out using a Twin Stage Impinger (TSI) at 60 L/min air flow showed the fine particle fraction (FPF) between 34.4% and 40.8%. The FPF was increased with increased drug loading. The outcome of this study revealed the potential of the polymer PEtOx as a carrier for developing CIP-loaded PEtOx NPs as DPI formulation for pulmonary delivery against LRTIs.

Stability of Inhaled Ciprofloxacin-Loaded Poly(2-ethyl-2-oxazoline) Nanoparticle Dry Powder Inhaler Formulation in High Stressed Conditions

“…The average particle size of the original blank PEtOx NPs is about 196.7 ± 24.0 nm and 5 mg and 25 mg CIP-loaded PEtOx NPs are 299.7 ± 18.2 nm and 200.0 ± 22.0 nm, respectively, as reported previously [ 17 ]. Stored blank and CIP-loaded PEtOx NPs’ average particle size and size distribution are presented in Figure 1 and Figure 2 , respectively, compared with freshly prepared samples.…”

“…In both studies, the stored formulations demonstrated comparably stable states at low temperatures and RH. Thus, particle-engineered techniques have been applied to develop more stable formulations in adverse conditions including spray-dried particles, drug-polymer conjugates and drug-loaded polymeric NPs [ 15 , 16 , 17 ]. However, it is still very important to determine the optimized conditions to store the DPI formulations to retain their aerosolization properties.…”

“…Thus, the search for suitable polymers for drug delivery is still the focal point of research. Recently, we developed the inhaled CIP-loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) in the form of a DPI formulation [ 17 ]. The prepared NPs demonstrated an initial burst release of 50% CIP within the first 12 h and then controlled release for up to 7 days.…”

“…Therefore, this study aimed to determine the storage stability of the formulated CIP-loaded PEtOx NPs at different temperatures and humidity. The NPs were prepared using the optimized conditions which were reported in our previous study [ 17 ]. In the present study, the storage stability of blank and CIP-loaded PEtOx NPs was studied in 25 °C/43% RH and 40 °C/75% RH.…”

Poly(2-alkyl-2-oxazoline)s: A polymer platform to sustain the release from tablets with a high drug loading

“…However, the poorly water-soluble fenofibrate showed faster dissolution from the PEtOx matrix compared to the pure API. After this first report on using PAOx as excipient for drug formulation, various PAOx grades have been demonstrated for the efficient preparation of solid dosage forms [ [27] , [28] , [29] , [30] , [31] , [32] , [33] ]. However, to the best of our knowledge, PAOx have not been reported as excipient for sustained release formulations despite that they appear to be ideally suited for this purpose based on the tunability of their physical properties in combination with a good processability.…”