Liposomal ciprofloxacin formulations have been developed with the aim of enhancing lung residence time, thereby reducing the burden of inhaled antimicrobial therapy which requires multiple daily administration due to rapid absorptive clearance of antibiotics from the lungs. However, there is a lack of a predictive methodology available to assess controlled release inhalation delivery systems and their effect on drug disposition. In this study, three ciprofloxacin formulations were evaluated: a liposomal formulation, a solution formulation and a 1:1 combination of the two (mixture formulation). Different methodologies were utilised to study the release profiles of ciprofloxacin from these formulations: (i) membrane diffusion, (ii) air interface Calu-3 cells and (iii) isolated perfused rat lungs. The data from these models were compared to the performance of the formulations in vivo. The solution formulation provided the highest rate of absorptive transport followed by the mixture formulation, with the liposomal formulation providing substantially slower drug release. The rank order of drug release/transport from the different formulations was consistent across the in vitro and ex vivo methods, and this was predictive of the profiles in vivo. The use of complimentary in vitro and ex vivo methodologies provided a robust analysis of formulation behaviour, including mechanistic insights, and predicted in vivo pharmacokinetics.

There is a need to understand how solvent structuring influences drug presentation in pharmaceutical preparations, and the aim of this study was to characterize the properties of propylene glycol (PG)/water supramolecular structures such that their functional consequences on drug delivery could be assessed. Shifts to higher wavenumbers in the C-H and C-O infrared stretching vibrations of PG (up to 8.6 and 11 cm(-1), respectively) implied that water supramolecular structures were being formed as a consequence of hydrophobic hydration. However, unlike analogous binary solvent systems, water structuring was not enhanced by the presence of the cosolvent. Two discrete populations of supramolecular structures were evident from the infrared spectroscopy: water-rich structures, predominant below a PG volume fraction (f(PG)) of 0.4 (unmoving water bending vibration at 1211 cm(-1)) and PG-rich structures, predominant above 0.4 f(PG) (both C-H and water peaks moved to lower wavenumbers). The un-ionized diclofenac log-linear solubility and transmembrane transport altered dramatically when f(PG) > 0.55 (a 10-fold increase in transport from 0.28 ± 0.06 μg·cm(-2)·h(-1) at 0.2 f(PG) to 2.81 ± 0.16 μg·cm(-2)·h(-1) at 0.9 f(PG)), and this demonstrated the ability of the PG rich supramolecular structures, formed in the PG/water solvent, to specifically modify the behavior of un-ionized diclofenac.

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Certain xenobiotics, such as paraquat, are sequestered into the lungs from the systemic circulation by the polyamine transporter system (PTS). The aim of this study was to investigate whether ion-pairing a drug (theophylline) with a PTS substrate (spermine) provides a means of using this active transport mechanism to target drug delivery to the lungs. Fourier transform infrared spectroscopy showed that two of the amine groups of spermine interact with C-N and C═O of theophylline, leaving two free amines to interact with the PTS. In A549 cells, which possess a functional PTS (spermidine K and V, 0.6 ± 0.3 μM and 1.8 ± 0.3 pmol·min per 10 cells, respectively), uptake of the theophylline-spermine ion-pair was increased 1.8-fold compared to free theophylline at 37 °C, but not at 4 °C. In an isolated perfused rat lung model (IPL) a 3.6-fold increase in lung theophylline concentration was observed after vascular administration of the ion-pair compared to free theophylline. Theophylline was cleared from the IPL with similar kinetics irrespective of whether it was delivered as the free drug or an ion-pair, although lung levels remained elevated after washout following delivery as an ion-pair. In vitro simulation of the theophylline-spermine break down demonstrated that a drop in pH from 9.6 to 7.4, such as that undergone by the ion-pair in biological matrices, induces rapid and almost complete dissociation of the ion-paired species. However, infusion of the ion-pair formulations via the vasculature provides almost immediate delivery to the pulmonary capillary bed permitting PTS-mediated active sequestering of ion-paired theophylline into the lungs.

This study investigated how the in situ construction and payload delivery from soft diclofenac loaded hydroxypropylmethylcellulose (HPMC) coated microparticles was influenced by the superstructure of the cosolvent in which the particles were suspended. A dual nozzle spray was used to produce microparticles in a propylene glycol (PG)???water mixture and data generated from the structural features of the vehicle, the physical properties of the particles and drug transport from the suspensions were used to characterise the particle???vehicle interactions. Infrared spectroscopy indicated supramolecular structures were formed in the bulk PG???water cosolvent upon mixing, but no solvent structural modification was observed as a consequence of microparticle self-assembly. Forming the microparticles in a premixed cosolvent, i.e., with a preformed superstructure, did not allow the polymer to deposit on the surface of the microparticles. The suspensions that did not contain the HPMC coated microparticles demonstrated a reduced diclofenac transmembrane transport rate (7.9 ?? 0.4 ??g cm???2 h???1) compared to soft HPMC coated particles (27.7 ?? 3.0 ??g cm???2 h???1). The HPMC???diclofenac hydrogen bonding interactions observed in the polymer coated material, the increased availability of the diclofenac in the solution state (drug degree of saturation rose from 3.0 ?? 0.2 to 11.0 ?? 1.2) and the slower microparticle formation kinetics (>1 order of magnitude) supported the conclusion that the cosolvent supramolecular structuring controlled HPMC deposition at the particle interface. Analysis of the solid material recovered from the suspensions suggested that the cosolvent supramolecular structures could be used to modify the diclofenac solid???liquid equilibrium and generate a complex liquid with an unusually high chemical potential. Graphical abstract: In situ self assembly of soft diclofenac loaded microparticles in superstructured fluids botto