Development of favipiravir dry powders for intranasal delivery: An integrated cocrystal and particle engineering approach via spray freeze drying.

The therapeutic potential of pharmaceutical cocrystals in intranasal applications remains largely unexplored despite progressive advancements in cocrystal research. We present the application of spray freeze drying (SFD) in successful fabrication of a favipiravir-pyridinecarboxamide cocrystal nasal powder formulation for potential treatment of broad-spectrum antiviral infections. Preliminary screening via mechanochemistry revealed that favipiravir (FAV) can cocrystallize with isonicotinamide (INA), but not nicotinamide (NCT) and picolinamide (PIC) notwithstanding their structural similarity. The cocrystal formation was characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy, and unit cell determination through Rietveld refinement of powder X-ray analysis. FAV-INA crystalized in a monoclinic space group P21/c with a unit cell volume of 1223.54(3) Å3, accommodating one FAV molecule and one INA molecule in the asymmetric unit. The cocrystal was further reproduced as intranasal dry powders by SFD, of which the morphology, particle size, in vitro drug release, and nasal deposition were assessed. The non-porous flake shaped FAV-INA powders exhibited a mean particle size of 19.79 ± 2.61 µm, rendering its suitability for intranasal delivery. Compared with raw FAV, FAV-INA displayed a 3-fold higher cumulative fraction of drug permeated in Franz diffusion cells at 45 min (p = 0.001). Dose fraction of FAV-INA deposited in the nasal fraction of a customized 3D-printed nasal cast reached over 80 %, whereas the fine particle fraction remained below 6 % at a flow rate of 15 L/min, suggesting high nasal deposition whilst minimal lung deposition. FAV-INA was safe in RPMI 2650 nasal and SH-SY5Y neuroblastoma cells without any in vitro cytotoxicity observed. This study demonstrated that combining the merits of cocrystallization and particle engineering via SFD can propel the development of advanced dry powder formulations for intranasal drug delivery.

Synthesis of the first remdesivir cocrystal: design, characterization, and therapeutic potential for pulmonary delivery.

While cocrystal engineering is an emerging formulation strategy to overcome drug delivery challenges, its therapeutic potential in non-oral applications remains not thoroughly explored. We herein report for the first time the successful synthesis of a cocrystal for remdesivir (RDV), an antiviral drug with broad-spectrum activities against RNA viruses. The RDV cocrystal was prepared with salicylic acid (SA) via combined liquid-assisted grinding (LAG) and thermal annealing. Formation of RDV-SA was found to be a thermally activated process, where annealing at high temperature after grinding was a prerequisite to facilitate the cocrystal growth from an amorphous intermediate, rendering it elusive under ambient preparing conditions. Through powder X-ray analysis with Rietveld refinement, the three-dimensional molecular structure of RDV-SA was resolved. The thermally annealed RDV-SA produced by LAG crystalized in a non-centrosymmetric monoclinic space group P21 with a unit cell volume of 1826.53(17) Å3, accommodating one pair of RDV and SA molecules in the asymmetric unit. The cocrystal formation was also characterized by differential scanning calorimetry, solid-state nuclear magnetic resonance, and Fourier-transform infrared spectroscopy. RDV-SA was further developed as inhaled dry powders by spray drying for potential COVID-19 therapy. The optimized RDV-SA dry powders exhibited a mass median aerodynamic diameter of 4.33 ± 0.2 µm and fine particle fraction of 41.39 ± 4.25 %, indicating the suitability for pulmonary delivery. Compared with the raw RDV, RDV-SA displayed a 15.43-fold higher fraction of release in simulated lung fluid at 120 min (p = 0.0003). RDV-SA was safe in A549 cells without any in vitro cytotoxicity observed in the RDV concentration from 0.05 to 10 µM.

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline.

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir-theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature-composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 µm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

Nanoparticulate Drug Delivery to the Retina.

Retinal diseases, such as age-related macular degeneration and diabetic retinopathy, are the leading causes of blindness worldwide. The mainstay of treatment for these blinding diseases remains to be surgery, and the available pharmaceutical therapies on the market are limited, partially owing to various biological barriers in hindering the delivery of therapeutics to the retina. The nanoparticulate drug delivery system confers the capability for delivering therapeutics to the specific ocular targets and, hence, potentially revolutionizes the current treatment landscape of retinal diseases. While the research to date indicates the enormous therapeutics potentials of the nanoparticulate delivery systems, the successful translation of these systems from the bench to bedside is challenging and requires a combined understanding of retinal pathology, physiology of the eye, and particle and formulation designs of nanoparticles. To this end, the review begins with an overview of the most prevalent retinal diseases and related pharmacotherapy. Highlights of the current challenges encountered in ocular drug delivery for each administration route are provided, followed by critical appraisal of various nanoparticulate drug delivery systems for the retinal diseases, including their formulation designs, therapeutic merits, limitations, and future direction. It is believed that a greater understanding of the nano-biointeraction in eyes will lead to the development of more sophisticated drug delivery systems for retinal diseases.

Effects of the Glass-Forming Ability and Annealing Conditions on Cocrystallization Behaviors via Rapid Solvent Removal: A Case Study of Voriconazole.

The kinetic entrapment of molecules in an amorphous phase is a common obstacle to cocrystal screening using rapid solvent removal, especially for drugs with a moderate or high glass-forming ability (GFA). The aim of this study was to elucidate the effects of the coformer's GFA and annealing conditions on the nature of amorphous phase transformation to the cocrystal counterpart. Attempts were made to cocrystallize voriconazole (VRC) with four structural analogues, namely fumaric acid (FUM), tartaric acid (TAR), malic acid (MAL), and maleic acid (MAE). The overall GFA of VRC binary systems increased with decreasing glass transition temperatures (Tgs) of these diacids, which appeared as a critical parameter for predicting the cocrystallization propensity such that a high-Tg coformer is more desirable. A new 1:1 VRC-TAR cocrystal was successfully produced via a supercooled-mediated re-cocrystallization process, and characterized by PXRD, DSC, and FTIR. The cocrystal purity against the annealing temperature displayed a bell-shaped curve, with a threshold at 40 °C. The isothermal phase purity improved with annealing and adhered to the Kolmogorov-Johnson-Mehl-Avrami kinetics. The superior dissolution behavior of the VRC-TAR cocrystal could minimize VRC precipitation upon gastric emptying. This study offers a simple but useful guide for efficient cocrystal screening based on the Tg of structurally similar coformers, annealing temperature, and time.

Converting nanosuspension into inhalable and redispersible nanoparticles by combined in-situ thermal gelation and spray drying.

While nanoparticulate drugs for deep lung delivery hold promise for particular disease treatments, their size-related physical instability and tendency of being exhaled during breathing remain major challenges to their inhaled formulation development. Here we report a viable method for converting drug nanosuspensions into inhalable, stable and redispersible nano-agglomerates through combined in-situ thermal gelation and spray drying. Itraconazole (ITZ) nanosuspensions were prepared by flash nanoprecipitation, and co-spray dried with two different grades of the gel-forming polymer, methylcellulose (MC M20 and MC M450) as protectants. MC M20 was found superior in protecting ITZ nanoparticles against thermal stress (through nanoparticle entrapment within its gel network structure) during spray drying. In terms of redispersibility, an Sf/Si ratio (i.e., ratio of nanoparticle sizes after and before spray drying) of unity (1.02 ± 0.03), reflecting full particle size preservation, was achieved by optimizing the suspending medium content and spray drying parameters. Formulation components, nanosuspension concentration and spray drying parameters all showed a significant impact on the aerosol performance of the resulting agglomerates, but an absence of defined trends or correlations. Overall, the MC-protected nano-agglomerates displayed excellent in-vitro aerosol performance with fine particle fractions higher than 50% and mass median aerodynamic diameters within the 2-3 µm range, which are ideal for deep lung delivery.

Interplay between Amphiphilic Stabilizers and Cholesterol in the Stabilization of Itraconazole Nanoparticles Prepared by Flash Nanoprecipitation.

While flash nanoprecipitation (FNP) has proven to be an extremely rapid and highly efficient nanoparticle fabrication process for hydrophobic drugs, physical instability associated with nonequilibrium molecular orientation of amphiphilic stabilizers (ASs) in nanoparticles remains a major snag in the general application of this nanotechnology, particularly for a drug with ACDLog P in the range of ∼2-9. This study was aimed at elucidating the costabilizing role of cholesterol (CLT) in the FNP of AS-stabilized nanoparticles of itraconazole (ITZ), a model drug with an ACDLog P of 4.35 ± 1.22 and log P of 5.66. The presence of CLT was shown to reduce the initial particle size and markedly improve the short-term storage stability of ITZ nanoparticles. The stability-enhancement by CLT can be linked to its higher miscibility or stronger interaction with the AS hydrophobic moiety than with ITZ (as reflected by the absolute differences of their solubility parameter values). Surface analyses employing X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) suggest that, through the coprecipitation of CLT with ITZ to form a mixed hydrophobic drug core, the CLT molecules that are exposed on the core surface serve to afford a stronger and more timely surface anchorage of the AS hydrophobic moieties, thereby facilitating the rearrangement of AS molecules toward the stable micelle-like structure. The present findings offer a mechanistic insight into the interplay between amphiphilic stabilizer and costabilizer in enhancing the physical stability of drug nanoparticles and may carry important implications for the development of more stable and efficacious nanoparticle therapeutics.