Pharmacokinetic Comparison of Favipiravir Oral Solution and Tablet Formulations in Healthy Thai Volunteers.

This study compared the pharmacokinetics and safety of favipiravir oral solution with those of tablet formulations, which were agents repurposed to treat nonsevere coronavirus disease 2019 in Thailand. In an open-label, single-dose, randomized, crossover study, 24 healthy subjects under fasting conditions were randomly assigned to a single dose of 200 mg of favipiravir, either as an oral solution of 200 mg/15 mL (test product) or a tablet (reference product), separated by a 7-day washout period. Fifteen plasma samples were collected over 12 hours after drug administration. Plasma favipiravir levels were quantified using in-house developed ultra-high-performance liquid chromatography-tandem mass spectrometry. The test/reference geometric mean ratio along with 90%CI for the maximum plasma concentration, area under the concentration-time curve (AUC) to the time of the last quantifiable concentration, and AUC after single-dose administration, extrapolated to infinity were 115.3% (90%CI, 107.7%-123.3%), 100.4% (90%CI, 96.9%-104.0%), and 100.4% (90%CI, 96.8%-104.2%), respectively. These results were within the predefined acceptance criteria for bioequivalence (80.0%-125.0%). No adverse events were observed in either group. The oral solution formulation could offer the advantage of easier swallowing in broader patient groups.

Basis to Aid Crisis: Favipiravir Oral Solution for Hospital Compounding During COVID-19 Drug Shortage.

The COVID-19 pandemic outbreak has been overwhelming the healthcare system worldwide. A rapidly growing number of younger pediatric patients in Thailand necessitated the formulation of favipiravir, the most locally accessible antiviral agent against COVID-19, into a child-friendly dosage form as a safer alternative to a dispersion of crushed tablets in simple syrup. While striving to quickly develop a liquid formulation that is feasible for any local hospital production units, an oral solution was chosen due to its simplicity. Despite the large dose and poor aqueous solubility of favipiravir, a combination of pH control and use of poloxamer as a solubilizing agent has enabled us to streamline the manufacturing process of a 200 mg/15 mL oral solution for hospital compounding. To ensure its efficacy and safety, a specification for quality control was also established in accordance with the ICH quality guidelines and USP. The finished product stability was subsequently demonstrated under the conditions of 5°C ± 3°C, 25°C ± 2°C/75% RH ± 5% RH, 30°C ± 2°C/75% RH ± 5% RH, and 40°C ± 2°C/75% RH ± 5% RH. The results indicated that our formulation can be stored at 30°C ± 2°C/75% RH for 30 days, which will very well serve the need to allow drug distribution and patient use during the crisis, while the shelf-life can be extended to 60 days when stored at 5°C ± 3°C. Thus, accessibility to an essential medical treatment has been successfully enhanced for pediatric patients in Thailand and neighboring countries during the COVID-19 outbreak.

In vitro characterisation of terbutaline sulphate particles prepared by thermal ink-jet spray freeze drying.

Thermal ink-jet spray freeze-drying (TIJ-SFD) was used to produce inhalable particles of terbutaline sulphate, the aerosolisation properties of which were compared to the commercial Bricanyl formulation. Scanning electron micrograph images showed the particles to be spherical, highly porous and suitable for aerosolisation from a simple, capsule-based dry-powder device (Cyclohaler) without the need for additional excipients. Particle size was dependent upon the concentration of solution jetted, as well as the distance between the print head and the surface of the liquid nitrogen. Starting with a 5% (w/v) solution and maintaining this distance at 3cm produced spherical, porous particles of volume median diameter (VMD) 14.1 ± 0.8 µm and mass median aerodynamic diameter (MMAD) 4.0 ± 0.6 µm. The fine particle fraction (proportion of aerosol with MMAD ≤ 4.46 µm) was 22.9 ± 3.3%, which compared favourably with that of the marketed dry powder inhaler formulation of terbutaline (Bricanyl Turbohaler; 25.7 ± 3.8%), tested under the same conditions. These findings show that TIJ-SFD is a useful tool to predict the viability of a DPI formulation during preformulation physicochemical characterisation.

Investigation into the effect of varying l-leucine concentration on the product characteristics of spray-dried liposome powders.

OBJECTIVES: Spray-dried formulations offer an attractive delivery system for administration of drug encapsulated into liposomes to the lung, but can suffer from low encapsulation efficiency and poor aerodynamic properties. In this paper the effect of the concentration of the anti-adherent l-leucine was investigated in tandem with the protectants sucrose and trehalose. METHODS: Two manufacturing methods were compared in terms of their ability to offer small liposomal size, low polydispersity and high encapsulation of the drug indometacin. KEY FINDINGS: Unexpectedly sucrose offered the best protection to the liposomes during the spray drying process, although formulations containing trehalose formed products with the best powder characteristics for pulmonary delivery; high glass transition values, fine powder fraction and yield. It was also found that l-leucine contributed positively to the characteristics of the powders, but that it should be used with care as above the optimum concentration of 0.5% (w/w) the size and polydispersity index increased significantly for both disaccharide formulations. CONCLUSIONS: The method of liposome preparation had no effect on the stability or encapsulation efficiency of spray-dried powders containing optimal protectant and anti-adherent. Using l-leucine at concentrations higher than the optimum level caused instability in the reconstituted liposomes.

Thermal ink-jet spray freeze-drying for preparation of excipient-free salbutamol sulphate for inhalation.

The use of thermal ink-jet spray freeze-drying (TIJ-SFD) to engineer inhalable, excipient-free salbutamol sulphate (SS) particles was assessed. A modified Hewlett-Packard printer was used to atomise aqueous SS solutions into liquid nitrogen. The frozen droplets were freeze-dried. It was found that TIJ-SFD could process SS solutions up to 15%w/v; the porous particles produced had a physical diameter of ca. 35 µm. Next generation impactor (NGI) analysis indicated that the particles had a smaller aerodynamic size (MMAD ranging from 6 to 8.7 µm). Particles prepared from the lowest concentration SS solution were too fragile to withstand aerosolisation, but the 5%w/v solution yielded particles having the best combination of strength and aerodynamic properties. Comparison with a commercial SS formulation (Cyclocap®) showed that the SFD preparation had an almost equivalent FPF (6.4 µm) when analysed with a twin-stage impinger (TSI; 24.0 ± 1.2% and 26.4 ± 2.2%, respectively) and good performance when analysed with NGI (FPF (4.46 µm):16.5 ± 2.0 and 27.7 ± 1.7, respectively). TIJ-SFD appears to be an excellent method to prepare inhalable particles. It is scalable yet allows assessment of the viability of the pulmonary route early in the development since it can be used with very small volumes (<0.5 mL) of solution.