(M1330-01-06) Formulation of a Poorly Soluble Antiviral Drug as Microparticle Powder for Nasal Breath Intake Against Respiratory Infections

Purpose: Transmission of respiratory viruses occurs through person-to-person contact when an infected subject coughs or sneezes, and his respiratory secretions reach another person’s nose and mouth. These viruses include influenza, respiratory syncytial virus, SARS-CoV-2, coronaviruses, and adenoviruses. Nasal administration is a targeting strategy to obtain a loco-regional deposition of antiviral drugs directly onto the infected upper airway epithelium. This study aims to construct a nasal microparticulate powder of ritonavir as an antiviral drug. Therefore, upon nasal breath, the powder properties enable deposition, mucoadhesion and high drug concentration and absorption on upper airways to treat airborne infections.

Methods: Nasal microparticulate powders of ritonavir (RTV) alone or with sodium hyaluronate (NaHA) and Soluplus^® or phosphatidylcholine (PC 85G and 90G; Lipoid) were spray-dried (SD) using a Büchi B-191 (parameters and compositions in Table 1). The feed solution was prepared as follows: RTV and phosphatidylcholine, when present, where accurately weighed and dissolved in absolute ethanol. Then, this solution was added dropwise (approximately 1 ml/min) under magnetic stirring to water, contained NaHA or Soluplus® solubilized. This suspension was stirred for 1h, analyzed for particle size by PCS (Nano-S90, Malvern), then spray-dried. Microparticulate powders were characterized for RTV content, morphology, and density. The dissolution rate of RTV powders was assessed in simulated nasal electrolyte solution (SNES) at 37 °C in the basket apparatus. Ritonavir quantification was carried out with either reverse phase-HPLC or UV spectrometry. Good linearity was obtained in the concentration range of 1 to 100 µg/ml with both methods. The transport of RTV from the nasal powders across excised rabbit nasal mucosa ex vivo using vertical Franz-type diffusion cells (diffusion area: 0.58 cm²) is currently ongoing.

Results: Ritonavir (RTV) is characterized by low aqueous solubility, poor bioavailability, and exhibits an exceedingly slow intrinsic dissolution rate [1]. Its equilibrium solubility in water at 25 °C was found at 5.1±0.1 µg/ml after 24h. RTV solubility increased by 3 folds in presence of 10% (v/v) ethanol. Such low solubility may be a limit for its nasal administration considering the short residence time of the formulation in the nose. In order to improve this aspect and to have an antiviral powder with properties enabling its aerosolization, deposition, and mucoadhesion, microparticulate powders of RTV were engineered by spray-drying of aqueous dispersions. The different compositions of the spray-dried powders at increasing concentration of RTV (% w/w) are listed in Table 1. Soluplus® was used as solubilizing polymer that forms micelles (CMC of 7.6 mg/L). mucoadhesive properties were conveyed to the microparticulate powders by adding NaHA. Sodium hyaluronate could form an amorphous dispersion with the drug, further improving water solubility. Both these aspects are being investigated in ongoing experiments and solid state characterization. Lastly, the effect of phosphatidylcholine was positive for three reasons: i) as dispersing agent to maintain RTV in suspension during spray drying, ii) to improve the powder aerosolization, and iii) to favor controlled agglomeration of the microparticles [2]. This was already actually evidenced for RTV #9, #11, #12, and #15 which spontaneously formed soft clusters, more flowable than the original microparticles (Table 2). The suspensions obtained by adding drop wise the RTV ethanol solution to water revealed the presence of a nanoprecipitate of RTV (Table 2). In particular, with Soluplus® the nanoprecipitate size was the smallest, possibly due to formation of micelles by Soluplus®. Interestingly, nanoprecipitates with a Z-average > 300 nm were present also without Soluplus®, but polydispersity was grater. The spray-dried powders were fairly flowable, suitable for powder metering into the nasal device and subsequent aerosolization (Table 2). The shape of the particles for nasal breath intake is a relevant parameter for the powder aerodynamics. RTV raw material were crystals and spray drying modified completely its morphology (Figure 1 - Panel A). RTV #2 and #6 had corrugated particles, while the shape of RTV #11 and #12 was spherical with smooth surface. Subsequent crystallographic studies will confirm any amorphous nature of these particles. The first dissolution study confirmed the expected negligible dissolution of RTV raw material which began after 60 min due to poor powder wettability. Conversely, RTV #12, #13 and #15 was wetted more rapidly in 20 minutes, reaching almost 100% RTV dissolved within 1h (Figure 1 - Panel B). The aerodynamic assessment of the spray-dried powders and their combination with a nasal device is still ongoing.

Conclusion: This study shed light on how to formulate a poorly soluble antiviral drug, such as ritonavir. Ritonavir, or other antiviral drugs, formulated as microparticulate nasal powder can timely stop viral replication by administering it by a nasal breath to target deposition from nose to trachea.

References: [1] Law D, Schmitt EA, Marsh KC, Everitt EA, Wang W, Fort JJ, Krill SL, Qiu Y. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J Pharm Sci. 2004.
[2] Balducci AG, Ferraro L, Bortolotti F, Nastruzzi C, Colombo P, Sonvico F, Russo P, Colombo G. Antidiuretic effect of desmopressin chimera agglomerates by nasal administration in rats. Int J Pharm. 2013
Acknowledgements: Dr. Sabrina Banella owes heartfelt gratitude to IPEC Americas Foundation for the Patrick DeLuca Emerging Researcher Award (2023).


Table 1. Microparticles composition and spray drying conditions.


Table 2. Spray dryer yield, drug content, Carr’s index, Hausner ratio, Z-Average, and dispersity of the microparticulate powders.


Figure 1. Panel A: SEM micrographs of ritonavir raw material and spray-dried powders. Panel B: In vitro dissolution of RTV raw material and spray-dried powders in SNES at 37 °C.