Towards Effective Antiviral Oral Therapy: Development of a Novel Self-Double Emulsifying Drug Delivery System for Improved Zanamivir Intestinal Permeability

Abstract

Self-double emulsifying drug delivery systems have the potential to enhance the intestinal permeability of drugs classified under the Biopharmaceutics Classification System (BCS) class III. One such example is the antiviral agent zanamivir, exhibiting suboptimal oral absorption (with a bioavailability range of 1-5%). To address this challenge, we have developed an innovative oral formulation for zanamivir: a self-double nanoemulsifying Winsor delivery system (SDNE-WDS) consisting of the microemulsion, which subsequently yields final double nanoemulsion (W₁/O/W₂) upon interaction with water. Two distinct formulations were prepared: SDNE-WDS1, classified as a W/O microemulsion, and SDNE-WDS2, discovered to be a bicontinuous microemulsion. The inner microemulsions displayed a consistent radius of gyration, with an average size of 35.1 ± 2.1 nm. Following self-emulsification, the resultant zanamivir-loaded nanoemulsion droplets for zSDNE-WDS1 and zSDNE-WDS2 measured 542.1 ± 36.1 and 174.4 ± 3.4 nm, respectively. Both types of emulsions demonstrated the ability to enhance the transport of zanamivir across a parallel artificial membrane. Additionally, in situ rat intestinal perfusion studies involving drug-loaded SDNE-WDSs revealed a significantly increased permeability of zanamivir through the small intestinal wall. Notably, both SDNE-WDS formulations exhibited effective permeability (P_eff) values that were 3.5-5.5-fold higher than those of the low/high permeability boundary marker metoprolol. This research emphasizes the success of SDNE-WDSs in overcoming intestinal permeability barriers and enabling the effective oral administration of zanamivir. These findings hold promise for advancing the development of efficacious oral administration of BCS class III drugs.

Keywords: bioavailability; intestinal permeability; microemulsion; nanoemulsion; oral drug absorption; self-double emulsifying drug delivery system; zanamivir.

Scheme 1

Illustration depicting the preparation process of drug-loaded SDNE-WDSs.

Figure 1

Confocal Laser Scanning Microscopy images of W₁/O/W₂ emulsions following self-emulsification of SDNE-WDS1 and SDNE-WDS2: (i) Blue marker DPhA in the oil phase; (ii) Red probe rhodamine B in W₁; (iii) Optical microscopy images; (iv) Superimposition of images (i,ii), illustrating merged fluorescent signals (blue and red). Magnification ×63.

Figure 2

TEM images of W₁/O/W₂ emulsions following self-emulsification of zSDNE-WDS1 and zSDNE-WDS2. Specimens were negatively stained using a 2% uranyl acetate solution.

Figure 3

Radii of gyration of the inner aqueous droplets of SDNE-WDS1 and SDNE-WDS2 comprised varying zanamivir concentrations.

Figure 4

Conductivity values of the water-in-oil, bicontinuous, and oil-in-water microemulsions as a function of increasing water content in SDNE-WDS2-based formulations. The conductivity values are presented as means ± standard deviation (means ± SD); n = 3.

Figure 5

Mean droplet diameters of drug-loaded carriers over time following incubation at room temperature (RT), 4 and 40 °C. (A) Zanamivir-loaded SDNE-WDS1; (B) Zanamivir-loaded SDNE-WDS2. The results are represented as (means ± SD); n = 3.

Figure 6

Surface charge assessment of drug-loaded carriers over time after incubation at RT, 4 and 40 °C. (A) Zanamivir-loaded SDNE-WDS1; (B) Zanamivir-loaded SDNE-WDS2. The zeta potential values are donated as (means ± SD); n = 3.

Figure 7

Release profiles of 400 µg/mL zanamivir from SDNE-WDS1, SDNE-WDS2, and a zanamivir solution. All formulations were tested in PBS at pH 6.8 while maintaining a temperature of 37 °C. The presented data represents the means ± SD; n = 9.

Figure 8

In vitro effective permeability values (P_app) of 400 µg/mL zanamivir loaded SDNE-WDSs following self-emulsification, as calculated from the results obtained through the PAMPA studies conducted at pH 7.4. The results are provided as means ± SE; n = 4.

Figure 9

In situ effective permeability values (P_eff) of 400 µg/mL zanamivir solution and zanamivir encapsulated within SDNE-WDSs, determined by perfusion of emulsions in the jejunum of rats. The results are shown as means ± SD; n = 6 for the zanamivir solution and n = 8 for SDNE-WDSs. Statistical significance is indicated as follows: ** p < 0.001; *** p < 0.0001.