(M0930-01-05) Loratadine Nanosuspension-Loaded In Situ Gel: A Promising Thermo-Responsive Delivery System for the Treatment of Allergic Rhinitis

Purpose: Development and evaluation of the physiochemical and rheological properties of a thermo-responsive nasal in situ gel loaded with loratadine nanosuspension to improve drug solubility and prolong drug residence time in the nasal cavity for treating allergic rhinitis.

Methods: Initially, loratadine nanosuspension (LOR-NS) was prepared by the precipitation-ultrasonication method. The organic phase was prepared by dissolving loratadine (LOR) in ethanol at 25 mg/mL concentration. The anti-solvent phase was prepared using various stabilizers (Pluronic F68 (F68), polyvinyl pyrrolidone, and Tween 20). LOR-NS was pre-freezed at (-80°Ϲ) for 12 h before being freeze-dried for 48 h to form solid nanocrystals. LOR-NS was characterized for particle size, polydispersity index (PDI), and zeta potential using Zetasizer, particle morphology using transmission electron microscope (TEM), drug content using UV-vis spectroscopy, in vitro release using Franz diffusion cells, and stability at 4 and 25°C for two months. The in situ nasal gel was prepared using a combination of Pluronic F127 (F127) and F68 (20:2.5%) by the cold method, to achieve a phase transition temperature (T_sol→gel) of 32-35°C at the nasal cavity. Then LOR-NS was incorporated into the prepared in situ gel to form LOR-NS loaded in situ gel (F1), which was kept at 4°C for further studies. For comparison, LOR-free nanosuspension was loaded into in situ gel (F2) prepared with F127 and F68 (20:2.5%), which was used as a control. F1 and F2 was adjusted to a pH range of 7.2-8.3, which simulates that of the nasal mucosa in allergic rhinitis. F1 and F2 in situ gels were characterized in terms of gelation time (T_gel) and T_sol→gel by the tube inversion method. Additionally, the T_sol→gel and curing temperature (T_curing) were investigated by temperature-sweep tests using a controlled-stress rheometer (CRS). The rheological behavior and mucoadhesive properties (tested by assessing the rheological synergism between the in situ gels and pig gastric mucins) were determined using CSR. The cumulative amount of LOR release was determined using Franz diffusion cells, drug content was quantified using UV-vis spectroscopy, and physicochemical and rheological stability were investigated for 2 months at 4°C.

Results: LOR-NS has a particle size of 195.1±7.9 nm with PDI of 0.14±0.00 and zeta potential of -17.2±1.4 mV. TEM images showed a uniform spherical droplets. LOR content was 95.0±2.7% with a complete drug release attained after 3.5 h. After 2 months, LOR-NS was physically unstable at 25°C, showing precipitation and agglomeration. Whereas LOR-NS was physically stable at 4°C, showing no precipitation. The particle size, PDI, and zeta potential slightly increased, attaining 226.6±4.1 nm, 0.2±0.04, and -14.1±0.6 mV, respectively. No significant reduction in drug content was found in LOR-NS after 2 months at 4°C. The pH of F1 and F2 was adjusted to 7.6±0.3 and 7.9±0.4, respectively. The T_gel and T_sol→gel obtained by the test inversion method and the T_sol→gel and T_curing obtained from the phase transition profiles during the temperature-sweep studies for F1 and F2 are illustrated in Table 1. The rheological studies showed that F1 and F2 exhibited pseudoplastic flow and viscoelastic properties with elastic modulus (G’) dominated viscous modulus (G”). F1 showed lower viscoelastic properties compared to those of F2, owing to the incorporation of LOR-NS into F1 in situ gel. Additionally, F1 and F2 showed mucoadhesive characteristics by evaluating the rheological synergism of elastic modulus (∆G’) between the in situ gels and 2% mucins, indicating potential adherence with the nasal mucosa and a reduction in the mucociliary clearance (MCC). For instance, ∆G’ for F1 and F2 at 1 rad/sec, which simulates the frequency of MCC, was 8380 and 4033.3 Pa, respectively. LOR content in F1 and F2 was 96.6±1.3 and 94.8±1.9%, respectively. The in vitro release studies showed that the rate of LOR release from F1 was faster than that of F2, attaining a complete release after 4.5 and 6.5 h, respectively. This can be attributed to the lower rheological behavior of F1 compared to those of F2. Stability studies over 2 months of storage at 4°C demonstrated that F1 and F2 were physically stable, showing no precipitation or turbidity. F1 and F2 maintained their drug content of 93.9±4.1 and 93.1±1.4%, respectively. The T_gel and T_sol→gel of stored F1 and F2 showed no significant difference between compared those reported initially (Table 1). Additionally, F1 showed a slight reduction in viscosity, whereas F2 maintained its viscosity. Moreover, although the elastic property of stored F1 and F2 was maintained, a slight reduction in the viscous propriety was observed.

Conclusion: The major challenge of the low solubility of LOR was resolved by the development of nanosuspension. Additionally, the in situ gelation system offered benefits of controlling drug release and prolonging mucoadhesive properties between the gels and nasal cavity by enhancing the viscoelastic properties of gels. Therefore, combining the two delivery systems of nanosuspension and in situ gel could potentially enhance the nasal delivery of LOR for the management of the inflammatory symptoms of allergic rhinitis.

Acknowledgements: This work was financially supported by the Deanship of Scientific Research and Innovation of Al-Zaytoonah University of Jordan.

Table 1. Gelation time (Tgel) and sol–gel transition temperature (Tsol→gel) determined by the tube inversion method and Tsol→gel and curing temperature (TCuring) determined by the temperature-sweep studies of F1 and F2 in situ gels. Data were obtained initially and after two months of storage at 4°C. Data are presented as mean± SD (n = 3).