RESUMEN
The research aimed to develop novel bioadhesive sodium alginate (Na-Alg) microspheres laden pessaries for intravaginal delivery of tenofovir disoproxil fumarate (TDF), to overcome limitations of conventional dosage forms. Twelve batches of microspheres formulated by emulsification gelation method indicated that drug-polymer ratios and polymer type affected particle size, drug release, and entrapment efficiency (%EE). Microspheres of batch EH-8 with drug: polymer ratio of 1:4 containing equal amounts of Na-Alg and HPMC K100M displayed optimal %EE (62.09 ± 1.34 %) and controlled drug release (97.02 ± 4.54 % in 12 h). Particle size analysis in Matersizer indicated that microspheres (EH-8) displayed a surface-mean diameter of 11.06 ± 0.18 µm. Ex-vivo mucoadhesion studies on rabbit mucosa indicated that microspheres (EH-8) adhered well for 12 h. Microspheres integrated into pessaries displayed a sustained release profile (95.31 ± 1.37 % in 12 h) in simulated vaginal fluid. In vivo studies in rabbits indicated that pessaries displayed a significantly higher Cmax (41.18 ± 3.57 ng/mL) (P < 0.005) and reduced Tmax (1.00 ± 0.01 h) (P < 0.0001) of TDF concentrations in vaginal fluid compared to oral tablets. The microparticulate pessaries with the ability to elicit higher vaginal fluid levels in the crucial initial hours of insertion demonstrates a potential novel platform to offer better self-protection to HIV-negative women against HIV during sexual intercourse.
Asunto(s)
Alginatos , Infecciones por VIH , Animales , Femenino , Humanos , Conejos , Tenofovir , Microesferas , Alginatos/uso terapéutico , Pesarios , Administración Intravaginal , Infecciones por VIH/tratamiento farmacológico , Polímeros/uso terapéuticoRESUMEN
Tenofovir disoproxil fumarate (TDF)-loaded bioadhesive chitosan microparticles (CM) were developed by an emulsification internal gelation technique. Among different batches produced, ECH-4 was found to display a high % entrapment efficiency (68.93 ± 1.76%) and sustained drug release of 88.05 ± 0.38% at 24 h. Solid state characterization of ECH-4 employing DSC and PXRD indicated that the TDF existed in an amorphous state as a solid-solid solution in chitosan. Scanning electron microscopy revealed CM of ECH-4 was spherical in shape with a rough surface topography. Laser scattering analysis using Malvern Master sizer indicated that particle size of ECH-4 was in the range of 0.52 ± 0.10 µm to 284.79 ± 21.42 µm with a surface-mean diameter of 12.41 ± 0.06 µm. Ex vivo mucoadhesion studies using rabbit mucosa as a substrate indicated that 10.34 ± 2.08% of CM of ECH-4 was retained at the end of 24 h. The microparticles of ECH-4 were incorporated into dispersible tablets (DT-TCM) intended for intravaginal administration, in view to arrest the pre-exposure transmission of HIV during sexual intercourse. In vitro release from the dispersible tablet (F3) into simulated vaginal fluid (pH 4.5) displayed a sustained release profile of TDF as 89.98 ± 1.61% of TDF was released at 24 h. The in vitro dissolution profile of the DT-TCM was found to be similar to that of TDF loaded CM with the values of f1 (difference factor) and f2 (similarity factor) being 1.52 and 78.02, respectively. Therefore, DT-TCM would be a promising novel drug delivery platform for pre-exposure prophylaxis against HIV.