Controlled Dissolution of Griseofulvin Solid Dispersions from Electrosprayed Enteric Polymer Micromatrix Particles: Physicochemical Characterization and <i>in Vitro</i> Evaluation

The oral bio­avail­ability of a poorly water-soluble drug is often inadequate for the desired therapeutic effect. The bio­avail­ability can be improved by enhancing the physico­chemical properties of the drug (e.g., dissolution rate, permeation across the gastro­intestinal tract). Other approach include shielding the drug from the gastric metabolism and targeted drug release to obtain optimal drug absorption. In this study, a poorly water-soluble model drug, griseo­fulvin, was encapsulated as disordered solid dispersions into Eudragit L 100-55 enteric polymer micro­matrix particles, which were produced by electro­spraying. Similar micro­matrix particles were also produced with griseo­fulvin-loaded thermally oxidized mesoporous silicon (TOPSi) nanoparticles dispersed to the polymer micro­matrices. The <i>in vitro</i> drug dissolution at pH 1.2 and 6.8, and permeation at pH 7.4 across Caco-2/HT29 cell monolayers from the micro­matrix particles, were investigated. The micro­matrix particles were found to be gastro-resistant, while at pH 6.8 the griseo­fulvin was released very rapidly in a fast-dissolving form. Compared to free griseo­fulvin, the permeability of encapsulated griseo­fulvin across the intestinal cell monolayers was greatly improved, particularly for the TOPSi-doped micro­matrix particles. The griseo­fulvin solid dispersions were stable during storage for 6 months at accelerated conditions. Overall, the method developed here could prove to be a useful oral drug delivery solution for improving the bio­avail­ability of poorly water-soluble or otherwise problematic drugs

<i>In Vitro</i> and <i>Ex Vivo</i> Evaluation of Polymeric Nanoparticles for Vaginal and Rectal Delivery of the Anti-HIV Drug Dapivirine

Prevention strategies such as the development of microbicides are thought to be valuable in the fight against HIV/AIDS. Despite recent achievements, there is still a long road ahead in the field, particularly at the level of drug formulation. Drug nanocarriers based on polymers may be useful in enhancing local drug delivery while limiting systemic exposure. We prepared differently surface-engineered poly­(ε-caprolactone) (PCL) nanoparticles (NPs) and tested their ability to modulate the permeability and retention of dapivirine in cell monolayers and pig vaginal and rectal mucosa. NPs coated with poly­(ethylene oxide) (PEO) were shown able to reduce permeability across monolayers/tissues, while modification of nanosystems with cetyl trimethylammonium bromide (CTAB) enhanced transport. In the case of coating NPs with sodium lauryl sulfate (SLS), dapivirine permeability was unchanged. All NPs increased monolayer/tissue drug retention as compared to unformulated dapivirine. This fact was associated, at least partially, to the ability of NPs to be taken up by cells or penetrate mucosal tissue. Cell and tissue toxicity was also affected differently by NPs: PEO modification decreased the <i>in vitro</i> (but not <i>ex vivo</i>) toxicity of dapivirine, while higher toxicity was generally observed for NPs coated with SLS or CTAB. Overall, presented results support that PCL nanoparticles are capable of modulating drug permeability and retention in cell monolayers and mucosal tissues relevant for vaginal and rectal delivery of microbicides. In particular, PEO-modified dapivirine-loaded PCL NPs may be advantageous in increasing drug residence at epithelial cell lines/mucosal tissues, which may potentially increase the efficacy of microbicide drugs

Microfluidic Assembly of a Multifunctional Tailorable Composite System Designed for Site Specific Combined Oral Delivery of Peptide Drugs

Multifunctional tailorable composite systems, specifically designed for oral dual-delivery of a peptide (glucagon-like peptide-1) and an enzymatic inhibitor (dipeptidyl peptidase 4 (DPP4)), were assembled through the microfluidics technique. Both drugs were coloaded into these systems for a synergistic therapeutic effect. The systems were composed of chitosan and cell-penetrating peptide modified poly(lactide-<i>co</i>-glycolide) and porous silicon nanoparticles as nanomatrices, further encapsulated in an enteric hydroxypropylmethylcellulose acetylsuccinate polymer. The developed multifunctional systems were pH-sensitive, inherited by the enteric polymer, enabling the release of the nanoparticles only in the simulated intestinal conditions. Moreover, the encapsulation into this polymer prevented the degradation of the nanoparticles’ modifications. These nanoparticles showed strong and higher interactions with the intestinal cells in comparison with the nonmodified ones. The presence of DPP4 inhibitor enhanced the peptide permeability across intestinal cell monolayers. Overall, this is a promising platform for simultaneously delivering two drugs from a single formulation. Through this approach peptides are expected to increase their bioavailability and efficiency <i>in vivo</i> both by their specific release at the intestinal level and also by the reduced enzymatic activity. The use of this platform, specifically in combination of the two antidiabetic drugs, has clinical potential for the therapy of type 2 diabetes mellitus