Electrospun NFs have received special attention as drug delivery systems owing to their distinct functional feature and easy fabrication techniques . The polymeric system for this study was carefully selected following considerations of the several FDA approved. They are biodegradable poly (α-hydroxy ester) based polymer family like poly (lactic acid) and poly(ε-caprolactone). This work focuses on developing novel electrospun polymeric NFs for buccal delivery of VEN to avoid the hepatic metabolism, enzymatic degradation in the GIT and develop an effective control of drug release. VEN-loaded NFs were successively fabricated by the electrospinning method using biocompatible polymers. All the parameters involved in the electrospinning process were carefully optimized, such as polymer concentration, polymer ratio in case of composite fibers, flow rate, applied voltage, and tip-to-collection distance. In the present study, the polymer solution (PLA, PCL and PLA/PCL blend) and VEN in their respective solvents were electrospun under the applied electrical potential of 20kV over a tip-to-collector distance of 15cm and flow rates of 1.0, 0.6, and 0.3 mL/h, respectively.
The morphological studies and size of the cast films and NFs were evaluated by SEM. The smooth fracture surface of the cast film of PLA and PCL is attributed to its relatively brittle fracture manner in the two films before the electrospinning process. While electrospinning of 10%PLA yielded optimum fibers with an average diameter of 400–500 nm under well-defined conditions. Their morphology may be due to the selected binary solvent system of CHM: DMF (80:20) that has low surface tension, suitable viscosity, high miscibility, and high conductivity which aid in the production of nanofibers . Similarly, the boiling point of each solvent in the binary system plays a significant role in NFs formation in which DMF has a higher boiling point than CHM that offers enough time for the spinning process completion correctly without any beads formation . As the increment of PCL concentration from 10–14%, there was a gradual increase in the fiber diameter. The observation indicated that with an increase in the PCL concentration, there is an increase in the electrical force exerted on the jet, which in turn increases the mass throughput. That results in chain entanglement and consequently increasing the average diameter size of NFs [51–53]. Representative SEM images of plain and medicated NFs revealed smooth and regular NFs with no drug crystals identified on/or outside the surface. Additionally, the film with blend fiber at PLA/PCL ratio of 80:20 is characterized with the smoothest surface and the highest orientation. These observations confirmed the high compatibility of the drug with a polymer-solvent matrix that belongs to a homogeneously distributed drug within the fiber preparation. Also, it was clear that the integration of VEN in the polymer solutions has no significant effect on either the viscosity of the polymeric solutions or the average diameter size of NFs. We focused our attention on the PLA/PCL binary system to obtain a narrow and smooth diameter of VEN-NFs.
FTIR spectra manifest that the assignable peaks of the drug are visible in all the drug-loaded NFs, in addition to the lack of novel absorption peaks. These outcomes confirm that no chemical interaction occurs between the drug and the utilized polymers during the preparation of NFs .
The XRD patterns of the prepared NFs may be inferred to the less perfect crystalline structure indicating a subdued degree of the crystallinity of these NFs. During the electrospinning process, the fast solidification of the fibers restricted the order of three-dimensional polymer lattice and retards the crystallization process . These results are in agreement with the literature [42, 55].
DSC thermograms confirms a fact of the semi-crystalline nature of PLA polymer. PCL accelerates the crystallization rate of PLA with a small effect on its final crystallinity degree [56, 44]. These PCL crystals designed in the boundaries may supply the nucleating sites for PLA to crystallize. An overall decrease was revealed in the crystallinity of both PCL and PLA configuration in NFs composite in correlation with XRD analysis . Of these, blending PLA and PCL can overcome the shortcomings of both PLA and PCL [57, 58].
The heat flow value of VEN in blends decreased indicating that the drug-loaded fibers samples contain free amorphous regions. It may be attributed to the extremely rapid vaporization of the solvent from the NFs during the electrospinning process, leading to the failure of the drug molecules to form a complete crystalline lattice within the NFs . DSC studies confirmed that the drug molecules were evenly distributed at the molecular level in the nanofibers matrix and were existent in an amorphous state, hence favor the adequate compatibility and the stability of the composite NFs . Further, the drug is not influencing much the melting and glass transition temperatures of the blend constituents that are in good agreement with FTIR and XRD spectra.
All prepared nanofibers (F1, F2, and F3) revealed the immense encapsulation efficiency percentage owing to the exceptional high surface area of NFs and the absence of drug loss during NFs preparation .
In vitro release study of VEN from nanofibers represented as sustained/controlled release of drug as drug disperses to the release medium across the carrier regularly . The cumulative amount of drug released manifested the fast drug release from the buffer solution may be ascribed to the high solubility of VEN in water and its availability to contact directly with the diffusion cellulose membrane . Many endeavors have evidenced that hydrophilic drugs commonly tend to migrate to the surface of NFs when they were implanted in hydrophobic polymers . Meanwhile, PCL NFs revealed the lowest release rate attributed to the partial crystallinity of PCL and the presence of five hydrophobic -CH2 moieties in its repeating units . Thus, the limited diffusion of the drug from the nanofibers occurred. Otherwise, PLA NFs showed a higher cumulative release rate that referred to the high amorphous PLA in nature. The degradation of PCL does not create acidic byproducts, unlike the degradation of PLA. It makes PCL more adequate nanomaterial for the improvement of long-term implantable devices for its sluggish degradation rate . F3 drug release profile confirmed the enhancement of the blend features due to the presence of both polymers in the same matrix. These explanations affirmed that the NFs effectively sustainably deliver the drug and thereby enhancing patient compliance. Generally, the drug release from NFs mats was modulated by a mixed mechanism of drug diffusion from nanopores of the NFs and degradation of the polymeric matrix . Besides, there are insufficient physical and chemical interactions between the hydrophilic drug molecules and the hydrophobic polymers matrix, as evident in the study of ATR- FTIR spectra.
The release mechanism of VEN and F1 is fitted well with the Fickian mechanism indicated that the release of the drug is mainly mediated by its diffusion across the polymeric matrix . While the release of F2 and F3 followed an anomalous non-Fickian one signified that the release was controlled by drug diffusion and polymer erosion . It consists of two dominant driving forces, namely drug desorption and diffusion-controlled release kinetics . When we took all the obtained outcomes together, it was concluded that F3 was a promising delivery system of VEN, and hence it deserved to undergo further studies.
The ex vivo results could emphasize the enhancement of the sustained drug release and the noticeable decrease in the permeability of the drug from NFs (ρ < 0.05) compared to the dug solution. VEN is a BCS class I drug that suffers from a rapid absorption leading to a short duration of action . These results pointed that the prepared NF formulation could be a facile and green approach to be used for buccal administration with minimal drug permeation, less expected systemic absorption, and thereby convenience for patients.
Buccal histopathology is useful to study the toxicity effects of the selected formulation on the integrity of buccal mucosa. The exhibited observations are ascribed to the pH value of VEN NFs (6.58 ± 0.32), which was within the pH range of human buccal mucosa (6-7.5), reflecting its safety for buccal administration . Additionally, it may be related to the good biocompatibility, favorable mechanical properties, low immunogenic reactions, and chemical versatility of the utilized alloplastic (PLA and PCL) materials .
In vitro cytotoxicity is referred to as safe and cytocompatible electrospun NFs. These may be owing to its highly biocompatible composition and mild formulation procedures undertaken. According to these preliminary toxicity results, the WST-1 assay judged that F3 is non-toxic and cytocompatible as exhibited values of IC50 indicating too high viability of the exposure cells up to 2 days. These results propose that the VEN scaffold has the potential for biomedical applications.