Cardiovascular diseases are among the leading causes of death in the world. Cerebral ischaemia represents one of the major cardio-vascular health concerns because of not only the morbidity but its role in the development of dementia and other disabilities. Consid-
ering the effect of cerebral ischaemia on overall public health, it is obvious that proper management of such conditions is essential to achieve the best possible outcome, therefore prompt and targeted treatment can enormously contribute to both public and individual health . However, pharmacodynamic properties of papaverine are beneficial for the treatment of stroke; its unfavourable bio-pharmaceutical behavior confines the clinical applicability. The benzylisoquinoline-type opium alkaloid papaverine (Fig. 1) has a
non-specific direct relaxant effect on smooth muscle. The vasodi-lation is resulted by the inhibition of phosphodiesterase enzymes and the direct actions on calcium channels .
Orally administered papaverine has been shown to increase regional cerebral blood flow in humans. Papaverine hydrochlo-ride is slightly soluble in water, and its poor peroral bioavailability is associated with high intra- and interindividual variability. This
variation can be explained by the extensive first pass metabolism and the inadequate absorption depending on incomplete in vivo drug release . Furthermore, the utilization of alternative admin-istration routes is hastened by tha fact that papaverine has been
reported to carry the risk of potential liver damage [4,5]. As a result of these properties, papaverine can only be administered parenter-ally in emergency cases, such as cerebral ischemia in order to ensure the therapeutic drug levels in the brain and the rapid onset. Since the administration of invasive parenteral dosage forms has sev-eral unfavourable features, these problems can be addressed by using alternative dosage forms, such as inhalation or buccal, rectal or transdermal administration routes .
Nanofibers have been successfully applied in various fields of the medicine, such as tissue engineering scaffolds, in wound healing, vascular graft implants and drug delivery [7–9] because of their pharmaceutically luring advantages, such as high surface area to volume ratio and very high porosity [10,11].
Electrospinning represents the most commonly used fiber form-ing technique, which utilizes electrical forces to produce nanofibers from polymers . Wide variety of polymers can be used to con-trol the drug release kinetics or to modify the dissolution . The incorporation of poorly water-soluble drugs into polymer-based nanofibers is of special interest because of the increased solubility and the consequent improved oral bioavailability. Such improve-ment in the solid state properties can be enabled by the high
amorphization efficacy of the fiber forming process and by the unique characteristics of the formed fibrous system [14–16].
The oral cavity is a possible site for the delivery of drugs. With the mucosal delivery local pharmacological effects can be achieved. For this application, the residence time and the local drug concen-tration are the most important factors, influencing the amount of
absorbed drug . Systemic effects can also be achieved via trans-mucosal routes, which is due to the highly vascularized, rich blood supplied and relatively permeable properties of the mucosa. Per-meation and consequently the bioavailability can increase by using
enhancers (for example polysorbate, sodium lauryl sulfate) [18,19]. Because of the advantages provided by buccal formulations, such as rapid onset of effect, good ioavailability, elimination of hep-atic first-pass metabolism and consequently the reduced amount of drug, the buccal delivery could be an alternative administration of the parenteral routes [20–26].
Chemically-modified cellulose derivatives (ethers and esters) are commonly used for buccal drug delivery . The first genera-tion of mucoadhesive polymers such as the hydroxypropyl cellulose (HPC) and poly(vinyl-alcohol) (PVA) are able to form non-covalent
bonds with the mucosa, thus ensuring a better oral residence and drug release at the absorption site. HPC presents high mucoadhe-sive potential and its further advantage is the aqueous solubility, thus avoiding the need of the use of organic solvents during
production [27–29]. Most of the natural and semisynthetic poly-mers exhibit poor spinnability thus the application of polymer of good spinnability could improve fiber forming capability. The combination of two polymers enables adequate composite fiber
The fiber forming mechanism is very complex and the elec-trospinnability of polymer gels is widely studied, but still not completely understood. The surface tension, conductivity, entan-glement concentration, viscosity and the dynamic moduli: storage (G’) and loss (G”) modulus are the most commonly examined properties. The conductivity measurement could be informative when the polymer solutions containing ionogenic polymer in dif-
ferent concentrations and then the conductivity can correlate with the polymer concentration. In case of the total mass of the uncharged polymers and the active pharmaceutical ingredients are the same, the conductivity and the surface tension remain
Molar refraction was successfully used to examine the intermolecular forces between polymer and plasticizer . Deter-mination of molar refractions could be applied to examine the interactions between the polymers. Best of our knowledge the molar refraction effect on the fiber forming process has not been published yet.
The primary aim of the present study was to prepare papaverine hydrochloride loaded buccal nanofibrous films, and to deter-mine the optimum composition of HPC-PVA aqueous solutions for electrospun fiber formation based on the rheological and molar reflectance characterization of the system. With this formulation intended for transmucosal drug administration, the unique prop-erties of the nanofibrous sheets and the benefits of the buccal formulation could be combined preferably.