Christina Karavasili

Electrospun PVP-indomethacin constituents for transdermal dressings and drug delivery devices.

A method in layering dressings with a superficial active layer of sub-micrometer scaled fibrous structures is demonstrated. For this, polyvinylpyrolidone (PVP)-indomethacin (INDO) fibres (5% w/v PVP, 5% w/w indomethacin, using a 50:50 ethanol-methanol solvent system) were produced at different flow rates (50 μL/min and 100 μL/min) via a modified electrospinning device head (applied voltage varied between 15 ± 2 kV). We further assessed these structures for their morphological, physical and chemical properties using SEM, AFM, DSC, XRD, FTIR and HPLC-UV. The average diameter of the resulting 3D (ca. 500 nm in height) PVP-INDO fibres produced at 50 μL/min flow rate was 2.58 ± 0.30 μm, while an almost two-fold increase in the diameter was observed (5.22 ± 0.83 μm) when the flow rate was doubled. However, both of these diameters were appreciably smaller than the existing dressing fibres (ca. 30 μm), which were visible even when layered with the active spun fibres. Indomethacin was incorporated in the amorphous state. The encapsulation efficiency was 75% w/w, with complete drug release in 45 min. The advantages are the ease of fabrication and deposition onto any existing normal or functionalised dressing (retaining the original fabric functionality), elimination of topical product issues (application, storage and transport), rapid release of active and controlled loading of drug content (fibre layer).

Development of new drug delivery system based on ordered mesoporous carbons: characterisation and cytocompatibility studies

Ordered mesoporous carbons that encapsulate the poorly soluble compounds ibuprofen and indomethacin were systematically studied by means of X-ray diffraction (XRD), differential scanning calorimetry (DSC) and X-ray photon electron spectroscopy (XPS). The results showed marked differences in the release profiles of the two drug molecules in simulated gastric fluids. In vitro toxicity profiles appear to be compatible with potential therapeutic applications bringing them to the forefront as carriers of poorly water soluble drugs.

Smart materials: in situ gel-forming systems for nasal delivery.

In the last decade in situ gelling systems have emerged as a novel approach in intranasal delivery of therapeutics, capturing the interest of scientific community. Considerable advances have been currently made in the development of novel formulations containing both natural and synthetic polymers. In this paper we present recent developments on in situ gelling systems for nasal delivery, highlighting the mechanisms that govern their formation.

Bioactive Self-Assembling Lipid-Like Peptides as Permeation Enhancers for Oral Drug Delivery

Amphiphilic, lipid-like, self-assembling peptides are functional biomaterials with surfactant properties. In this work, lipid-like peptides were designed to have a hydrophilic head composed of aspartic acid or lysine and a six alanine residue hydrophobic domain and have a length similar to that of biological lipids. The aim of this work was to examine the potential of using ac-A6 K-CONH2 , KA6 -CONH2 , ac-A6 D-COOH, and DA6 -COOH lipid-like peptides as permeability enhancers to facilitate transport through the intestinal barrier. In vitro transport studies of the macromolecular fluorescent marker fluorescein isothiocyanate (FITC)-dextran (4.4 kDa) through Caco-2 cell monolayers show the permeation enhancement ability of the lipid-like peptides. We observed increased FITC-dextran transport across the epithelial monolayer up to 7.6-fold in the presence of lipid-like peptides. Furthermore, we monitored the transepithelial resistance and performed immunofluorescence studies of the cell tight junctions. Ex vivo studies showed increased mucosal to serosal absorption of FITC-dextran in rat jejunum in the presence of the ac-A6 D-COOH peptide. Furthermore, a small increase in the serosal transport of bovine serum albumin was observed upon addition of ac-A6 D-COOH. Lipid-like peptides are biocompatible and they do not affect epithelial cell viability and epithelial monolayer integrity. Our results suggest that short, lipid-like peptides may be used as permeation enhancers to facilitate oral delivery of diagnostic and therapeutic molecules.

Electrosprayed mesoporous particles for improved aqueous solubility of a poorly water soluble anticancer agent: in vitro and ex vivo evaluation

ABSTRACT Encapsulation of poorly water‐soluble drugs into mesoporous materials (e.g. silica) has evolved as a favorable strategy to improve drug solubility and bioavailability. Several techniques (e.g. spray drying, solvent evaporation, microwave irradiation) have been utilized for the encapsulation of active pharmaceutical ingredients (APIs) into inorganic porous matrices. In the present work, a novel chalcone (KAZ3) with anticancer properties was successfully synthesized by Claisen‐Schmidt condensation. KAZ3 was loaded into mesoporous (SBA‐15 and MCM‐41) and non‐porous (fumed silica, FS) materials via two techniques; electrohydrodynamic atomization (EHDA) and solvent impregnation. The effect of both loading methods on the physicochemical properties of the particles (e.g. size, charge, entrapment efficiency, crystallinity, dissolution and permeability) was investigated. Results indicated that EHDA technique can load the active in a complete amorphous form within the pores of the silica particles. In contrast, reduced crystallinity (˜79%) was obtained for the solvent impregnated formulations. EHDA engineered formulations significantly improved drug dissolution up to 30‐fold, compared to the crystalline drug. Ex vivo studies showed EHDA formulations to exhibit higher permeability across rat intestine than their solvent impregnated counterparts. Cytocompatibility studies on Caco‐2 cells demonstrated moderate toxicity at high concentrations of the anticancer agent. The findings of the present study clearly show the immense potential of EHDA as a loading technique for mesoporous materials to produce poorly water‐soluble API carriers of high payload at ambient conditions. Furthermore, the scale up potential in EHDA technologies indicate a viable route to enhance drug encapsulation and dissolution rate of loaded porous inorganic materials.

Preparation and characterization of bioadhesive microparticles comprised of low degree of quaternization trimethylated chitosan for nasal administration: effect of concentration and molecular weight

Toward the development of microparticulate carriers for nasal administration, N-trimethylchitosan chloride (TMC) of low molecular weight (LMW) and high molecular weight (HMW) and low degree of quaternization (16% and 27%, respectively) was co-formulated into microparticles comprising of dipalmatoylphosphatidylcholine (DPPC) and poly(lactic-co-glycolic) acid (PLGA) via the spray-drying technique. The chitosan derivatives were characterized by means of nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), and Fourier transfrom infrared (FTIR) spectroscopy. The size and morphology of the produced microparticles were assessed by scanning electron microscopy (SEM), whereas their mucoadhesive properties were investigated by means of atomic force microscopy-force spectroscopy (AFM-FS). The results showed that microparticles exhibit mucoadhesion when TMC is present on their surface above a threshold of TMC (>0.3% w/w).

Comparison of different zeolite framework types as carriers for the oral delivery of the poorly soluble drug indomethacin

Microporous zeolites of distinct framework types, textural properties and crystal morphologies namely BEA, ZSM and NaX, have been employed as carriers to assess their effect on modulating the dissolution behavior of a BCS II model drug (indomethacin). Preparation of the loaded carriers via the incipient wetness method induced significant drug amorphization for the BEA and NaX samples, as well as high drug payloads. The stability of the amorphous drug content was retained after stressing test evaluation of the porous carriers. The dissolution profile of loaded indomethacin was evaluated in simulated gastric fluid (pH 1.2) and simulated intestinal fluids FaSSIF (fasted) and FeSSIF (fed state) conditions and was found to be dependent on the aluminosilicate ratio of the zeolites and the degree of crystalline drug content. The feasibility of the zeolitic particles as oral drug delivery systems was appraised with cytocompatibility and cellular toxicity studies in Caco-2 cultures in a time- and dose-dependent manner by means of the MTT assay and flow cytometry analysis, respectively. Intracellular accumulation of the zeolite particles was observed with no apparent cytotoxic effects at the lower concentrations tested, rendering such microporous zeolites pertinent candidates in oral drug delivery applications.

Controlled Release of 5-Fluorouracil from Alginate Beads Encapsulated in 3D Printed pH-Responsive Solid Dosage Forms

Three-dimensional printing is being steadily deployed as manufacturing technology for the development of personalized pharmaceutical dosage forms. In the present study, we developed a hollow pH-responsive 3D printed tablet encapsulating drug loaded non-coated and chitosan-coated alginate beads for the targeted colonic delivery of 5-fluorouracil (5-FU). A mixture of Eudragit® L100-55 and Eudragit® S100 was fabricated by means of hot-melt extrusion (HME) and the produced filaments were printed utilizing a fused deposition modeling (FDM) 3D printer to form the pH-responsive layer of the tablet with the rest comprising of a water-insoluble poly-lactic acid (PLA) layer. The filaments and alginate particles were characterized for their physicochemical properties (thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction), their surface topography was visualized by scanning electron microscopy and the filaments’ mechanical properties were assessed by instrumented indentation testing and tensile testing. The optimized filament formulation was 3D printed and the structural integrity of the hollow tablet in increasing pH media (pH 1.2 to pH 7.4) was assessed by means of time-lapsed microfocus computed tomography (μCT). In vitro release studies demonstrated controlled release of 5-FU from the alginate beads encapsulated within the hollow pH-sensitive tablet matrix at pH values corresponding to the colonic environment (pH 7.4). The present study highlights the potential of additive manufacturing in fabricating controlled-release dosage forms rendering them pertinent formulations for further in vivo evaluation.