Early Osteogenic Marker Expression in hMSCs Cultured onto Acid Etching-Derived Micro- and Nanotopography 3D-Printed Titanium Surfaces.

Polyetheretherketone (PEEK) titanium composite (PTC) is a novel interbody fusion device that combines a PEEK core with titanium alloy (Ti6Al4V) endplates. The present study aimed to investigate the in vitro biological reactivity of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) to micro- and nanotopographies produced by an acid-etching process on the surface of 3D-printed PTC endplates. Optical profilometer and scanning electron microscopy were used to assess the surface roughness and identify the nano-features of etched or unetched PTC endplates, respectively. The viability, morphology and the expression of specific osteogenic markers were examined after 7 days of culture in the seeded cells. Haralick texture analysis was carried out on the unseeded endplates to correlate surface texture features to the biological data. The acid-etching process modified the surface roughness of the 3D-printed PTC endplates, creating micro- and nano-scale structures that significantly contributed to sustaining the viability of hBM-MSCs and triggering the expression of early osteogenic markers, such as alkaline phosphatase activity and bone-ECM protein production. Finally, the topography of 3D-printed PTC endplates influenced Haralick's features, which in turn correlated with the expression of two osteogenic markers, osteopontin and osteocalcin. Overall, these data demonstrate that the acid-etching process of PTC endplates created a favourable environment for osteogenic differentiation of hBM-MSCs and may potentially have clinical benefit.

Tobramycin Supplemented Small-Diameter Vascular Grafts for Local Antibiotic Delivery: A Preliminary Formulation Study.

Peripheral artery occlusive disease is an emerging cardiovascular disease characterized by the blockage of blood vessels in the limbs and is associated with dysfunction, gangrene, amputation, and a high mortality risk. Possible treatments involve by-pass surgery using autologous vessel grafts, because of the lack of suitable synthetic small-diameter vascular prosthesis. One to five percent of patients experience vascular graft infection, with a high risk of haemorrhage, spreading of the infection, amputation and even death. In this work, an infection-proof vascular graft prototype was designed and manufactured by electrospinning 12.5% w/v poly-L-lactic-co-glycolic acid solution in 75% v/v dichloromethane, 23.8% v/v dimethylformamide and 1.2% v/v water, loaded with 0.2% w/wPLGA. Polymer and tobramycin concentrations were selected after viscosity and surface tension and after HPLC-UV encapsulation efficiency (EE%) evaluation, respectively. The final drug-loaded prototype had an EE% of 95.58% ± 3.14%, with smooth fibres in the nanometer range and good porosity; graft wall thickness was 291 ± 20.82 µm and its internal diameter was 2.61 ± 0.05 mm. The graft's antimicrobic activity evaluation through time-kill assays demonstrated a significant and strong antibacterial activity over 5 days against Staphylococcus aureus and Escherichia coli. An indirect cell viability assay on Normal Human Dermal Fibroblasts (NHDF) confirmed the cytocompatibility of the grafts.

Combining Biologically Active ß-Lactams Integrin Agonists with Poly(l-lactic acid) Nanofibers: Enhancement of Human Mesenchymal Stem Cell Adhesion.

Regulating stem cell adhesion and growth onto functionalized biomaterial scaffolds is an important issue in the field of tissue engineering and regenerative medicine. In this study, new electrospun scaffolds of poly(l-lactic acid) (PLLA), as bioresorbable polymer, and ß-lactam compounds agonists of selected integrins, as functional components with cell adhesive properties, are designed. The new ß-lactam-PLLA scaffolds contribute significantly in guiding protein translation involved in human bone marrow mesenchymal stem cells (hBM-MSC) adhesion and integrin gene expression. Scanning electron microscopy, confocal laser scanning microscopy, and Western Blot analyses reveal that GM18-PLLA shows the best results, promoting cell adhesion by significantly driving changes in focal adhesion proteins distribution (ß1 integrin and vinculin) and activation (pFAK), with a notable increase of GM18-targets subunits integrin gene expression, α4 and ß1. These novel functionalized submicrometric fibrous scaffolds demonstrate, for the first time, the powerful combination of selective ß-lactams agonists of integrins with biomimetic scaffolds, suggesting a designed rule that could be suitably applied to tissue repair and regeneration.

Tissue Engineered Esophageal Patch by Mesenchymal Stromal Cells: Optimization of Electrospun Patch Engineering.

Aim of work was to locate a simple, reproducible protocol for uniform seeding and optimal cellularization of biodegradable patch minimizing the risk of structural damages of patch and its contamination in long-term culture. Two seeding procedures are exploited, namely static seeding procedures on biodegradable and biocompatible patches incubated as free floating (floating conditions) or supported by CellCrownTM insert (fixed conditions) and engineered by porcine bone marrow MSCs (p-MSCs). Scaffold prototypes having specific structural features with regard to pore size, pore orientation, porosity, and pore distribution were produced using two different techniques, such as temperature-induced precipitation method and electrospinning technology. The investigation on different prototypes allowed achieving several implementations in terms of cell distribution uniformity, seeding efficiency, and cellularization timing. The cell seeding protocol in stating conditions demonstrated to be the most suitable method, as these conditions successfully improved the cellularization of polymeric patches. Furthermore, the investigation provided interesting information on patches' stability in physiological simulating experimental conditions. Considering the in vitro results, it can be stated that the in vitro protocol proposed for patches cellularization is suitable to achieve homogeneous and complete cellularizations of patch. Moreover, the protocol turned out to be simple, repeatable, and reproducible.

Improvement of the Firocoxib Dissolution Performance Using Electrospun Fibers Obtained from Different Polymer/Surfactant Associations.

An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed.

Metal Nanoparticles Embedded in Cellulose Nanocrystal Based Films: Material Properties and Post-use Analysis.

The dispersion of nanoparticles having different size-, shape-, and composition-dependent properties is an exciting approach to design and synthesize multifunctional materials and devices. This work shows a detailed investigation of the preparation and properties of free-standing nanocomposite films based on cellulose nanocrystals (CNC) loaded with three different types of metal nanoparticles. CNC-based nanocomposites having zinc oxide (ZnO), titanium dioxide (TiO2), and silver oxide (Ag2O) have been obtained through evaporation-induced self-assembly (EISA) in acqueous solution. Morphological and optical characteristics, chemical properties, wettability, and antimicrobial assays of the produced films were conducted. Furthermore, disintegrability in composting condition of CNC based nanocomposites was here investigated for the first time. The morphological observations revealed the formation of a chiral nematic structure with uniformly distributed nanoparticles. The bionanocomposite films based on the metal nanoparticles had effective antimicrobial activity, killing both Escherichia coli RB ( E. coli RB) and Staphylococcus aureus 8325-4 ( S. aureus 8325-4). The simplicity method of film preparation, the large quantity of cellulose in the world, and the free-standing nature of the nanocomposite films offer highly advantageous characteristics that can for the new development of multifunctional materials.

Ether-Oxygen Containing Electrospun Microfibrous and Sub-Microfibrous Scaffolds Based on Poly(butylene 1,4-cyclohexanedicarboxylate) for Skeletal Muscle Tissue Engineering.

We report the study of novel biodegradable electrospun scaffolds from poly(butylene 1,4-cyclohexandicarboxylate-co-triethylene cyclohexanedicarboxylate) (P(BCE-co-TECE)) as support for in vitro and in vivo muscle tissue regeneration. We demonstrate that chemical composition, i.e., the amount of TECE co-units (constituted of polyethylene glycol-like moieties), and fibre morphology, i.e., aligned microfibrous or sub-microfibrous scaffolds, are crucial in determining the material biocompatibility. Indeed, the presence of ether linkages influences surface wettability, mechanical properties, hydrolytic degradation rate, and density of cell anchoring points of the studied materials. On the other hand, electrospun scaffolds improve cell adhesion, proliferation, and differentiation by favouring cell alignment along fibre direction (fibre morphology), also allowing for better cell infiltration and oxygen and nutrient diffusion (fibre size). Overall, C2C12 myogenic cells highly differentiated into mature myotubes when cultured on microfibres realised with the copolymer richest in TECE co-units (micro-P73 mat). Lastly, when transplanted in the tibialis anterior muscles of healthy, injured, or dystrophic mice, micro-P73 mat appeared highly vascularised, colonised by murine cells and perfectly integrated with host muscles, thus confirming the suitability of P(BCE-co-TECE) scaffolds as substrates for skeletal muscle tissue engineering.

Stability Evaluation of Ivermectin-Loaded Biodegradable Microspheres.

A stability study was performed on ivermectin (IVM)-loaded biodegradable microparticles intended for injection in dogs. The rational was to evaluate the performances upon irradiation of a drug, such as IVM, with a few criticalities with respect to its stability, and toxicity. The goal was to provide valuable information for pharmaceutical scientists and manufacturers working in the veterinary area. The microspheres based on poly(D,L-lactide) and poly-(ε-caprolactone) and loaded with IVM and with the addition of alpha-tocopherol (TCP) as antioxidant were prepared by the emulsion solvent evaporation method and sterilized by gamma irradiation. Microsphere characterization in term of size, shape, polymer, and IVM stability upon irradiation was performed. The results show that the type of polymer significantly affects microsphere characteristics and performances. Moreover, suitably stable formulations can be achieved only by TCP addition.

Preparation and characterization of an advanced medical device for bone regeneration.

Tridimensional scaffolds can promote bone regeneration as a framework supporting the migration of cells from the surrounding tissue into the damaged tissue and as delivery systems for the controlled or prolonged release of cells, genes, and growth factors. The goal of the work was to obtain an advanced medical device for bone regeneration through coating a decellularized and deproteinized bone matrix of bovine origin with a biodegradable, biocompatible polymer, to improve the cell engraftment on the bone graft. The coating protocol was studied and set up to obtain a continuous and homogeneous polylactide-co-glycolide (PLGA) coating on the deproteinized bone matrix Orthoss® block without occluding pores and decreasing the scaffold porosity. The PLGA-coated scaffolds were characterized for their morphology and porosity. The effects of PLGA polymer coating on cell viability were assessed with the 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium assay. The polymer solution concentration and the number of polymeric layers were the main variables affecting coating efficiency and porosity of the original decellularized bone matrix. The designed polymer coating protocol did not affect the trabecular structure of the original decellularized bone matrix. The PLGA-coated decellularized bone matrix maintained the structural features, and it improved the ability in stimulating fibroblasts attachment and proliferation.

A proof of concept to define the parameters affecting poly-L-lactide-co-poly-ε-caprolactone shape memory electrospun nanofibers for biomedical applications.

This study is a proof of concept performed to evaluate process parameters affecting shape memory effect of copolymer poly-L-lactide-co-poly-ε-caprolactone (PLA:PCL) 70:30 ratio based nanofibrous scaffolds. A design of experiment (DOE) statistical approach was used to define the interaction between independent material and process variables related to electrospun scaffold manufacturing, such as polymer solution concentration (w/v%), spinning time (min), and needle size (Gauge), and their influence on Rf% (ability of the scaffold to maintain the induced temporary shape) and Rr% (ability of the scaffold to recover its original shape) outputs. A mathematical model was obtained from DOE useful to predict scaffold Rf% and Rr% values. PLA-PCL 15% w/v, 22G needle, and 20-min spinning time were selected to confirm the data obtained from theoretical model. Subsequent morphological (SEM), chemical-physical (GPC and DSC), mechanical (uniaxial tensile tests), and biological (cell viability and adhesion) characterizations were performed.

A preliminary study on the morphological and release properties of hydroxyapatite-alendronate composite materials.

Inhibition of osteoclasts by bisphosphonate is one strategy to be explored in order to avoid a revision surgery. The purpose of this preliminary work is to synthesize hydroxyapatite-alendronate (HA-ALN) composites as carrier for ALN that could improve its site specific activity. HA-ALN composites were prepared by the co-precipitation method. Process parameters such as HA:ALN w/w ratio (1:1, 5:1 and 10:1) and HA incubation times (6, 24, 48 and 72 h) were evaluated. Morphological, physical-chemical characterization and biocompatibility tests were performed. TEM and SEM analyses confirmed ALN precipitation as fine network onto HA. The results of physical-chemical characterization confirmed the presence of ALN in the composites and its interaction with HA. ALN content resulted between 60% and 80% in the HA:ALN 5:1 and 10:1 ratios composites. ALN release reached 80% from HA-ALN 10:1 composites. Biological tests revealed that complexation with HA increased ALN biocompatibility by three times. These preliminary results demonstrated that HA-ALN composites could be considered a carrier to control ALN release.

Electrospun tubular vascular grafts to replace damaged peripheral arteries: A preliminary formulation study.

Polymeric tubular vascular grafts represent a likely alternative to autologous vascular grafts for treating peripheral artery occlusive disease. This preliminary research study applied cutting-edge electrospinning technique for manufacturing prototypes with diameter ≤ 6 mm and based on biocompatible and biodegradable polymers such as polylactide-polycaprolactone, polylactide-co-glycolide and polyhydroxyethylmethacrylate combined in different design approaches (layering and blending). Samples were characterized about fiber morphology, diameter, size distribution, porosity, fluid uptake capability, and mechanical properties. Biocompatibility and cell interaction were evaluated by in vitro test. Goal of this preliminary study was to discriminate among the prototypes and select which composition and design approach could better suit tissue regeneration purposes. Results showed that electrospinning technique is suitable to obtain grafts with a diameter < 6 mm and thickness between 140 ± 7-175 ± 4 µm. Scanning electron microscopy analysis showed fibers with suitable micrometric diameters and pore size between 5 and 35 µm. polyhydroxyethylmethacrylate provided high hydrophilicity (≃ 100°) and optimal cell short term proliferation (cell viability ≃ 160%) in accordance with maximum fluid uptake ability (300-350%). Moreover, addition of polyhydroxyethylmethacrylate lowered suture retention strength at value < 1 N. Prototypes obtaining combining polylactide-co-glycolide and polylactide-coglycolide/ polyhydroxyethylmethacrylate with polylactide-polycaprolactone in a bilayered structure showed optimal mechanical behavior resembling native bovine vessel.

Microfluidic-assisted synthesis of multifunctional iodinated contrast agent polymeric nanoplatforms.

Contrast Induced Nephropathy is the most severe side-effect arising after non-ionic iodinated contrast agents (CAs) intravenous administration. The use of antioxidants (i.e., N-Acetylcysteine; NAC) is one of the attempted prevention approaches. Herein, we describe the microfluidic-assisted synthesis of iodinated polymeric nanoparticles (NPs) as new multifunctional blood pool CA. The aim of this research is to co-encapsulate Iohexol (IOX; iodinated CA) and NAC (preventive agent) into poly-D,L-lactide-co-glycolide (PLGA) and PEGylated-PLGA (PLGA-PEG) NPs to exploit CA diagnostic proprieties and NAC preventing antioxidant activity. A microfluidic-assisted nanoprecipitation protocol has been set-up for PLGA and PLGA-PEG NPs, evaluating the effect of formulation and microfluidic parameters by analysing the size, PDI and IOX and NAC encapsulation efficiency. The optimized NPs (PLGA-PEG, L:G 50:50, 5% PEG, Mw 90 kDa) formulated with a size of 67 ± 2.8 nm with PDI < 0.2, spherical shape, and an IOX and NAC encapsulation efficiency of 38% and 20%, respectively. The IOX and NAC encapsulation was confirmed by FTIR and DSC. In vitro release study showed an IOX retention into the polymeric matrix and NAC sustained release up to 24-48 h stating microfluidics as powerful tool for the formulation of multifunctional nanoplatforms. Finally, the protective effect of NPs and NAC were preliminary assessed on human kidney cells.

Influence of the nanofiber chemistry and orientation of biodegradable poly(butylene succinate)-based scaffolds on osteoblast differentiation for bone tissue regeneration.

Innovative nanofibrous scaffolds have attracted considerable attention in bone tissue engineering, due to their ability to mimic the hierarchical architecture of an extracellular matrix. Aiming at investigating how the polymer chemistry and fiber orientation of electrospun scaffolds (ES) based on poly(butylene succinate) (PBS) and poly(butylene succinate/diglycolate) (P(BS80BDG20)) affect human osteoblast differentiation, uniaxially aligned (a-) and randomly (r-) distributed nanofibers were produced. Although human osteoblastic SAOS-2 cells were shown to be viable and adherent onto all ES materials, a-P(BS80BDG20) exhibited the best performance both in terms of cellular phosphorylated focal adhesion kinase expression and in terms of alkaline phosphatase activity, calcified bone matrix deposition and quantitative gene expression of bone specific markers during differentiation. It has been hypothesized that the presence of ether linkages may lead to an increased density of hydrogen bond acceptors along the P(BS80BDG20) backbone, which, by interacting with cell membrane components, can in turn promote a better cell attachment on the copolymer mats with respect to the PBS homopolymer. Furthermore, although displaying the same chemical structure, r-P(BS80BDG20) scaffolds showed a reduced cell attachment and osteogenic differentiation in comparison with a-P(BS80BDG20), evidencing the importance of nanofiber alignment. Thus, the coupled action of polymer chemical structure and nanofiber alignment played a significant role in promoting the biological interaction.

Coated electrospun alginate-containing fibers as novel delivery systems for regenerative purposes.

AIM: The aim of the present work was to develop biodegradable alginate (ALG)-containing fibrous membranes intended for tissue repair, acting as both drug delivery systems and cell growth guidance. METHODS: Membranes were prepared by electrospinning. Since ALG can be electrospun only when blended with other spinnable polymers, dextran (DEX) and polyethylene oxide (PEO) were investigated as process adjuvants. ALG/DEX mixtures, characterized by different rheological and conductivity properties, were prepared in phosphate buffer or deionized water; surfactants were added to modulate polymer solution surface tension. The Design of Experiments (DoE) approach (full factorial design) was used to investigate the role of polymer solution features (rheological properties, surface tension, and conductivity) on electrospun fiber morphology. A high viscosity at 1,000 s-1 (1.3-1.9 Pa.s) or a high pseudoplasticity index (≥1.7), combined with a low surface tension (30-32 mN/m) and a low conductivity (800-1,000 µS/cm), was responsible for the production of ALG/DEX homogeneous fibers. Such ranges were successfully employed for the preparation of ALG-containing fibers, using PEO, instead of DEX, as process adjuvant. ALG/DEX and ALG/PEO fibers were subsequently subjected to cross-linking/coating processes to make them slowly biodegradable in aqueous medium. In particular, ALG/PEO fibers were cross-linked and coated with CaCl2/chitosan solutions in water/ethanol mixtures. Due to DEX high content, ALG/DEX fibers were soaked in a polylactide-co-glycolide (PLGA) solution in ethyl acetate. RESULTS: Both cross-linking and coating processes made fibers insoluble in physiological medium and produced an increase in their mechanical resistance, assessed by means of a tensile test. PLGA-coated ALG/DEX and chitosan-coated ALG/PEO fibers were biocompatible and able to support fibroblast adhesion. CONCLUSION: The DoE approach allowed to draw up guidelines useful for the preparation of homogeneous fibers, starting from mixtures of ALG and non-ionic polymers. Such fibers, upon coating, resulted to be good cell substrates, allowing cell adhesion and growth.

Engineered polymeric microspheres obtained by multi-step method as potential systems for transarterial embolization and intraoperative imaging of HCC: Preliminary evaluation.

The aim of this study was the development of novel fluorescent microspheres as embolic agent for transarterial embolization (TAE) of advanced stages of hepatocellular carcinoma (HCC). TAE is a minimally invasive procedure that induces tumour regression blocking the blood flow by injection of microparticles. The microspheres currently used in clinical application cannot be visualized in vivo. Surgeon could exploit the intraoperative detection of embolic agents during resection of the malignant mass. Biocompatible indocyanine green (ICG)-loaded microspheres (CAB-CS-ICG) were prepared using a multi-step method. Chitosan (CS)-ICG particles were prepared via spray-dryer and then loaded into cellulose acetate butyrate (CAB) microspheres, fabricated by emulsion solvent extraction method. Technological parameters such as yield, size, encapsulation efficiency and morphology were studied. CAB-CS-ICG microspheres showed spherical shape and smooth surface, as well as good injectability through a 21 G×1½ needle. ICG release from CAB-CS-ICG was very low due to the strong interaction between CS and ICG. This result was also confirmed by in vitro fluorescence imaging studies, conducted using Photodynamic Eye (PDE) for the detection of particles incubated in human plasma. CAB-CS-ICG were capable to maintain the fluorescence selectivity for 4weeks. Our data suggested the potential usefulness of CAB-CS-ICG in TAE application as embolic agents and following imaging of tumour during surgical procedure.

Design of smart GE11-PLGA/PEG-PLGA blend nanoparticulate platforms for parenteral administration of hydrophilic macromolecular drugs: synthesis, preparation and in vitro/ex vivo characterization.

Active drug targeting and controlled release of hydrophilic macromolecular drugs represent crucial points in designing efficient polymeric drug delivery nanoplatforms. In the present work EGFR-targeted polylactide-co-glycolide (PLGA) nanoparticles were made by a blend of two different PLGA-based polymers. The first, GE11-PLGA, in which PLGA was functionalized with GE11, a small peptide and EGFR allosteric ligand, able to give nanoparticles selective targeting features. The second polymer was a PEGylated PLGA (PEG-PLGA) aimed at improving nanoparticles hydrophilicity and stealth features. GE11 and GE11-PLGA were custom synthetized through a simple and inexpensive method. The nanoprecipitation technique was exploited for the preparation of polymeric nanoparticles composed by a 1:1weight ratio between GE11-PLGA and PEG-PLGA, obtaining smart nanoplatforms with proper size for parenteral administration (143.9±5.0nm). In vitro cellular uptake in EGFR-overexpressing cell line (A549) demonstrated an active internalization of GE11-functionalized nanoparticles. GE11-PLGA/PEG-PLGA blend nanoparticles were loaded with Myoglobin, a model hydrophilic macromolecule, reaching a good loading (2.42% respect to the theoretical 4.00% w/w) and a prolonged release over 60days. GE11-PLGA/PEG-PLGA blend nanoparticles showed good in vitro stability for 30days in physiological saline solution at 4°C and for 24h in pH 7.4 or pH 5.0 buffer at 37°C respectively, giving indications about potential storage and administration conditions. Furthermore ex vivo stability study in human plasma using fluorescence Single Particle Tracking (fSPT) assessed good GE11-PLGA/PEG-PLGA nanoparticles dimensional stability after 1 and 4h. Thanks to the versatility in polymeric composition and relative tunable nanoparticles features in terms of drug incorporation and release, GE11-PLGA/PEG-PLGA blend NPs can be considered highly promising as smart nanoparticulate platforms for the treatment of diseases characterized by EGFR overexpression by parenteral administration .

Electrospun fibers as potential carrier systems for enhanced drug release of perphenazine.

Solubility represents an important challenge for formulation of drugs, because the therapeutic efficacy of a drug depends on the bioavailability and ultimately on its solubility. Low aqueous solubility is one of the main issues related with formulation design and development of new molecules. Many drug molecules present bioavailability problems due to their poor solubility. For this reason there is a great interest in the development of new carrier systems able to enhance the dissolution of poorly water-soluble drugs. In this work, fibers containing an insoluble model drug and prepared by an electrospinning method, are proposed and evaluated to solve this problem. Two hydrophilic polymers, polyvinylpyrrolidone (Plasdone® K29/32) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were used to increase the water solubility of perphenazine. The physico-chemical characterization suggests that the drug loaded in the fibers is in the amorphous state. Both polymeric carriers are effective to promote the drug dissolution rate in water, where this active pharmaceutical ingredient is insoluble, due to the fine dispersion of the drug into the polymeric matrices, obtained with this production technique. In fact, the dissolution profiles of the fibers, compared to the simple physical mixture of the two components, and to the reference commercial product Trilafon® 8mg tablets, show that a strong enhancement of the drug dissolution rate can be achieved with the electrospinning technique.

Fabrication, Physico-Chemical, and Pharmaceutical Characterization of Budesonide-Loaded Electrospun Fibers for Drug Targeting to the Colon.

The objective of this study was to fabricate and characterize electrospun fibers loaded with budesonide with the aim of controlling its release in the gastrointestinal tract. Budesonide is a nonhalogenated glucocorticosteroid drug, highly effective in the treatment of some inflammatory bowel diseases with local action throughout ileum and colon. At this aim, Eudragit® S 100, a polymer soluble at pH > 7, commonly used for enteric release of drugs, has been successfully spun into ultrafine fibers loaded with Budesonide (B) at 9% and 20% (w/w) using the electrospinning process. The physico-chemical characterization by scanning electron microscopy, X-ray diffraction, FTIR spectroscopy, and thermal analyses indicated the amorphous nature of budesonide in the electrospun systems. Dissolution rate measurements using a pH-change method showed negligible drug dissolved at pH 1.0 and sustained release at pH 7.2. Therefore, the pharmaceutical systems proposed, made of fibers, represent an effective method for drug targeting to terminal ileum and colon with the aim of improving the local efficacy of this drug.

I. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: nanoparticles and co-mixing.

Nateglinide is a non-sulphonylurea insulinotropic oral antidiabetic agent. The main problem in formulating an oral dosage form is its low solubility in aqueous media. This problem is particularly critical for an anti-diabetic drug because it should be administered just before the meals and be quickly bioavailable to cover the post-prandial glycemic peak. In this work, some technological approaches have been studied to improve the dissolution rate of nateglinide. Furthermore, two different polymorphs of nateglinide (H and B) have been tested to evaluate the influence of the crystal habitus on the dissolution behavior of the drug. The results have clearly demonstrated that wettability plays a key role in the dissolution behavior of nateglinide. As a matter of fact the physical dispersion of the drug with colloidal silica or hydrophilic swellable polymers strongly enhances the dissolution rate of nateglinide. The two polymorphs tested did not show significant differences in terms of dissolution behavior.